14th Annual meeting ( ISEND )
 
 

International Symposium on Epilepsy in Neurometabolic Diseases (ISEND)

Time:March 26-28, 2010 Taipei, Taiwan
Venue:Howard Plaza Hotail, Taipei Taiwan

O01 OVERVIEW OF EPILEPTIC SEIZURES IN NEUROMETABOLIC DISEASES

Ching-Shiang Chi1, Hsiu-Fen Lee2, Chi-Ren Tsai2, Liang-Hui Chen2
1 Department of Pediatrics, Tungs’ Taichung Metroharbor Hospital, Taichung, Taiwan
2 Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan

Objectives:

Metabolic disorders constitute an important cause of neurologic diseases. There are more than 10,000 well-recognized and characterized inherited disorders in human, many of which impact central nervous system function either directly or indirectly. Among them, nearly 200 disorders are associated with seizures or epilepsy. Here we reviewed epileptic seizures in children with neurometabolic diseases in Taiwan
 

Methods:

From 1978 to October 2009, we collected children with neurometabolic diseases. The diagnosis was based on characteristic clinical features, metabolic survey, enzyme activities, tissue biopsies, genetic analysis, and specific MRI and MRS findings. We analyzed the epileptic seizures as well as electroencephalography (EEG) in these patients.
 

Results:

Total 213 cases, aged from 1 day to 15 years, were enrolled. One hundred and four patients (104/213; 48.8%) presented with seizures, 57 out of 104 (54.8%) had seizures as an initial manifestation, 47 (45.2%) had seizures during the course of illness, 60 (57.7%) were refractory to antiepileptic drug therapy. With the seizure types, 65 patients (62.5%) had generalized seizures, including generalized tonic seizure, generalized tonic-clonic seizure, and myoclonic seizure, 18 (17.3%) had partial seizures, 17 (16.3%) had mixed seizure types, and four (3.8%) had epileptic syndromes. Eight cases were presented with pseudoseizures. The most common intractable seizures occurred in the heavy metals disorders (7/8; 87.5%), lysosomal storage disorders (7/9; 77.8%), and mitochondrial disorders (27/43; 62.8%). In our study, specific EEG features in neurometabolic disorders included comb-like rhythm, vanishing EEG, high voltage activity, marked photosensitivity, burst-suppression, and hypsarrhythmia.
 

Conclusion:

Epileptic seizures or syndromes are often a part of the clinical picture of inherited neurometabolic disorders. Some patterns of clinical presentations and/or EEG findings may indicate underlying neurometabolic diseases. Thus, neurometabolic work-up has become an imperative for those patients with psychomotor retardation and /or intractable seizures.

O02 INBORN ERRORS OF METABOLISM AND SEIZURES IN CHILDREN: AN OVERVIEW FROM CHINA

Jiong Qin1, Yangling Yang1
1Department of Pediatrics, Peking University First Hospital, Beijing, China

Objectives:

To briefly summarize the current status of researches on the inborn errors of metabolism (IEM), and the significance of such disorders in seizures of children in China.
 

Methods:

Browse the main literature database of medicine in China in the past two decades, and retrospectively summarize the data of urinary metabolic analysis from an university based department of pediatrics in Beijing, to analyze the conditions of IEM in the practice of child neurology.
 

Results:

The main disorders of IEM including most diseases in this field, including IEM involving organic acid, amino acid, fatty acid, and mitochondrial encephalopathy, etc. An eighteen-year study on phenylketonuria by China-Japan Friendship Hospital included otally 603 patients, with various patterns of seizures in 119 cases. Six single base mutations were detected in 18 unrelated northern Chinese BH4 deficiency families, and the mutations at nucleotides 259C-T and 286G-A were common mutations. The results from 29 late-treated patients with classical PKU indicate a well matched genotype and intellectual phenotype association in classical PKU patients. A 13 year data from Peking University First Hospital Department of Pediatrics included 16542 children, amongwhom 5210 were with seizures. IEMs were diagnosed in 2247 cases afterwards, including organic aciduria 489, aminoacidopathy 1586, and fatty acid disorders 172 cases.
 

Conclusion:

IEMs are relatively common in the practice of child neurology. Many types of IEMs were reported in China. Seizures are fairly common features in the IEMs.

O03 NEUROPHYSIOLOGICAL CHARACTERISTICS OF NEUROMETABOLIC DISEASES IN CHILDREN

Joyce Y. Wu1
1Division of Pediatric Neurology, Mattel Children’s Hospital at University of California, Los Angeles, United States
Dr. Wu will review the clinical neurophysiological characteristics of the various categories of neurometabolic disorders in children. This will include a comprehensive summary of the type, location, timeline, and incidence of the various abnormalities on a variety of clinical neurophysiologic tests, including evoked potential, surface EEG, electrocorticography and intracranial recording, and MEG.

O04 MOLECULAR BASIS OF METABOLIC ENCEPHALOPATHY – NEUROGENETIC DISEASE: FROM MOLECULE TO PATIENT

Yoshiyuki Suzuki1
1International University of Health and Welfare Graduate School, Tokyo, Japan
Child neurology started with clinical and pathological analysis of neurological diseases in children with brain damage, presenting with mental retardation, epileptic disorders and various somatic disabilities. Among them lysosomal diseases have been my major targets for scientific research. Recently new methods of biochemical analysis were developed, leading to discoveries of unexpected metabolic errors in neurodegenerative diseases. Gene analysis particularly has become a powerful tool for investigation of molecular events in individual patients with diseases of unknown etiology. At present almost 7,000 single gene disorders are listed in the McKusick’s catalog of inherited diseases. Many of them present with progressive neurological manifestations caused by single gene mutations, resulting in loss of enzyme activity and diverse phenotypic manifestations. At present we can make diagnosis of patients and heterozygous carriers by gene mutation analysis. However, even with plenty of information about phenotypes and molecules in individual patients, we do not know much about pathogenesis of each disease, and treatment is not possible particularly for brain damage. In my research on the black box of human cells and tissues, I have been trying to elucidate the pathogenesis of Krabbe disease, GM1-gangliosidosis, galactosialidosis, and other neuronopathic lysosomal diseases. In this talk I will mainly focus on the therapeutic aspect of β-galactosidase deficiency disorders (β-galactosidosis) as a model experiment. I will briefly summarize our research data of diagnostic, pathogenetic, and therapeutic studies (chemical chaperone therapy). This experimental approach disclosed some new molecular events in disease cells and tissues. I hope to step up in the near future to human patients toward my final goal of molecular therapy of inherited brain disease.

O05 THE NEUROPATHOLOGY OF EPILEPSY-RELATED NEUROMETABOLIC DISEASES

Hans H. Goebel1
1Department of Neuropathology, University Mainz Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

Objectives:

Neurometabolic diseases (NMD) are often hereditary, associated with epilepsy, especially myoclonus epilepsy and grand mal seizures. Most hereditary NMD belong to the single-organelle multi-organ disorders, encompassing lysosomal, peroxisomal, and mitochondrial conditions, of which lysosomal diseases are the best explored ones. Within the context of this presentation, the sphingolipidoses and the neuronal ceroid-lipofuscinoses (NCL) are the most important ones, among them sialidosis and late-infantile NCL which are associated with myoclonus epilepsy. It is the purpose of this review to present the neuropathology of epilepsy-related NMD.
 

Methods:

Electron microscopy is a pivotal diagnostic technique recognizing lysosomal conditions, which may be divided into vacuolar and avacuolar forms. The nosography is based on biochemical (substrate) and molecular criteria.
 

Results:

While there is an abundance of diverse ultrastructural features in lysosomal diseases, based on the diversity of intralysosomally stored biochemical substrates, peroxisomal diseases have a rather limited electron microscopic expression concerning the pathology of peroxisomes, best identified in liver and kidney rather than in the nervous system, and cholesterol needles in adrenoleukodystrophy. Among the emerging and rapidly expanding group of mitochondrial encephalomyopathies, MERRF (myoclonus epilepsy and ragged red fibres) is most prominent among the myoclonus epilepsies, but many other forms of mitochondrial encephalomyopathies are also associated with seizures. Another progressive myoclonus epilepsy is Lafora disease marked by polyglucosan inclusions in neurons, liver cells, and sweat gland epithelial cells.
 

Conclusion:

NMD affect cerebral and non-cerebral tissues. The latter ones, e.g. skin, muscle, rectum, nerve, and blood lymphocytes are variably involved and require a differential diagnostic approach for an in-vivo recognition of an individual NMD.

O06 NEUROIMAGING PERSPECTIVES IN PEDIATRIC NEUROMETABOLIC DISEASES

Robert A. Zimmerman1
1 Children’s Hospital of Philadelphia, Philadelphia, United States
The purpose of neuroimaging is to identify the presence or absence of abnormalities that help to identify a disease process, findings that when present, focus the differential diagnosis to one or more entities, and, when treatment is possible, allow for assessment of the effectiveness of therapy.

To this end, the armamentarium of the neuroimager has been constantly changing over the past two decades. Improvement in imaging techniques have occurred both in sequence design, e.g., FLAIR, diffusion imaging with ADC maps, diffusion tensor imaging with fractional anisotropy maps, as well as perfusion imaging with arterial spin labeling (ASL), as well as in the equipment used (1.5 Tesla to 3 Tesla, and even higher field strengths). Not only has MR imaging evolved, but so has magnetic resonance spectroscopy (MRS), with the development of multivoxel techniques (2D & 3D), improved short TE studies and identification of more metabolites.

The application of these imaging and spectroscopy techniques in conjunction with further advances in understanding the metabolism of diseases and their genetic origins has lead to improvements in specificity with which some neurometabolic diseases can be identified and followed.

This presentation deals with the overview of these developments from the view of the neuroradiologist in approaching the neurometabolic diseases as to the findings on MRI & MRS that are found in the gray matter, cortex and deep structures, and the white matter.

O07 CLINICAL AND SCIENTIFIC PERSPECTIVES ON EPILEPSY AMONG NEUROMETABOLIC DISEASES IN CHILDREN

Raman Sankar1,2
1 Pediatric Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
2 Pediatric Neurology, Mattel Children’s Hospital at UCLA, Los Angeles, California, United States
This presentation will address questions of interest pertaining to areas of knowledge which are not advanced enough at present to provide very clear answers. A wealth of detail regarding specific metabolic aberrations, how new understanding of the biochemical pathways has facilitated diagnosis and treatment will be furnished by the distinguished experts gathered here. New knowledge about the involvement of specific genes will also be brought up to date. Nevertheless, it remains difficult to see clearly why a particular metabolic defect produces epilepsy. How do abnormal metabolites alter neuronal excitability? What is the present state of understanding as how an abnormal metabolic milieu can impact on neuronal migration, excitability, injury, survival, and plasticity to produce the myriad phenotypes we see in terms of epilepsy (this group’s – including my own – biased focus) as well as the associated neurodevelopmental (cognitive and behavioral) problems?

Areas we shall attempt to explore include how a neurometabolic disorder may influence bioenergetics, mitochondrial function, and approaches to manipulating the metabolic milieu (such as the ketogenic diet). Metabolic defects may influence normal neurotransmitter (e.g. GABA) synthesis as well as abnormal neurotransmitter (e.g. GHB) synthesis. Even before the development of synapses, ambient GABA produces excitatory drive to neurons and controls migration. Some abnormal metabolites may produce excitotoxicity. A number of disorders may interfere with the functioning of Na-K-ATPase. Abnormal metabolites may contribute to inflammation. Is there a role for immunomodulation in treating children with neurometabolic disorders? Many questions, few answers, constituting a great recipe for this symposium to stimulate the generation of new hypotheses and catalyze novel clinical research.

O08 AMINO ACID METABOLIC DISORDERS AND INFANTILE EPILEPSY

Wang-Tso Lee1
1 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
Seizure is not an unusual clinical manifestation in children with disorders in amino acid metabolism. Neurological manifestations in patients with phenylketonuria usually appear insidiously. However, chronic exposure to elevated phenylalanine may result in microcephaly and seizures, including infantile spasms. Severe biopterin disorders may also present with developmental delay and seizures. For patients with maple syrup urine disease (MSUD), seizures commonly occur in neonatal stage. But in intermittent MSUD or thiamine-responsive MSUD, seizures usually develop in later stage. In glycine encephalopathy, seizures, like early myoclonic encephalopathy, are very common, and usually present in fist weeks of life. However, for patients with late-onset glycine encephalopathy, the clinical presentations may be different, and seizures may be uncommon. In addition to these disorders, patients with sulfite oxide deficiency, serine synthesis disorders, or GABA-related disorders (like SSADH deficiency) may also present with different types of seizures. Although seizures or epilepsy are common neurological manifestations for some kinds of amino acid-related metabolic disorders, involuntary movements, which are also common in these disorders, may also be mistaken to be seizures or epilepsy. Careful evaluation and correct diagnosis may avoid the unnecessary treatment in these patients

O09 NONKETOTIC HYPERGLYCINEMIA

Shigeo Kure1
1 Tohoku University School of Medicine, Sendai, Japan
Nonketotic hyperglycinemia (NKH), also referred to as glycine encephalopathy, is an inborn error of metabolism characterized by accumulation of glycine in body fluids. Neonatal seizures, coma and profound hypotonia are typical presentations of typical NKH. In milder cases delayed psychomotor development and behavioral abnormality are main symptoms. NKH is caused by deficiency of glycine cleavage system (GCS), which consists of four individual proteins; P, T, and H-proteins (Tada et al., Tohoku J Exp Med, 1969).

In this presentation, I will talk about recent advances in study of NKH, which include, 1) mutation spectrum of NKH, 2) development of a novel enzymatic diagnosis and 3) pathophysiology: 1) GLDC mutations were identified in ~70% of the mutant alleles while the rest of the alleles carried AMT mutations. GCSL mutations cause Leigh syndrome, but not NKH. Mutation spectra of GLDC and AMT are heterogeneous (Kure et al., Hum Mutat, 2006). We established a detection system of genomic deletion within GLDC by multiplex-ligation probe amplification (MLPA) method, and found that 20~30% of NKH mutant allele have genomic deletions, in which multiple GLDC exons are involved (Kanno et al., J Med Gent, 2006). 2) We have developed the [1-13C]glycine breath test, which enabled us to evaluate the enzymatic activity of the GCS without risking liver biopsy (Kure et al, Ann Neurol, 2006). 3) Development of mice model of NKH revealed that overexcitation of the NMDA type glutamate receptor by high level of glycine is involved in the etiology of NKH (Kojima-Ishii, Pediatr Res, 2007). NKH is frequently associated with brain malformations such as microcephaly or hypogenesis of corpus callosum. The GCS is abundantly expressed in neural stem cells in fetal period (Ichinohe et al, Eur J Neurosci, 2004), which may explain the etiology of brain malformations associated with NKH.

O10 METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) DEFICIENCY AND INFANTILE EPILEPSY

Asuri N. Prasad1,4, CA Rupar1,2,3, C Prasad1,4
1Department of Pediatrics, University of Western Ontario, London, Canada
2Department of Biochemistry, University of Western Ontario, London, Canada
3Department of Children’s Health Research Institute, University of Western Ontario, London, Canada
4 London Health Sciences Centre, London, Canada

Objectives:

A recessively inherited defect leading to deficiency of the enzyme 5, 10-methylenetetrahydrofolate reductase (MTHFR) underlies one form of hyperhomocysteinemia. We describe the association of MTHFR deficiency and epilepsy, emphasizing the clinical neurobiological, biochemical, genetic, and therapeutic aspects.
 

Methods:

Case Study and review of literature.
 

Results:

A 9 year old female infant born to Caucasian non-consanguineous parents presented with infantile spasms and developmental regression in the first year. The biochemical profile of low plasma methionine (undetectable) and homocystinuria (234 µmoles/gm creatinine) suggested MTHFR deficiency. MTHFR assay in skin fibroblasts confirmed a severe deficiency (patient 0.92, control 13.3+/-4.6 nmole/mg/hr). Molecular genetic studies identified compound heterozygosity with R57Q and c1348+1g>a mutations. The c.1348+1g>a mutation is a novel mutation that removes a splice site at the end of exon 7 and introduces a premature stop codon that truncates the protein without exons 8-11. In addition, the patient was heterozygous for the common A222V polymorphism that is considered a risk factor for diseases that may be influenced by disruption of folate metabolism. CSF neurotransmitter analysis showed extremely low level of 5-methyl tetrahydrofolate of <5 (40-128 nmol/L). The course of epilepsy has been progressive and severe. Treatment protocols include; betaine, methionine, folic acid, and 5-methyltetrahydrofolate with questionable benefit. Epileptic seizures remain pharmacoresistant to antiepileptic medications singly and in combinations. Frequent bouts of status epilepticus have led to multiple hospitalizations, and neurosurgical interventions (corpus callosotomy, vagal nerve stimulation). At age 9 years, the patient remains severely impaired by vertebral compressive and limb fractures secondary to significant osteoporosis.
 

Conclusion:

Severe MTHFR deficiency is an important diagnostic consideration in infantile epileptic encephalopathies. Genotype phenotype correlations will be explored in the light of biochemical and molecular genetic data. While early diagnosis and interventions are possible, future research needs to focus on developing effective treatment strategies for this complex disorder.

O11 MAPLE SYRUP URINE DISEASE AND INFANTILE EPILEPSY

Jia-Woei Hou1,2
1Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan
2Fu-Jen Catholic University Medical School, Taipei, Taiwan

Objectives:

Maple syrup urine disease (MSUD) is an autosomal recessive aminoacidopathy secondary to an enzyme defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine, and valine. Accumulation of their corresponding keto-acids leads to encephalopathy if not treated in time. The clinical phenotypes with highlight on epilepsy patterns among patients with different forms of MSUD were analyzed.
 

Methods:

The diagnosis of MSUD was made and classified by its pattern of signs and symptoms and the patients’ clinical courses: classic type in three patients (2 boys and 1 girl), intermediate type in one boy, and thiamine-responsive type in one girl. Extensive investigations including tandem mass spectrometry, urine organic acids by chromatography-mass spectrometry, concentrations of plasma amino acids, urine dinitrophenylhydrazine test, electroencephalography (EEG), metabolic profile, DNA, and imaging studies were performed.
 

Results:

Features of MSUD in early infancy include poor feeding, vomiting, dehydration, lethargy, hypotonia, ketoacidosis, and seizures. Epilepsy manifested as tonic peddling-like patterns with suppression-burst rhythms on EEG. Leukodystrophy was noted in well-controlled patients with classic MSUD. Zinc deficiency with acrodermatitis enteropathica-like skin lesions, increased lipid peroxidation and decreased antioxidant defenses were also noted in MSUD patients even after restrict diet control. Founder mutation of the E2 (DBT) gene was noted among certain population.
 

Conclusion:

Although morbidities (such as seizures and encephalopathy) and mortality can almost be prevented with early diagnosis and appropriate treatment at presentation and during episodes of potential metabolic decompensation, additional biochemical disturbances (known or unknown) may play an important role in the pathogenesis of further nervous disorders.

O12 THE LONG-TERM OUTCOMES OF THE TAIWANESE PATIENTS WITH 6-PYRUVOYL-TETRAHYDROPTERIN SYNTHASE DEFICIENCY BEFORE OR AFTER THE NEWBORN SCREENING

Dau-Ming Niu1,3, Tze-Tze Liu2, Ling-Yee Cheng4, Kwang-Jen Hsiao5
1 Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
2 Genome Research Center, National Yang-Ming University, Taipei, Taiwan
3 Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan
4 Department of Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan
5 Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
Hyperphenylalaninemia is the most common inherited disorder of amino acid metabolism. It is caused by a deficiency of phenylalanine hydroxylase (PKU) or tetrahydrobiopterin (BH4), an important cofactor involved in the biogenic syntheses of tyrosine, L-DOPA, 5- hydroxytryptophan (5-HTP), nitric oxide, and glycerol. Apart from the classical PKU phenotype, deficiency of BH4 is often accompanied by seizures and various extrapyramidal neurological symptoms, such as truncal hypotonia, increased limb tone, postural instability, hypokinesia, choreatic or dystonic limb movements, gait difficulties, hypersalivation, swallowing difficulties, etc, due to impaired synthesis of catecholamines and serotonin. 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is the most predominant type of BH4 deficiency. Reports of the long-term treatment of PTPS deficiency are few. A considerable proportion of patients experience adverse outcomes, despite the detection of PTPS by newborn screening and early initiation of treatment. In Taiwan, PTPS deficiency is the cause of approximately one-third of all cases of HPA. The prevalence of PTPS deficiency in this country (1/100,000) is considerably higher than in Caucasian populations (1/1,000,000). This provides us an opportunity to observe the treatment outcome of this form of illness within a single medical center. In this study, we reviewed the characteristics of 8 PTPS-deficient patients with delayed treatment and 12 patents with early treatment. The relationships among clinical manifestations, biochemical findings, genotypes, and long-term outcomes were analyzed. For the patients with delayed treatment, most of them suffered from severe psychomotor, as in a vegetative-like state before treatment. After the long-term BH4 (2 and 4 mg/kg) and neurotransmitters (L-dopa: 10 to 15 mg/kg/day, 5-HTTP: 3-5mg/kg/day) replacements, all patients have remarkable improvements gradually after 15 years follow-up (final FIQ score was 62.8±13.06). For the patients with early treatment, the average FIQ score was 96.7 ±9.7 (range 86-119), considerably higher than previously reported.

O13 TREATABLE METABOLIC EPILEPSIES: CASE STUDIES

Phillip L. Pearl1
1Department of Neurology, Children’s National Medical Center, George Washington University School of Medicine, Washington DC, United States
A selected group of eminently treatable but otherwise catastrophic epileptic encephalopathies will be highlighted. These epilepsies represent a vexing clinical challenge because a sufficiently low diagnostic threshold must be maintained for rare and esoteric diseases. Pyridoxine (vitamin B6) dependency is the prototype and recently identified as antiquitin deficiency involving lysine degradation. Urinary pipecolic acid is a valuable laboratory aid in addition to the standard concomitant administration of 100 mg IV during EEG. CSF monoamine metabolic analysis will show a characteristic pattern analogous to aromatic aminoacid decarboxylase deficiency. Empirical discontinuation of therapy as a diagnostic maneuver is inadvisable, and the diagnosis must be re-suspected even in initial treatment failures. The enigmatic folinic acid dependency is allelic to pyridoxine dependency, and patients may respond to either or both therapies. Pyridoxal-5-phosphate dependency is a newly recognized variant which is due to pyridox(am)ine oxidase deficiency and requires supplementation with the biologically active form of pyridoxine. Newborn screening may lead to a misdiagnosis of PKU whereas an infant presenting with seizures may have a biopterin-responsive hyperphenylalaninemia. Dihydropteridine reductase deficiency additionally requires folinic acid which may result in resolution of basal ganglia calcifications. Cerebral folate deficiency, also treatable with folinic acid, is associated with decreased CSF 5-methyltetrahydrofolate with normal peripheral folate levels. Seizures (including infantile spasms or myoclonic) may be the sole feature in biotinidase deficiency, which is not universally covered in newborn screening. Glucose transporter 1 deficiency has an enlarging phenotype, requires CSF analysis for hypoglycorrhachia, and is treatable with the ketogenic diet, offering an alternative metabolic fuel to glucose. A neonate presenting with seizures and diabetes may have a potassium-regulated ATP channelopathy of pancreas and brain, DEND (developmental disorder, epilepsy, neonatal diabetes) whereas the hyperglycemia is corrected by insulin but a profound encephalopathy will result if treatment is not instead a sulfonylurea. In contrast, congenital hyperinsulinism with hyperammonemia (HI/HA), a mutation of glutamate dehydrogenase, is associated with generalized epilepsy and learning disabilities, and is treated with diazoxide and protein restriction. Serine biosynthesis disorders are treatable with combined L-serine and glycine but otherwise result in microcephaly and epilepsy. Creatine synthesis disorders feature intellectual disability and epilepsy, may be diagnosed with abnormal guanidinoacetic acid (GAA) levels in urine or plasma (or MR spectroscopy), and respond to creatine and ornithine supplementation and arginine restriction. Benzodiazepines appear to have an ameliorative role in hyperekplexia, an epilepsy mimicker due to mutations in the glycine inhibitory receptor or transport system associated with sudden death.

O14 HEAT STRESS AND ACUTE ENCEPHALOPATHY IN CHILDHOOD DUE TO INHERITED ORGANIC AND FATTY ACID DISORDERS

Seiji Yamaguchi1
1Department of Pediatrics, Shimane University School of Medicine, Izumo, Shimane, Japan

Objectives:

Hyperpyrexia in childhood occasionally triggers some serious febrile illnesses such as febrile convulsions, deliria, or acute encephalopathies including influenza-associated encephalopathy (IAE). On the other hand, it is known that aspirin also potentially causes Reye encephalopathy. It was reported that hyperpyrexia might be responsible for impaired fatty acid oxidation (FAO) in IAE. We investigated the effect of heat stress or some drugs that might be related to encephalopathy on FAO.
 

Methods:

Cell lines from 15 cases of FAO disorders including CPT2 deficiency, VLCAD deficiency, MTP deficiency or MCAD deficiency as well as 6 controls were examined for acylcarnitine (AC) profiles by the in vitro probe assay using MS/MS. The AC profiles in cells cultured at 37oC and 41oC were compared in the presence or absence of some drugs.
 

Results and Discussions:

1) Heat stress (at 41oC compared with at 37oC) increased acetylcarnitine (C2), which reflects the production of acetyl-CoA in all cells from FAO disorders and controls. It is suggested that heat stress generally facilitates FAO. 2) In controls and MCAD deficiency, ACs from the short to long-chain species decreased. 3) In long-chain FAO disorders including CPT2- VLCAD- MTP-deficiencies, long-chain ACs (at least C16) significantly increased. 4) In glutaric acidemia type 2 (GA2), which is caused by a defect of ETF or ETF-DH and results in multiple acyl-CoA dehydrogenation deficiency, the short- to medium-chain ACs (C4 to C10) decreased at 41oC, while the long-chain ACs (C12 to C16) significantly increased. These findings indicate that heat stress might inhibit long-chain FAO. Patients with impaired FAO may be more vulnerable to heat stress. 5) Palmitate loading in the presence of aspirin showed an elevation of C12. 6) Bezafibrate, one of the hyperlipidemic drugs, improved long-chain FAO defects. It may be concluded that some acute encephalopathy in childhood is related to temporarily or congenitally impaired FAO.

O15 EPILEPSY IN CHILDREN WITH METHYLMALONIC ACADEMIA

Yue-Hua Zhang1, Yan-Ling Yang1, Yu-Wu Jiang1, Xin-Hua Bao1, Jiong-Qin1, Xi-Ru Wu1
1Department of Pediatrics, First Hospital of Peking University, Beijing, China

Objectives:

To summarize the clinical features of epilepsy in children with methylmalonic academia (MMA)
 

Methods:

In the past 13 years, children with unknown cause of mental retardation, seizures, motor deficit, recurrent vomiting, metabolic acidosis or lethargy were screened by urine organic acid analysis (gas chromatography-mass spectrometry, GC-MS). The medical records of hospitalized MMA patients associated with epilepsy were retrospectively reviewed.
 

Results:

489 patients with organic academia (3.0%) were confirmed in 16542 screened children. 291 of 489 patients with organic academia were diagnosed with MMA (59.5%). Some MMA patients combined with homocysteinemia. 62 of 291 MMA patients were hospitalized. 26 of 62 hospitalized patients associated with epilepsy (41.9%). Seizure onset age was from 8 days to 11 years. Partial seizures were presented in 17, generalized tonic-clonic seizures in 3, tonic seizures in 4, myoclonic seizures in 3 and infantile spasm in one. Five patients had two or more seizure types. Eight patients had a history of status epilepticus (30.8%). Four hours Video-EEG was done in 18 patients with epilepsy. Seizures were recorded in 9 patients. 18 of 26 MMA patients with epilepsy were further classified, 17 with cobalamin C disease ( 65.4%) and one with partial mutase deficiency (mut-). Vitamin B12-responsive patients had good outcome compared with vitamin B12-nonresponsive patients.
 

Conclusion:

Epilepsy is a common symptom of patients with MMA. Partial seizures is common than other seizure types. Status epilepticus is not rare. When children with unknown cause of epilepsy combined with other symptoms of central nervous system, GC-MS should be investigated for the further diagnosis.

O16 EPILEPSY IN UREA CYCLE DEFECTS

Wuh-Liang Hwu1, Yin-Hsiu Chien1, Ni-Chung Lee1
1 Department of Pediatrics and Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan

Objectives:

Urea cycle disorders (UCDs) are caused by the deficiency of one of the urea cycle enzymes. The primary manifestation of UCDs is hyperammonemia. Hyperammonenia is toxic to the brain and affects consciousness level rapidly. Seizure can be part of the clinical manifestations when brain edema occurs.
 

Methods:

Patients with UCDs in the National Taiwan University Hospital were reviewed. Clinical manifestations including symptoms and age of onset were analyzed.
 

Results:

In NTUH record, ornithine transcarbamylase (OTC) deficiency is the most common UCD. Both infants, children and adults, females and males patients were diagnosed. Cases of carbamoyl phosphate synthase deficiency were also found. Two cases of adult-onset citrullinemia II were detected because of hyperammonemia. There are other diseases that secondary hyperammonemia can be prominent. Those diseases include carnitine uptake defect and methylmalonic acidemia. Seizure was rare in these cases.
 

Conclusion:

Patients with severe deficiency of the urea cycle enzymes have symptoms during neonatal period. Other patients may have first symptoms at ages ranging from infancy to adulthood. Fluid therapy needs to be cautious, supplying ample energy but without aggravating brain edema. UCDs, when properly managed, rarely present seizure.

O17 CARNITINE AND FATTY ACID OXIDATION DEFECTS IN INFANTILE EPILEPSY

Ingrid Tein1
1Division of Neurology, Dept. of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

Objectives:

To determine the risk factors for infantile epilepsy in primary and secondary disorders of fatty acid oxidation (FAO) and the indications for L-carnitine (Cn) supplementation.
 

Background:

Primary FAO disorders are an important group of diseases because they are potentially rapidly fatal and source of major morbidity. They may present with recurrent hypoglycemic hypoketotic encephalopathy or Reye-like syndrome, seizures, and developmental delay. All 23 known conditions are autosomal-recessive. Early recognition and prompt institution of therapy and appropriate preventive measures may be life saving, significantly decreasing long-term morbidity, particularly with respect to seizures and CNS sequelae. Fatty acids serve 3 major functions. First, partial oxidation of fatty acids by liver produces ketones which are an important auxiliary fuel for brain to spare glucose oxidation and proteolysis during prolonged fasting. Second, fatty acids serve as a major fuel for skeletal and cardiac muscle. Resting and exercising muscle (mild to moderate prolonged exercise), depend primarily on FAO. Third, high rates of hepatic gluconeogenesis and ureagenesis needed for maintaining fasting homeostasis are sustained by the production of ATP, reducing equivalents, and metabolic intermediates derived from FAO. FAO is also important in shivering thermogenesis and during acute infections. In the medium- and long-chain defects, there is a risk for hypoketotic, hypoglycemic coma during fasting or infections with secondary cerebral injury and seizures. In short-chain acyl-CoA dehydrogenase (SCAD) deficiency, cerebral injury and seizures are more likely related to accumulation of short-chain fatty acid metabolites, such as ethylmalonic acid which may be neurotoxic by inhibiting mitochondrial CK, increasing lipid and protein oxidation products, decreasing glutathione, and inhibiting electron transport chain activity at Complexes I and III leading to decreased ATP and excessive oxidative stress.

L-Cn is an essential cofactor for long-chain FAO. Cn also modulates the intramitochondrial acyl-CoA/CoA sulfhydryl ratio, providing cells with a critical source of free CoA for operation of essential CoA requiring processes such as the citric acid cycle, pyruvate oxidation, etc. The role of the Cn system is to maintain homeostasis in the acyl-CoA pools of the cell, keeping the acyl-CoA/CoA pool constant even under conditions of very high acyl-CoA turnover. Cn also provides a shuttle mechanism for acyl groups between mitochondria, peroxisomes and microsomes and is therefore essential in complex lipid-synthetic and –breakdown pathways. Cn also has a detoxifying role in trapping potentially toxic acyl-CoA metabolites, that may increase during acute metabolic crises, and serves as an antioxidant.
 

Methods:

A literature review was conducted including recommendations from a consensus statement by a North American panel of neurologists and metabolic experts on Cn therapy in childhood epilepsy.
 

Results and Conclusions:

In primary FAO disorders, the essential indication for Cn therapy is the Cn uptake (OCTN2) defect, characterized by Cn-responsive cardiomyopathy and very low plasma and tissue Cn (<5% normal). In the OCTN2 defect, high-dose oral Cn at 100 mg/kg/day in four divided daily doses is critical and life-saving, significantly reversing the pathology in this otherwise progressive and lethal disease. In intramitochondrial ß-oxidation defects with secondary Cn deficiency, the results of Cn therapy have been highly variable and insufficiently evaluated. Cn has been given to limit the intracellular concentrations of potentially toxic acyl-CoA intermediates within the cell through transesterification and to liberate CoA which is a critical intracellular cofactor. However, there has been no objective study to prove that Cn has had a beneficial effect. There is also evidence to suggest that Cn may have deleterious effects in long-chain FAO disorders in which there is an accumulation of long-chain acyl-CoAs, which become long-chain acylcarnitines which in excess may have membranotoxic and arrhythmogenic effects and thus warrant further study. In secondary FAO disorders, intravenous L-Cn is clearly indicated for valproate (VPA)-induced hepatotoxicity, overdose, and other acute metabolic crises associated with Cn deficiency. Oral L-Cn is strongly suggested for the following groups as well: patients with certain secondary Cn-deficiency syndromes, symptomatic VPA-associated hyperammonemia, multiple risk factors for VPA hepatotoxicity, or renal-associated syndromes; infants and young children on VPA; patients with epilepsy on the ketogenic diet who have hypocarnitinemia; patients receiving dialysis; and premature infants who are receiving total parenteral nutrition.

O18 NEUROLOGICAL ASPECTS OF LYSOSOMAL STORAGE DISEASES

Hiroyuki Ida1
1Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan
Lysosomal storage disease (LSD) is caused by loss of lysosomal enzyme activity and results in accumulation of substrates. As a result, cell dysfunction, biochemical and pathological abnormality occur and subsequently patients manifest clinical symptoms. Their manifestations are hepatosplenomegaly, bone deformity, joint stiffness, muscle weakness, neurological deterioration, convulsion and so on. When we focus on epilepsy LSDs show symptomatic epilepsy including progressive myoclonic epilepsy (PME). Autosomal recessively inherited PMEs include Lafora disease, Unverricht-Lundborg disease, the neural ceroid lipofuscinoses, type 1 sialidosis and Gaucher disease type 3. Almost all the autosomal recessively inherited PMEs are lysosomal storage disease except Lafora disease. I will present the clinical manifestations, pathophysiology and genes of PMEs related to LSDs in this lecture. And genotype/phenotype correlation and treatment of Gaucher disease type 3 with PME will be discussed.

O19 INFANTILE EPILEPSY IN LYSOSOMAL STORAGE DISEASES

Shyi-Jou Chen1
1Department of Pediatrics, Tri-Service General Hospital and National Defense medical Center, Taipei, Taiwan
Lysosomal storage disorders (LSD) are rare inborn errors of metabolism. The incidence of LSD is approximately 1 in 1500 to 7000 live births. To date, over forty diseases of LSD are illustrated. Some diseases of the LSD present with neuromuscular manifestations. Most often these manifestations include hypotonia or weakness. However, seizures are a common neurologic presentation in other LSD and often combined with variant degrees of neurologic deficit(s) and/or developmental regression.

Here we reviewed diseases of LSD presenting infantile epilepsy and associated neurologic problems, including diseases of (1) type III Gaucher disease, (2) neuronal ceroid lipofuscinoses (NCLs), (3) Sialidoses type II, (4) LSD with white matter involvement in terms of metachromatic leukodystrophy and Krabbe disease (globoid-cell leukodystrophy): the two most common leukodystrophies and demyelination in both the CNS and PNS, (5) GM1 and GM2 gangliosidosis, Niemann–Pick disease and Fabry disease. Currently, Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase was reported.

Infantile spasms (IS), epilepsy with myoclonic seizures, progressive myoclonic epilepsies (PMEs), epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic-astatic seizures and epilepsy with (multi-)focal seizures are almost their epileptic manifestation.

We highlighted the characteristics of seizure and EEG in the correlated diseases of LSD.

O20 CNS PATHOLOGY IN LYSOSOMAL STORAGE DISORDERS.

Ralph Z. Kern1
1Personalized Genetic health, Genzyme Corporation, Cambridge, United States

Objectives:

1) Gain understanding of general principles of CNS pathology in LSDs. 2) Describe primary and secondary pathology in Fabry Disease. 3) Review pathogenesis of neuronopathic Gaucher Disease and link between Parkinson’s Disease and glucocerebrosidase mutations. 4) Describe the animal model of late infantile onset Neuronal Ceroid Lipofuscinosis and potential treatment opportunities
 

Conclusion:

The pathogenesis of CNS manifestations of LSDs involves a complex interplay between a primary biochemical abnormality, toxic and cytopathic cellular dysfunction, elaboration of toxic mediators, and secondary pathology. Interaction of LSD mutations and population susceptibility genes may link LSDs with other more prevalent neurodegenerative disorders. The challenge of CNS delivery of effective and timely intervention is highlighted in the CLN-2 animal model.

O21 EFFECTS OF GINKGO BILOBA EXTRACT AND PROGESTERONE ON EXPRESSION OF GLUCOCORTICOID RECEPTOR IN CORTEX OF THE RAT AFTER RECURRENT SEIZURES

Ding-An Mao1, Xue Gu1, Tao Bo1, Li-Qun Liu1, Jian Li1
1 Department of Pediatrics, the Second Xiangya Hospital, Central South University, Changsha, China

Objectives:

To investigate the expression of glucocorticoid receptor(GR) in the cortex of the infantile rats following recurrent seizures and the effects of Ginkgo biloba extract and progesterone on them, and discuss the relationship between GR and developing brain hurt and the protective mechanisms of Ginkgo biloba extract and progesterone on the brain injury.
 

Methods:

96 SD rats of 7-day-old were randomly divided into four groups: the control group, the seizure group, the Ginkgo biloba extract intervention group and the progesterone intervention group. Seizures in rats were induced by inhalant flurothyl daily in six consecutive days. Brain tissue was sampled at different time points (1d, 3d, 7d) in each group after last seizure. The expression of GR proteins in the cortex was detected by immunohistochemistry and Western blot methods.
 

Results:

Western blot method was used in comparing the protein expression of GR among the three groups in cortex. In the control group, the expression of cytoplasmic GR protein was extensive, the older the more increased. The expression of cytoplasmic GR protein in the seizure group significantly decreased than those in the control group and the Ginkgo biloba extract intervention group on PN-15d and PN-19d (P<0.05).Then the expression of cytoplasmic GR protein was no significant difference on PN-13d (P>0.05). The expression of cortical cytoplasm of GR protein in the progesterone intervention group was significantly higher than those in the seizure group on PN-13d (P<0.05). And on PN-15d, the expression of cytoplasmic GR protein in the seizure group was significantly decreased than those in the control group and the progesterone intervention group (P<0.05), then the expression of cortical cytoplasm of GR protein was similar on PN-19d (P>0.05). In immunohistochemistry method it showed that there were no significant differences in the expression GR in the cerebral cortex between the control group and the seizure group on ARS-1d (PN-13d) (P>0.05). On ARS-3d (PN-15d) and ARS-7 d (PN-19d) they were significantly lower than the control group (P<0.05). Comparing with the seizure group, the GR expressions in the cerebral cortex in the Ginkgo biloba extract intervention group were no significant difference between the two groups on PN-13d (P>0.05). But on PN-15d and PN-19d they were significantly higher than the seizure group (P<0.05). The GR expressions in the cerebral cortex in the progesterone intervention group were significantly higher than the seizure group on PN-13d and PN-15d. Between the two groups there was no significant difference (P>0.05) on PN-19d.
 

Conclusion:

Recurrent seizures in neonatal rats modify GR expression in the cortex of rats. This phenomenon raised the possibility that abnormal GR expression might play an important role in developmental brain injury. The increase of the abnormal levels of GR in the cortex is probably related to the protective effects of Ginkgo biloba extract and progesterone on the infantile brain injury induced by seizures.

O22 CLINICAL ANALYSIS OF NIEMANN-PICK DISEASE TYPE C - 7 CASES

Hui Xiong1,, Xinhua Bao1, Yuehua Zhang1, Weiwei Lu1, Jiong Qin1, Xiru Wu1
1Department of Pediatrics, Peking University First Hospital, Beijing, China

Objectives:

Clinical manifestations, biochemical profiles and follow-up of Niemann-Pick disease type C (NP-C) children were summarized and analyzed to improve its diagnosis and management.
 

Methods:

Clinical information on features of 7 cases of NP-C inpatients being followed up from 2007 to 2009 were collected and analyzed. Bone marrow aspiration examination and acid sphingomyelinase activity assay were performed.
 

Results:

Among the 7 cases, five were male and two were female. Six were classical type of NP-C, half of which were started at late infantile and half at juvenile, between 4 to 8 years old, and 2 of them were siblings. These 6 cases presented primarily with neurologic symptoms. They started to develop ataxia and dysarthria, followed by dementia, dysphagia, dystonia and seizures within a couple of years. Epilepsy occurred 1~4 years after the onset. Supranuclear vertical gaze palsy was found at the beginning. Four cases had gelastic cataplexy. The other one case was found with splenomegaly at 4 months old. Hypotonia and delay of developmental milestones became evident by the age of 12 months. She had epileptic seizure at the age of 7.5, then rapidly progressed to anarthric, pyramidal tract involvement and bedridden without supranuclear gaze palsy. Cranial MRI showed signs of leukodystrophy. Lipid profiles of all cases demonstrated reduced level of total cholesterol, LDL-C and HDL-C. Bone marrow aspirates revealed foamy storage cells and sea-blue histiocytes. However, acid sphingomyelinase activity was normal or mildly decreased.
 

Conclusion:

NP-C is a rare autosomal recessive lysosomal storage disorder, whose clinical characteristics, biochemical and pathologic findings are different from type A and B. It has variant clinical features depending on the age at onset. Epilepsy and gelastic cataplexy are relatively common. Lipid profiles represent a biomarker of NP-C. Early diagnosis and genetic counseling should be emphasized in China.

O23 INTRACRANIAL GENE DELIVERY OF AAV-GALC VECTOR CORRECTS NEUROPATHOLOGY IN MURINE GLOBOID CELL LEUKODYSTROPHY

Dar-Shong Lin1, Chih-Kuang Chuang1, Shuan-Pei Lin1
1Department of Pediatrics, Mackay Memorial Hospital, Taipei,Taiwan

Objectives:

Globoid cell leukodystrophy is a devastating, neurodegenerative lysosomal storage disease. It is an autosomal recessive disease caused by a deficiency of galactocerebrosidase (GALC). Affected infants present symptoms between 3 to 6 months of age, followed by loss of previously achieved milestone and rapid deterioration of motor function, with death usually occurring before 2 years of age. Currently no cure therapy is available. Twitcher mouse, a murine model of GLD, is used for evaluating novel intracranial AAV-mediated gene therapy.
 

Methods:

We inoculated AAV2/5-GALC vector directly into the cortex, hippocampus and cerebellum of neonatal Twitcher mice and assayed the GALC activity, psychosine accumulation, demyelination, astrogliosis, and axonal degeneration in the CNS.
 

Results:

AAV vectors were distributed globally in the cerebrum, brainstem, cerebellum and whole spinal cord in treated Twitcher. AAV-treated Twitcher had folds of normal GALC activity, greater reduced psychosine accumulation, abrogated astrogliosis, attenuated demylination, and ameliorated axonal degeneration, resulting significantly extended lifespan up to 66 days compared to untreated Twitcher mice died around 38 days of age.
 

Conclusion:

Intracranial delivery of AAV using axonal transportation resulted in the wide distribution of transgenic expression along the neuroaxis, correction of neuropathology and ameioration of phenotype in murine model of GLD. AAV has shown promise for the treatment of the CNS disease associated with lysosomal storage disease. Furthermore, this study provides a basis for a strategy of axonal transporting AAV- GALC globally to correct neuropathology as a possible means of GLD treatment.

O24 EPILEPSY IN MITOCHONDRIAL DISEASE

Jong-Hee Chae1
1Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea
Epilepsies are group of heterogeneous clinical syndrome, which affect more than 50 million people. Particularly the incidence is high in children younger than 5 years of age.

In contrast with genetic epileptic syndrome, acquired epilepsy usually results from injury associated with episodes such as prolonged febrile seizures, status epilepticus, hypoxia or trauma. These initial insults result in complex molecular, biochemical and structural changes and eventually the development of spontaneous recurring seizures associated with neuronal cell death, which is referred to as epileptogenesis.

Mitochondrial diseases are clinically variable disorders caused by dysfunction of mitochondrial energy metabolism, which are also highly prevalent in children. Epileptic seizures are well known to be the one of the major presenting symptoms in some of the typical mitochondrial syndrome such as MERRF or MELAS. Mitochondria have critical cellular functions that influence neuronal excitability including production of ATP, fatty acid oxidation, control of apoptosis and necrosis, regulation fo aminoacid cycling, neurotransmitter biosynthesis, and regulation of cytosolic calcium homeostasis. Recently many clinical reports that suggest mitochondrial oxidative stress and syndrunftion are key factors that not only result from seizures, but may also contribute epileptogenesis. There are some suggesting evidence; 1)Epilepsy frequently occurs with inheritied mitochondrial syndromes , 2) Role of mitochondrial oxidative stress in lowering seizure threshold in mice with deficiency of mitochondrial antioxidant, 3) Occurrence of epilepsy in humans also increased with age with mitochondrial oxidative stress. However, Mitochondrial oxidative stress and dysfunction as causes or consequences of epileptic seizures are still not clear.

Here, neuronal cell death in epileptogenesis associated mitochondrial dysfunction and possible development of new drugs that reinforce the mitochondrial function or protection of mitochondrial dysfunction as an antiepileptic role will be discussed.

O25 EPILEPTIC SEIZURES IN INFANTS AND CHILDREN WITH MITOCHONDRIAL DISEASES IN TAIWAN

Hsiu-Fen Lee1, Chi-Ren Tsai1, Chou-Huei Chen1, Ching-Shiang Chi2
1 Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan
2Department of Pediatrics, Tung’s Taichung Metroharbor Hospital, Taichung, Taiwan

Objectives:

Knowledge of mitochondria and the relationship of mitochondrial dysfunction to human diseases have evolved over the past century. Central nervous system (CNS) is frequently affected because it needs more ATPs to carry out cellular work. Here we report the epileptic seizures in infants and children with mitochondrial diseases in Taiwan.
 

Methods:

From January 1983 to June 2009, 69 patients, 42 males and 27 females, diagnosed with mitochondrial diseases were classified into syndromic mitochondrial diseases (SMDs) and nonsyndromic mitochondrial diseases (NSMDs). The median age at the initial clinical presentation was 15 months (range, 1 month to 15 years). We analyzed the epileptic seizures in patients with mitochondrial diseases.
 

Results:

Among the 69 recruited patients, 34 (49.3%) were classified as having SMDs and 35 (50.7%) were classified as having NSMDs. Forty-three patients (62.3%) presented with seizures, 20 had SMDs and 23 had NSMDs. Twenty out of 34 patients (58.8%) in the SMD group had seizures: 8 generalized seizures in terms of myoclonic and generalized tonic and/or clonic seizures, 7 focal seizures, 2 unclassified seizures, and 3 mixed seizure types. Twenty-three out of 35 patients (65.7%) in NSMD group had seizures: 10 generalized seizures, 7 focal seizures, 2 unclassified seizures, and 4 mixed seizure types. Sixty-three cases had done EEG: 10 normal EEG, 21 epileptiform discharges in terms of focal spikes, sharp waves or hypsarrhythmia, and 32 nonspecific findings, i.e. background slow or intermittent polymorphic slow waves. Thirty-five out of 43 cases (81.4%) with seizures had developmental delay (DD) or psychomotor retardation (PMR).
 

Conclusion:

Epileptic seizures in pediatric patients with mitochondrial diseases were not uncommon. Most of them were refractory to antiepileptic drugs treatment and associated with DD and PMR.

O26 CONGENITAL LACTIC ACIDOSIS (PYRUVATE DEHYDROGENASE DEFICIENCY) AND EPILEPSY

Chitra Prasad1,3,4, C. Anthony Rupar1,2,3,4, Asuri N. Prasad1,3,4
1Departments of Pediatrics University of Western Ontario, London, Canada
2Departments of Biochemistry, University of Western Ontario, London, Canada
3Children’s Health Research Institute, University of Western Ontario, London, Canada
4London Health Sciences Centre, London, Canada

Objectives:

The pyruvate dehydrogenase complex (PDHc) is a mitochondrial multienzyme complex that provides the link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the conversion of pyruvate into acetyl-CoA. We examine the association of PDHc deficiency and neurological manifestations including epilepsy.
 

Methods:

Case reports showing variable neurological phenotypes & review of literature.
 

Results:

The diagnosis of PDHc deficiency was established in patient 1 born to consanguineous parents of Lebanese descent based on apneic episodes, elevated lactate of 22 (0.5-2.2 mmol/L), agenesis of corpus callosum, PDH E1 skin fibroblast enzyme activity 11% of normal and homozygous missense R36C mutation in PDHB gene (Mol Genet Metab 2008 Apr; 93(4):371-80). He is now 9 years old with microcephaly with some social interaction. The second patient is a 4 year old female born to non-consanguineous parents who presented with structural brain malformations detected on fetal ultrasound. Lactate levels remain 4-6 mmol/L. Cultured skin fibroblasts showed deficient PDH activity of 0.15 ±0.02 (0.7-2.5 nmoles/min/mg protein) and a western blot with total PDHc antibody showed no E1 α or E1 β present. Patient 2 developed a variety of seizures of focal onset with secondary generalization. Brain MRI in the patient 2 showed callosal agenesis, generalized cortical and cerebellar atrophy, marked ventriculomegaly and mega cisterna magna.
 

Conclusion:

PDHc deficiency illustrates the consequences of failure of energy metabolism in the prenatal period and infancy. Epilepsy is reported in a third of patients with PDHc deficiency. Epileptogenesis likely involves multiple mechanisms. A ketogenic diet bypasses the defect and provides acetyl-CoA directly to the tricarboxylic acid cycle and can ameliorate the metabolic lactic acidosis, however the neurological outcome remains poor in the majority. Genetic counseling should be provided to the families as inheritance can be either X-linked or autosomal recessive.

O27 CONGENITAL LACTIC ACIDOSIS (PYRUVATE DEHYDROGENASE DEFICIENCY) AND EPILEPSY

Cheuk-Wing Fung1, Grace Poon1, Anne Kwok1, Pik-To Cheung1, Louis Low1, Chole Mak2, S Tam2, Simon Siu2, Virginia Wong1
1Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong, China
2Division of Clinical Biochemistry, Queen Mary Hospital, Hong Kong, China

Background:

Disorders of the mitochondrial respiratory chain may present with various neurologic features, including encephalopathy, myopathy and hearing loss. Non-neurologic presentations occur in over 30% of paediatric patients. We review the clinical presentations of patients with mitochondrial diseases in our centre.
 

Methods:

From 1995 to 2009, restropective review of medical records revealed 22 patients with mitochondrial diseases (15 males and 7 females). The diagnosis of mitochondrial disease is either based on the clinical phenotype or the Mitochondrial Disease Criteria proposed by Morava et al as definite mitochondrial disorders. Respiratory chain enzymology was performed in Murdoch Childrens Research Institute, Australia. Genetic analysis was either performed in the former centre or locally.
 

Results:

The age of presentation ranged from immediately after birth to 10 years of age. The most common clinical phenotype was Mitochondrial Encephalomyopathy, Lactic acidosis, and Stroke-like episodes (MELAS) (n=7, 32%). Only 2 carried the typical A3243 mutation. The second most common presentation was Leigh disease (LS) (n=6, 27%). Mutation in the SURF1 gene causing complex IV deficiency was found in 1 patient. A patient with Kearns-Sayre syndrome (KSS) and another with Pearson syndrome had a deletion in the mitochondrial DNA genome. One had Leber’s Hereditary Optic Neuropathy (LHON). A patient who had mutation in the POLG gene presented with a spinocerebellar ataxia syndrome with intractable epilepsy. 2 patients with complex IV deficiency had a phenotype of encephalomyopathy with or without epilepsy. A patient with complex I deficiency presented with a multi-system disease including cataract, hearing impairment, global developmental delay, short statue and recurrent hypoglycaemia. 2 patients had an ill-defined phenotype. Both met the Mitochondrial Disease Criteria as definite mitochondrial disorders. One presented with a fatal cardiomyopathy and corneal opacity of neonatal onset. The other had a combination of global developmental delay with regression, intractable epilepsy, cortical visual impairment and generalized dystonia. Further biochemical and genetic analysis was in progress. Significant mortality was found among the cohort (n=7, 32%).
 

Conclusion:

Mitochondrial oxidative phosphorylation defects form an important group of inborn error of metabolism causing significant morbidity and mortality in neurologically disabled children. High index of suspicion is necessary for a proper diagnosis including biochemical and genetic analysis.

O28 THE CHARACTERISTICS OF SEIZURES IN MALAYSIAN CHILDREN AND ADOLESCENTS WITH MELAS DUE TO A3243G MITOCHONDRIAL DNA MUTATION

Chee-Ming Teh1, Teik-Beng Khoo1, Hussain IHMI1, Wee-Teik Keng2, Gaik-Siew Ch’ng2, Lock-Hock Ngu2, MD Norsiah3
1 Paediatric Department, Paediatric Institute, Hospital Kuala Lumpur, Malaysia
2Genetic Department, Hospital Kuala Lumpur, Malaysia
3Molecular Diagnostic & Protein Unit, Institute for Medical Research, Malaysia

Objectives:

MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is a well-recognized phenotype of mitochondrial disorder, with ~80% of cases resulted from A3243G mtDNA mutation. Seizure is a known associated problem but not well-described in literature. The aim of this article is to study the seizure characteristics in children / adolescents with MELAS.
 

Methods:

This is a descriptive study. The medical records of all our patients with MELAS due to A3243G mtDNA mutation (confirmed by PCR technique) were reviewed.
 

Results:

11 out of 13 patients with MELAS had seizures. The mean age of presentation and diagnosis of MELAS was 6.5 and 9.6 years respectively. Half of them (n=6) had seizures as their initial symptom. Among those with seizures, 91% had complex partial seizures, 82% had generalized tonic-clonic seizures and 27% had simple partial seizures. Status epilepticus occurred in 3 patients. The interictal EEGs were all abnormal, showing focal, multi-focal or diffuse slowing. However, epileptiform discharges were only present in minority (n=2). During mean follow up of 3 years, 2 patients had only acute symptomatic seizures, 4 patients were seizure-free (for at least 6 months), 2 patients had infrequent seizures and 3 patients had intractable seizures. Most of the patients with better-controlled epilepsy were on benzodiazepine and lamotrigine, at times, combined with phenytoin.
 

Conclusion:

Seizure is a common manifestation and complication in MELAS due to A3243G mtDNA mutation. Benzodiazepine and lamotrigine, at times, combined with phenytoin, seem efficacious for seizure-control in this group of patients.

O29 CLINICAL FINDINGS AND DIAGNOSTIC FLOWCHART OF PEROXISOMAL DISEASES

Nobuyuki Shimozawa1
1Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan
Peroxisomes are single-membrane lined organelles present in all eukaryotic cells and catalyzing a range of essential metabolic functions. Inborn errors of peroxisomal metabolism, an expanding group of genetic disorders in humans, have been divided into two groups with disorders of peroxisome biogenesis (PBD) and single peroxisomal enzyme deficiencies. PBD include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD) and rhizomelic chondrodysplasia punctata (RCDP) type 1, all caused by a defect in PEX genes which encode peroxins, proteins necessary for peroxisome biogenesis and the import of peroxisomal matrix and membrane proteins. The peroxisomal matrix contains over 50 enzymes mainly related to lipid metabolism, of which ten single peroxisomal enzyme deficiencies have been identified. These include dysfunction of beta-oxidation enzyme, containing of X-linked adrenoleukodystrophy (ALD), acyl CoA oxidase deficiency, D-bifunctional protein deficiency, Sterol carrier protein 2 deficiency, and Rasemase deficiency, and deficient of plasmalogen synthesis, catalase deficiency, hyperoxaluria type 1 and classical Refsum disease. Furthermore, a novel phenotype similar to ZS caused by a contiguous deletion spanning the 5’ ends of ALD gene and DXS1357E in Xq28 (CADDS) has been reported, therefore, we classify the peroxisomal diseases into three groups including contiguous gene syndrome.

We have been studying peroxisomal diseases for more than 20 years, as the only diagnostic center in Japan, and doing molecular analysis on PBD and their related disorders. We found the first responsible gene for PBD, PEX2 in 1992, and then PEX6 in1996, PEX13 in1999, PEX3 in 2000 and PEX14 in 2004, therefore, until now all 13 responsible genes have been identified.

We have developed the screening system of peroxisomal diseases, using GC/MS analysis of very long chain fatty acids, phytanic acids and plasmalogen, and identified many Japanese patients, using biochemical and molecular analysis: 43 patients with ZS, 3 with NALD, 3 with RCDP, 3 with acyl-CoA oxidase deficiency, 10 with D-bifunctional protein deficiency, 1 with CADDS and over 100 patients and carriers with ALD. Hematopoetic stem cell transplantation (HSCT) is the only effective treatment for cerebral form of ALD, however, only one-third of patients with post-cerebral onset have undergone HSCT in Japan. Therefore, detection of pre-symptomatic patients by familiar analysis with enough genetic counseling is necessary.

Here I present the molecular and clinical aspects of peroxisomal diseases, and those screening and diagnostic system in Japan. We will develop these screen system of peroxisomal diseases also for other country in this opportunity.

O30 PEROXISOMAL DISORDERS WITH INFANTILE SEIZURES

Jao-Shwann Liang1
1Department of Pediatrics, Far Eastern Memorial Hospital, Taipei, Taiwan
Peroxisomes are organelles responsible for multiple metabolic pathways including the biosynthesis of plasmalogens and the b-oxidation of very-long-chain fatty acids (VLCFA). Lack of peroxisomes or dysfunction in any of their normal functions is the cellular basis for human peroxisomal disorders. Based on organelle structure and deficiencies, peroxisomal disorders can be subdivided into two major groups. In the first group, there is a defect in peroxisome biogenesis which is associated with either a generalized or multiple loss of peroxisomal functions. The peroxisome biogenesis disorders (PBDs) include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). The differences among these disorders are continuous, with overlap between abnormalities. Seizures are present in approximately one-third of affected individuals in PBDs and occurred in neonatal period or infancy. Seizures may be difficult to control despite use of appropriate medication. The second group includes disorders resulting from the deficiency of a single peroxisomal enzyme. In the second group, although the peroxisome is intact and functioning, there is a defect in one enzymatic process. However, these disorders can be severely as those in which peroxisomal activity is nearly or completely absent. X-linked adrenoleukodystrophy (X-ALD) is the most common disorder in this group.

Peroxisomal disorder can involve other organs, but mainly the nervous system. In general, developmental delay, vision and hearing impairment are common in peroxisomal disorder patients. Generalized hypotonia is present in most severe cases. Epileptic seizures are also a common characteristic of patients with certain peroxisomal disorder. However, the incidence of peroxisomal diseases is low; the correct diagnosis needs special examinations, and the life span of affected patients is limited. These conditions make it difficult to conduct satisfactory clinical investigations in peroxisomal disorders. Peroxisomal disorders are heterogeneous disease group, with different degrees of severity. The characteristics of epileptic seizures in patients with different peroxisomal diseases should be clarified further.

O31 LATEST FINDINGS IN PEDIATRIC EPILEPSY TREATMENT

Ki Joong Kim1
1Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
Antiepileptic drugs (AEDs) are the principal treatment modality for the patient with epilepsy regardless of the type of seizures or syndromes. New AEDs, introduced since 1993, provide more diverse options in the treatment of epilepsy. Despite the equivalent efficacy and better tolerability of these drugs, more than 25% of patients remain refractory to treatment. Moreover, the issues for pediatric patients are different from those for adults, and have not been addressed in the development and application of the new AEDs. In the past, choosing AEDs has mostly been dependent on the physician’s personal knowledge and experience. Current trend is to choose AEDs based on the scientific evidence. Recently published evidence-based treatment guidelines have helped physicians to choose the most reasonable AED, although they cannot fully endorse new AEDs because of the lack of well-designed, randomized controlled trials.

Although much progress has been made in understanding the mechanisms of ketogenic diet (KD), how the KD works remains still elusive. Several recent publications support that the KD is superior to conventional AEDs in treating refractory epilepsy in infants and children (e.g. infantile spasms). However, to obtain scientific information on effective treatment strategies for catastrophic epilepsy syndromes in children, high-quality collaborative studies like patient registry program should be performed in the near future.

Increasing numbers of pediatric patients with intractable epilepsy are being considered for surgical treatment. The key elements of candidacy for epilepsy surgery include medically intractable and disabling epilepsy, localizable epileptogenic zone, and low postoperative risk. At the same time, following questions should be considered seriously before doing epilepsy surgery: what is the chance for seizure-freedom after surgery, what are the risks associated with surgery, and what will be the risk of not doing surgery?

O32 MENKES DISEASE AND INFANTILE EPILEPSY

Asuri N. Prasad1,4, CA Rupar1,2,3, C Prasad1,4, S Levin1,4
1Department of Pediatrics, University of Western Ontario, London, Canada
2Departments of Biochemistry, University of Western Ontario, London, Canada
3Departments of Children’s Health Research Institute, University of Western Ontario, London, Canada
4London Health Sciences Centre, London, Canada

Objectives:

Menkes disease, an X linked recessive neurodegenerative disorder, results from a mutation in the gene coding for the copper transporting ATPase (ATP7a) leading to a systemic intracellular copper deficit. We describe the clinical presentation, and evolution of epilepsy in Menkes disease, with attention to diagnosis, genotype phenotype correlations and response to treatment interventions.
 

Methods:

Longitudinal case study and literature review
 

Results:

A 2 month old male infant presented with focal seizures initially controlled with Phenobarbital. However, the seizures evolved over 2 months to infantile spasms. The diagnosis of Menkes disease was established on clinical grounds (hypotonia, failure to thrive, and kinky hair), and a biochemical profile of low copper (2.2, 3.9-17.3µmol/L), and ceruloplasmin (0.07, 0.21-0.51g/L). Magnetic resonance imaging (Brain) showed progressive atrophy of grey matter, ventriculomegaly, tortuous intracranial vasculature and white matter signal changes consistent with loss of myelin and axons. During the encephalopathic stage, significant lactic acidosis was noted (blood lactate (4.2, 0.5-2.2 mmol/L), CSF lactate (5.0 mmol/L) and the MR spectroscopy demonstrated intracerebral lactate accumulation. A pathogenic mutation c.1831G>T (p.E611X) in exon 7 of the ATPase gene was confirmed on DNA sequence analysis; his mother, maternal grandmother and aunt were shown to be a carrier for the same mutation. The mutation results in a premature stop codon and a truncated protein product. Treatment with copper chloride injections produced no demonstrable neurological improvement, but improved general health. Presently, his epilepsy is treatment resistant (tonic spasms and multifocal myoclonus), while the EEG shows background slowing and multifocal epileptiform activity.
 

Conclusion:

The onset and evolution of epilepsy in Menkes disease is marked by different stages. Neurological manifestations are likely related to perturbations in copper dependent enzymatic pathways involved in neurotransmitter and energy metabolism. The early diagnosis and institution of copper supplementation has been shown to be beneficial particularly in patients with residual ATP7A activity.

O33 PYRIDOXINE DEPENDENT AND RESPONSIVE SEIZURES

Peter Baxter1
1 Sheffield Childrens Hospital, Sheffield, United Kingdom
With recent clinical, biochemical and genetic advances it is now becoming clear that pyridoxal phosphate (PLP) deficiency has a variety of aetiologies. With an antenatal onset, in neonates it causes a multisystem disorder including an encephalopathy which can be misdiagnosed as being due to birth asphyxia, other metabolic disorders such as glycine encephalopathy, structural abnormalities and/or intracranial haemorrhage. With a later onset infants and children mainly present with seizures, sometimes with a normal EEG. Seizures in some children without deficiency can also respond to PLP. Recent advances and the biochemical differential diagnosis will be discussed.

O34 CLINICAL EVALUATION OF PYRIDOXINE TREATMENT OF EPILEPSY

Shunsuke Ohtahara1, Yasuko Yamatogi1
1 Department of Child Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
Clinical seizures related to vitamin B6 are inclusively called vitamin B6 related seizures. Formerly, these were grossly classified into B6 deficiency seizures and B6 dependent seizures. Both types of seizures are suppressed by administration of vitamin B6. I proposed the vitamin B6 responsive seizures as the third category of vitamin B6 related seizures.

Vitamin B6 responsive seizures will be outlined in this paper. This type of seizures, meeting neither the categories of vitamin B6 deficiency seizures nor B6 dependent seizures, decrease or disappear responding to high-dose vitamin B6 administration without co-medication of antiepileptic drugs. The ages of seizure onset are variable. Most of our cases had their seizure onset in the first year of life, though ranging widely from ages 3 months to 12 years. Etiologically, many cases are idiopathic, but some are symptomatic with apparent organic brain lesions. With responded seizure or epilepsy types, the majority is West syndrome, though including some others with Lennox-Gastaut syndrome, grand mal seizures or partial motor seizures.

The efficacy of vitamin B6 on epilepsy will also be mentioned, mainly high-dose vitamin B6 treatment on West syndrome proposed by us, precisely referring to its effect on 216 successive cases and their long-term prognosis.

Its overall efficacy rate on WS was 13.5%, particularly high as 32% in cryptogenic WS. Interestingly, it was also effective in WS with gross brain pathologies.

In 1960, we observed no abnormality in tryptophan load test in most cases of childhood epilepsy including WS and recognized 10-30mg/day of vitamin B6 exerting no efficacy on WS. Since then, trials escalating its dose to 50-100mg/day gradually increased responders. Finally, the fore-mentioned large-scale trial revealed a dramatic efficacy of high-dose vitamin B6 such as 100-400mg/day. Notably, responders showed excellent long-term prognosis without antiepileptic drugs, suggesting that this treatment should not be underestimated.

It is a clinical disadvantage that only trial discriminates effective cases.

Energetic studies, including molecular genetics, are required to predict efficacy of high dose vitamin B6 before administration.

O35 EPILEPSY IN CHILDREN WITH BIOTINIDASE DEFICIENCY

Pratibha Singhi1, Puneet Jain1, Munni Ray1, Anju Gupta1, N. Khandelwal2
1 Department of Pediatrics and Radiodiagnosis2, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Objectives:

To study the clinical and EEG features of seizures in children with biotinidase deficiency and their response to biotin therapy.
 

Methods:

Seventeen consecutive patients with biotinidase deficiency registered in the neurodevelopmental clinic at the Postgraduate Institute of Medical Education and Research, Chandigarh between September 2004 to May 2009 were studied. Their medical records were reviewed and follow up was done to assess their response to biotin.
 

Results:

The mean age at presentation was 14 months (range day 3 to 12 years) and the mean interval between presentation and diagnosis was 9.6 months. Developmental delay was noted in 52.9% cases and regression of milestones was noted in two. Seizures were the chief complaints in 15 children (88.2%). Myoclonic seizures were the predominant (53.3%) type. Only two children had dermatitis and alopecia. Microcephaly was seen in 6 cases and hypotonia in 29.4%. Serum biotinidase levels varied from 1 to 5 nmol/min/ml (Normal:≥ 5 nmol/min/ml). EEG showed spikes and spike wave complexes in most cases. The main abnormalities on MRI brain were cortical atrophy, widening of CSF spaces and white matter hyperintensities. MRI Brain was normal in seven patients. Biotin, 10 mg/day, was started in all patients. The mean follow up period was 24.9 months. Two patients were lost to follow up and one patient died; 80% patients had seizure control and symptomatic relief following biotin therapy; 60% had some neurological sequalae.
 

Conclusion:

Seizures are common in biotinidase deficiency; prompt initiation of biotin therapy can help early seizure control.

O36 EPILEPTIC MECHANISMS IN SSADH DEFICIENCY, A DISORDER OF GABA METABOLISM

Phillip L. Pearl1,2, Lovy Shukla1, William H. Theodore2, Cornelis Jakobs3, K. Michael Gibson4
1Department of Neurology, Children’s National Medical Center, George Washington University School of Medicine, Washington DC, United States
2Clinical Epilepsy Branch, Natl Inst Neurol Dis Stroke, Natl Institutes of Health, Bethesda, United States
3 Metabolic Unit, Dept of Clinical Chemistry, VU Univ Medical Center, Amsterdam, Netherlands
4 Dept Biological Sciences, Michigan Technological Univ, Houghton, Houghton, United States

Objectives:

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a GABA degradative defect associated with high endogenous levels of GABA and γ-hydroxybutyrate (GHB) in physiologic body fluids and brain parenchyma. Epilepsy affects approximately half of patients. The murine model is associated with a transition from absence to generalized convulsive seizures in the third week with ultimately fatal status epilepticus.
 

Methods:

Characteristics of clinical seizures and EEG abnormalities are reported from a patient database. Electrocorticography, single cell electrophysiology, and radioligand binding studies are reported from murine null versus heterozygote and wild type genotypes.
 

Results:

Generalized seizures predominate in the clinical condition, including tonic-clonic, atypical absence, and myoclonic. EEG discharges are typically generalized spike-wave and may include photosensitivity and ESES. GHB induces spike-wave discharges in homozygous null mice via GHBr and GABABR-mediated mechanisms. These resemble absence seizures, and may be abolished by GABABR antagonists CGP 35348. Decreased binding of a GABAAR antagonist ([35S]TBPS) and GABABR antagonist (CGP54626) have been demonstrated in P19 and P14 null mice, respectively. Down regulation of GABAA and GABAB receptor subunits is observed by P14, along with decreased input resistance and resting membrane potential in hippocampal neurons. GABAB mediated synaptic potentials and GABAA mediated IPSPs are further reduced from P8-P14.
 

Conclusion:

Generalized epilepsy and epileptiform EEG discharges are characteristic of human SSADH deficiency, an apparent paradox in this hyperGABA’ergic disorder. Spontaneous, recurrent absence seizures appear in null mice by the third week of life, which may be induced by GHB and resolved with GABAB-R antagonists. Build-up of GHB in SSADH deficiency may cause early absence seizures through GABAB-R mediated activity. There is subsequent overuse dependent down regulation of GABAA and GABAB receptor activity, which may be associated with hyperexcitability concomitant with the transition to generalized convulsive activity.

O37 MAGNETIC RESONANCE IMAGING OF MONOAMINE METABOLIC DISORDERS

Shinn-Forng Peng1
1 Department of Radiology, School of Medicine, National Taiwan University, Taipei, Taiwan

Objectives:

To share Taiwanese experience about MR image, MR spectroscopy and diffusion tensor image of monoamine-related disorders.
 

Methods:

All patients and control subject received MR examinations using a 1.5-T echo-planar scanner (Sonata; Siemens, Erlangen, Germany). All MR examinations used a standard birdcage head coil in a 1.5-T MR system (Sonata; Siemens, Erlangen, Germany). At first, fast spin-echo (FSE) T2-weighted images (T2WIs) in the axial plane were obtained. Localized proton spectra were acquired using a short TE stimulated echo acquisition mode (STEAM) technique (TE= 10 ms). The 8-ml volumes of interest were localized in the brain parenchyma of interest. Diffusion tensor images were acquired with diffusion encoding gradients in six directions, i.e., {1, ±1, 0}, {0, ±1, 1}, {±1, 0, 1}, and diffusion sensitivity b = 1500 s/mm2.
 

Results:

1) Cerebral folate deficiency syndrome is a recently recognized cause of developmental delay, regression, and seizures. At least five distinct inherited disorders of folate transport and metabolism are known till now, and all of them cause systemic folate deficiency. Brain magnetic resonance (MR) imaging demonstrated hypomyelination, mild cerebellar atrophy and MR-based in vivo MR spectroscopy indicated a combined decrease of white-matter choline and myoinositol but mostly nonspecific changes at the basal ganglia. 2) Phenylketouria, Malignant phenylketonuria (MPKU), which results from a defect in the synthesis or metabolism of tetrahydrobiopterin (BH4), is a rare variant of an inborn error of amino acid metabolism. This study analyzed eight patients suffering from BH4 deficiency in a Taiwanese population identified by neonatal screening. Only one patient with seizure had signal changes at central white matters on MRI similar to those most prevalent in classical hyperphenylalaninemia. Lactate peaks were revealed on MRS in two patients who had lower IQ scores than the other patients. Besides, Myoinositol /Choline ratio was correlated positively with the average BH4 dosage (p=0.027, Correlation Coefficient=0.027). In addition, Choline/Creatine ratio was negatively correlated with the average 5-hydroxytryptophen dosage (p= 0.035, Correlation Coefficient=–0.742 respectively), which may be a useful indicator in the monitoring treatment. On magnetic resonance (MR) images of malignant PKU patients, hyperintense lesions are usually not shown at the periventricular white matter on T2-weighted images. Pathologic changes in the brain of untreated PKU patients were impaired myelination, gliosis and even white matter degeneration. However, substantial decrease in signal was observed in parietal-occipital central white matter in the fractional anisotropy and diffusion anisotropy maps. As compared with controls, patients with PKU had significantly lower fractional anisotropy in parietal-occipital central white matter. 3) Disorders of neurotransmitters, Aromatic L-amino acid decarboxylase (AADC) deficiency is an uncommon inherited neurometabolic disease. AADC deficiency is more prevalent in Taiwan than that in western countries. Because AADC is widely distributed in the brain parenchyma and participates in the synthesis of monoamines, deficiency of AADC will result in combined deficiency of dopamine, serotonin, and other catecholamines, and may lead to the abnormal development of the brain. In the AADC patients, the frontal horn was significantly widened than the controls (p<0.01), and the volume of caudate nucleus was also significantly smaller than that of controls (p = 0.02). The ratios of thickness of the splenium to that of the genu of corpus callosum were also significantly increased in patients with AADC deficiency (p <0.01). For three patients with follow-up MR images, all revealed mesitemporal atrophy, indicating mildly progressive cerebral atrophy. The evaluation of children with metabolic disorders is important but lengthy and time-consuming. Imaging examination including MR image, MR spectroscopy and diffusion tensor image, is part of the team work of neurometabolic evaluation.
 

Conclusion:

The evaluation of children with metabolic disorders is important but lengthy and time-consuming. Imaging examination including MR image, MR spectroscopy and diffusion tensor image is part of the team work of neurometabolic evaluation.

O38 PATHOPHYSIOLOGY OF EPILEPSY IN NEUROTRANSMITTER DISORDERS

Yoshiko Nomura1, Kazue Kimura1, Yuri Nagao1, Kei Hachimori1, Masaya Segawa1
1 Segawa Neurological Clinic for Children, Tokyo, Japan

Objectives:

Neurotransmitter disorders are known to cause movement disorders. Some neurotransmitter disorders, however, show epilepsy. Pathomechanism of the epilepsy of neurotransmitter disorders is discussed.
 

Methods:

Personal 46 cases of gene proved Segawa disease, one recessive dihydropteridine reductase (DHPR) deficiency and one aromatic amino acid decarboxylase (AADC) deficiency case were evaluated. Two cases with recessive 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency were reviewed.
 

Results:

No cases with Segawa disease showed epilepsy. AADC, DHPR and PTPS deficiency cases developed epilepsy, and all resisted to various anticonvulsants. Levodopa was not effective for the epilepsy. The cases with epilepsy revealed mental retardation, muscle hypotonia and failure in locomotion. They revealed atonia of REM sleep into non REM sleep.
 

Discussion and Conclusion:

Segawa disease is a dominantly inherited childhood onset dystonia caused by the mutation of GTP cyclohydrolase I gene. Psychomental development is normal, but occasionally develops depression. The pathophysiology is the non-progressive deficiency of the dopamine at the terminal of nigrostriatal dopamine neuron. The clinical course reflects the physiological age dependent decrement of the terminal dopamine. This does not affect any morphological changes or disturbances of higher cortical function. The recessive PTPS and DHPR deficiency involve the deficiency of serotonin activity besides that of dopamine in the terminal. The serotonin deficiency causes postural hypotonia and failure in locomotion. Leak out of atonia of REM sleep into non REM sleep reflects the deficiency of specific serotonin system involved in antigravity muscle and locomotion. These processes cause dysfunction of the pedunculopontine nucleus, and lead to the disturbances of nigrostriatal and ventro-tegmental dopamine neurons. These dopamine deficiencies in the developing brain induce the compensatory upward regulation of dopamine receptors. This causes the disinhibition of the thalamo-cortical pathway, and induces the epileptic spikes in the cortex, that is epilepsy. Early encouragement of locomotion is important for the management of this epilepsy.

P01 EVOLUTION AND VARIATION IN NEONATAL SUPPRESSION-BURST ENECEPHALOGRAMS

Inn-Chi Lee1,2,3
1 Department of Pediatric Neurology, Chung Shan Medical University Hospital, Taichung, Taiwan
2 Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan
3School of Medicine, Chung Shan Medical University, Taichung, Taiwan

Objectives:

Suppresion-burst (SB) activity of electroencephalogram (EEG) in newborn is a pattern of high-amplitude and slow-waves discharges with or without spikes, being alternating with periods of minimal activity of low amplitude (less than 10 μV). Although SB usually indicates a grave syndrome in neurodevelopment, the evolution of EEGs is varied and uncertain.
 

Patients and Methods:

We study 5 newborns with SB EEGs, included varied etiologies, evolution of EEGs and associated change of seizures semiology. Five cases include a nonketotic hyperglycinemia (NKH), a severe hypoxia-ischemic encephalopathy (SHIE), a citrullinemia, an Aicardi’s syndrome, and an Ohtahara syndrome with unidentified etiology.
 

Results:

The bursting activities were asynchronously alternating appeared in both hemispheres except in one EIEE with synchronous SB. The follow-up periods were ranged from 6 months to 6 years. The longest period of suppression on EEGs was in SHIE. Continuous backgrounds of EEGs was reached at 15 days in citrullinemia, 3 months in EIEE and in Acardi syndrome, and never to be continuous in SHIE and in NKH. Three cases being followed up over 2 years, myoclonic seizures still were prominent in both patients with NKH and SHIE, however, tonic seizures was predominant after 2-years in EIEE. EEGs after 2 years of age were changed to multi-focal independent spike foci in EIEE and frontal epileptic spike focus in NKH. Four cases have severe mental retardation except in one citrullinemia, in whom, almost was normal neurodevelopment at 6 months of age.
 

Conclusion:

We conclude neonatal SB on EEGs have varied pattern of evolution on EEGs and clinical courses, depending on different etiologies. They have grave outcomes except those with treatable metabolic disorders.

P02 CLINICAL PRESENTATION AND LABORATORY PROFILE IN SUSPECTED CASES OF NEUROMETABOLIC DISORDERS: A PRELIMINARY REPORT FROM BANGLADESH

Naila Zaman Khan1, Mustafa Mahbub1, Selina Huo Banu1, Mosiul Azam1, SC Majumdar1
1 Child Development and Neurology Unit, Dhaka Shishu (Childrens’) Hospital, Dhaka, Bangladesh

Background:

Neurometabolic disorders in children may present at any age with a wide range of clinical manifestations. Unexplained or intractable seizure is one important association. Consanguinity, regression of development, sibling death are some other clues to suspect neurometabolic disorders when laboratory support is limited. Laboratory findings, however, provides the confirmatory diagnosis which is unavailable in Bangladesh.
 

Objective:

To determine the association of consanguinity, regression of development, seizures, EEG findings and other laboratory investigations in children suspected to have neurometabolic disorders, to aid clinicians working in resource-poor countries.
 

Method:

A retrospective analysis from the records of the patients suspected to have neurometabolic disorders in the Child Development and Neurology Unit, Dhaka Shishu Hospital, during the period of July 2007 to October 2009. Tandem Mass Spectrometry (TMS) was done through a private laboratory in New Delhi, India in most.
 

Results:

Total 82 children were studied and the parents of 29 (35%) had history of consanguineous marriage. Seizure was associated with 64(78%) children and abnormal EEG findings recorded in 53(65%) . Plasma ammonia was measured in 54 cases and found increased in 34 (63%). Plasma lactate was examined in 53 cases and found high in 25 (31%). TMS was done in 77 (94%) children and abnormality found in 47/77(57%) cases. Serum biotinidase activity was advised for 31 children as per TMS result and measured in 18 children of which deficient activity was found in 10/18(56%); borderline in 4/18 (22%) and normal activity in 4/18 (22%) cases. Of three cases followed up with biotin supplementation all were found to be doing well neurologically.
 

Conclusion:

Early suspicion by background history and clinical presentation followed by stepwise laboratory investigation is necessary to identify neurometabolic disorders. Early and appropriate intervention can reduce neurodisability in many situations. A central laboratory for determining NMDs is needed urgently in Bangladesh.

P03 INCIDENCE OF SEIZURE IN NEUROMETABOLIC DISEASES UNDER CURRENT NEWBORN SCREENING IN TAIWAN

Tzu-Ying Yang1, Chung-Hao Wang1, Ting-Rong Hsu1, Cheng-Hung Huaung1, Dau-Ming Niu1, Kai-Ping Chang1
1 Department of Pediatrics, Taipei Veterans Hospital, Taipei, Taiwan

Objectives:

During the past, without adequate technique in diagnosis of neurometabolic disease, most of the children had developed vomiting, hypotonia, failure to thrive, seizure and eventually died in the very early of age. Since the use of tandem mass for screening the abnormal metabolites, we could early diagnose these diseases. As the consequence, fewer neurological manifestations had been presented in these children. We retrospectively review eight common neurometabolic diseases in Taiwan to find out the incidence of seizures in neurometabolic diseases.
 

Method:

We had screened the newborns in Taiwan since 2006 to 2009. Forty-nine newborns were diagnosed of phenylketonuria, homocystinuria, maple syrup urine disease, tyrosinemia, citrulinemia, glutaric aciduria type I (GA1) and methylmalonic academia. We investigated the incidences of seizure attack, neurologic deficits and the clinical prognosis in these newborns.
 

Results:

In the 49 newborns, only one with GA1 had seizure. In addition, newborns of GA1 also had significant higher rate of neurological deficits and mortality than other diseases. Most of the patients under diet or medical control present with development delay, only a few have severe neurological problems.
 

Conclusion:

Within these neurometabolic diseases, GA1 had significantly higher potential to develop seizure. Seizure could soon occur in infancy. Under early diagnosis and adequate treatment, few children had severe neurological deficit. However, developmental delay was still seen in these children.

P04 A CASE WITH NONKETOTIC HYPERGLYCINEMIA DIAGNOSED WITH NOVEL SCREENING METHODS —13C-GLYCINE BREATHING TEST AND MLPA METHOD

Hitomi Hino1, Masaaki Ohta1, Yuka Suzuki1, Mitsumasa Fukuda1, Eiichi Ishii1, Shigeo Kure2
1 Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan
2 Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan

Introduction:

Nonketotic hyperglycinemia (NKH) is an inborn metabolic disorder caused by the glycine cleavage system (GCS) deficiencies. The definitive diagnosis of NHK requires either measurement of GCS enzymatic activity or genetic analysis. Although most of the patients with NKH present with typical symptoms, definitive diagnosis in some cases is difficult because it requires invasive and time-consuming methods. Recently, rapid and non-invasive diagnostic techniques for NKH, 13C-glycine breathing test and multiplex-ligand-dependent probe amplification (MLPA) method have become available. We report a boy diagnosed as having NKH with novel diagnostic methods.
 

Case report:

The boy was born at full-term after uncomplicated pregnancy. Due to progressive worsening of apnea, he required assisted ventilation at 2 days of age. He also showed marked hypotonia and frequent seizures, erratic myoclonus and tonic seizures. His clinical and electrophysiological features are compatible with early myoclonic encephalopathy. Blood and CSF amino acid analysis revealed elevated glycine levels, and ratio of CSF to plasma glycine with 0.118 (normal, <0.03). [13C-]glycine breath test showed decreased 13CO2 excretion of 7.9% (normal, 24.1 ± 4.0%), which imply the reduced GCS activity. Mutational analysis of GLDC gene showed a compound heterozygosity; a missense mutation with 1382G>A resulting in amino acid change of R461Q, and a large deletion involving exons 1-25. Under the diagnosis of NKH, treatments with sodium benzoate and ketamine were initiated. He was successfully extubated at 45 days of age. He is now 10 months old with developmental mile stone of 5-6 months.
 

Discussion:

Our patient was diagnosed as NKH with the enzymatic and genetic analysis. To provide longer-term and accurate prospective, we need to accumulate information of the genotype-phenotype correlations utilizing the fast and reliable testing.

P05 EFFECTS OF GLUTAMATE ON NEURAL PROGENITOR/STEM CELLS CULTURED IN VITRO

Tingsong Li 1, Li Jiang 1
1 epartment of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, China

Objectives:

To explore the effects of glutamate on the neural progenitor/stem cells (NPCs) in vitro.
 

Method:

Immunofluorescence and Western blot were used to detect the expression of NR1 on NPCs cultured in vitro; Calcium imaging by Fluo-3/AM and single channel recording were used to investigate the function of NMDA receptors in NPCs; The single NPC was obtained by mechanical dissociation and grown for 4 days in medium containing 30 μM MK-801 and Glu at the different concentration of 50-1600 μM, TUNEL staining positive cells and the level of lactic acid dehydrogenase (LDH) in culture medium were measured to evaluate the effects of Glu on NPCs' survival; The number and diameter of neurosphere were measured to evaluate the effects of Glu on NPCs' proliferation.
 

Results:

The NR1 expression by immunofluorescence and western blot was positive. Calcium imaging showed the fluorescence intensity increased significantly after glutamate stimulation. Three types of currents were detected with the cell-attached recording: unipolar rectangular pulse discharge, flicking, burst and cluster. The level of LDH in the culture medium of 1600 μM Glu group increased significantly compared with other groups. There was no great difference in diameter or apoptotic rate of neurospheres among each group. However, the number of neurospheres in 800 μM Glu increased significantly than that in other groups.
 

Conclusion:

NPCs express functional NMDA receptor; Calcium influx conducted by NMDA receptor activation may participate in the process that Glu promotes the proliferation of neural progenitor/stem cells.

P06 NON KETOTIC HYPERGLYCINEMIA IN 2 CHILDREN PRESENTING WITH SEIZURES

Shahnaz H.Ibrahim1, Sarwari Arif1
1 Aga Khan University, Karachi, Parkistan
Inborn error of metabolism may present with a diverse spectrum of presentations varying from episodes of hypoglycemia, lethargy to full blown sepsis. Rarely may they present with subtle or obvious neurological manifestations ranging from seizure activity to encephalopathy.

We report two cases of Nonketotic Hyperglycinemia in infants who were born with an uneventful antenatal, perinatal course and developed lethargy, respiratory difficulty and seizures. Both infants had history of one sibling death in the early neonatal period. Biochemical markers revealed raised ammonia which responded to sodium benzoate treatment. Neuro-imaging was normal in both cases while one infant had pathological EEG suggestive of hypsarrythmia and infantile spasm.

Urine for organic acidemias was negative, while glycine levels in the plasma and CSF of both infants were high, with very high ratios conclusive of Nonketotic Hyperglycinemia.

Both the infants are alive at 2 years of age, on antiepileptic medications along with sodium benzoate for elevated levels of glycine

Both the children have significant global developmental delay with microcephaly.

P07 DRAMATIC RESPONSE TO DELAYED TREATMENT IN SEVERE 6-PYRUVOYL TETRAHYDROPTERIN SYNTHASE DEFICIENCY

Sau Wei Wong1, Lai Choo Ong1, LH Ngu2, TT Liu3
1 Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
2 Institute of Paediatrics, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia
3 Department of Education and Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

Objectives:

To describe the dramatic response to delayed treatment in a patient with severe 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency misdiagnosed to have cerebral palsy and epilepsy.
 

Method:

Case description.
 

Results:

An 18 year-old boy previously diagnosed to have choreoathetoid cerebral palsy and epilepsy was assessed for recurrent ‘status epilepticus’. These episodes consisted of prolonged head version, stiffening of limbs, hypersalivation and tongue protrusion with preserved consciousness. He was born term and had history of global developmental delay. He was wheelchair bound, had dysarthria, understood simple conversation and was almost totally dependent. He had frequent admissions to another hospital for ‘status epilepticus’, was treated as intractable epilepsy and was on three anti-epileptic drugs (AED). An episode of status dystonicus and features of parkinsonism were noted in clinic. Subsequent investigations confirmed diagnosis of PTPS deficiency (elevated serum phenylalanine, absent urinary biopterin, elevated urinary neopterin, low cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid and biopterin and elevated neopterin levels). He was commenced on tetrahydrobiopterin, 5-hydroxytryptophan, l-dopa/carbidopa, pyridoxine and folate. He was later confirmed to have c.259C>T homozygous mutation of PTS gene, inherited from both parents. There was dramatic response to treatment; dystonia and parkinsonism resolved and he could walk within one month. Speech improved and he was able to read and write slowly. He continued to improve and could perform most activities of daily living independently. He is now 23 year-old, AED free and travels independently to attend cooking and handicraft classes in a training centre.
 

Conclusion:

In PTPS deficiency, the global delay, dystonia and parkinsonism could masquerade as choreoathetoid cerebral palsy, whereas status dystonicus mimics seizures. Despite delayed diagnosis and treatment, a favourable response is still possible.

P08 GLUTARIC ACIDEMIA TYPE I REVEALED BY NEWBORN SCREENING PROGRAM IN TAIWAN: EXPERIENCE IN ONE MEDICAL CENTER

Cheng-Hung Huang1,2, Ting-Rong Hsu1,2, Dau-Ming Niu1,2
1 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
2 Department of Pediatrics, Veterans General Hospital, Taipei, Taiwan

Objectives:

To review 4 cases of glutaric academia type I(GA-1) revealed by newborn screening program. They were detected during 2006 to 2009, after glutaric academia type I was enrolled in Taiwan Newborn screening Program by 2 newborn screening canters.
 

Method:

We reviewed the initial C5DC level, serum aminoacids, urine organic acid data and the results of molecular study.. We also examined the image data including brain echo and brain MRI. The prognosis and its relation with treatment were also assessed.
 

Results:

The frequency of GA-1 based on newborn screening by MS/MS was 1/72534, which is lower than in Western country. The recall rate is 0.08%. Two cases of them suffered from nystagmus after birth, which was not reported in GA-1 patients in literature. Brain echo in all cases showed bilateral multiple subependymal cysts and ventricular septums .We did brain MRI for 2 cases in less than 2 weeks –old, these images all revealed symmetric widening of bilateral sylvian fissures and bilateral frontotemporal volume loss. One case suffered from severe dystonia due to inadequate treatment during acute episodes, in other cases developmental stones were within normal range.
 

Conclusion:

We revealed the frequency of GA-1, which is similar with previous report. Brain MRI in 2 neonates showed brain atrophy in very early stage, which suggested us that glutaric acid metabolites may cause prenatal damage in brain in GA-1 cases. Early and adequate treatments for GA-1 patients during acute episodes are very important and significantly related to their prognosis.

P09 CLINICAL ANALYSIS OF METHYLMALONIC ACIDEMIA IN 14 CASES

Li Gao1, Yan-Ping Liu1, Yan Wang1, Su-Jing Xu1, Nan-Nan Huang1
1Department of Pediatrics, Henan Provincial People's Hospital, Zhengzhou, China

Objectives:

To explore the clinical characteristics and treatment of methylmalonic acidemia (MMA) in earlier period and prognosis.
 

Method:

The clinical data of 14 patients with MMA diagnosed by gas chromatography-mass spectrometry (GC/MS) were analyzed to understand management and prognosis.
 

Results:

The patients consisted of 10 males and 4 females, whose age of onset ranged from 0 to 3 months. The main clinical manifestations were developmental delay (8 cases), abnormal tonus of muscle(8 cases), vomiting and bucking (4 cases), convulsion (4 cases), lethargy (1 case), poor feeding (8 cases), dyspnea (1 case), hepatomegaly and jaundice (2 cases), anaemia, hyperammonemia and metabolic acidosis(2 cases), abnormal EEG (4 cases), etc. The laboratory findings showed remarkable elevation of urinary or blood methylmalonic acid concentration in all cases.Some abnormalities were shown by the brain MRI or CT in 14 cases and electrophysiologic study (ABR and AEP) in 7 cases. 14 cases received therapy of vitamin B12 and supplementation of carnitine with low protein diet. The follow-up was made for a period ranging from 3 months to 12 months, 4 cases recovered completely under medical therapy, in association with seizure freedom and MRI improvement.
 

Conclusion:

The clinical manifestations of MMA are nonspecific. Gas chromatography-mass spectrometry (GC/MS) is an effective method to diagnose and identify methylmalonic academia. Early diagnosis and early treatment can help improve the prognosis obviously.

P10 MUTATIONS ANALYSIS OF MMACHC GENE IN EIGHT PATIENTS WITH METHYLMALONIC ACIDEMIA AND HOMOCYSTEINEMIA

Shu-Li Chen1, Jian-Xiang Liao1, Cheng-Rong Li1, Dong Cui1, Peng-Qiang Wen1, Quan Yuan1, Yu-Hui Hu1, Ping Song1
1Department of Pediatrics, Henan Provincial People's Hospital, Zhengzhou, China

Objectives:

Methylmalonic acidemia complicated with homocystinemia, cblC type, is a disorder of vitamin B12 (cobalamin) metabolism caused by mutations in the MMACHC gene. Recently, more than 40 mutations have been found in other countries. But there were not many reports in China. Eight patients had been detected to identify the mutation types in this study.
 

Method:

Eight patients were diagnosed to methylmalonic acidemia with homocystinemia in our hospital. Gas chromatography-mass spectrometry (GC-MS) was used for urine organic acids analysis. Homocystinemia was found by serum total homocysteine determination using a fluorescence polarization immunoassay. Then, the coding region of MMACHC gene was screened by polymerase chain reaction (PCR) and DNA direct sequencing.
 

Results:

They had markedly increased urine methylmalonic acid. Serum total homocysteine also multiplied 8~30 times in seven patients. Another patient who had been dead was not detected. However, they were determined cblC disease through gene diagnosis. In this study, six mutations were found in all patients, and four mutations were located in exon 4. Respectively, the six mutations were c.609G>A, c.482G>A, c.617G>A, c.365A>T, c.658_660delAAG and c.146_154delCCTTCCTGG. The c.609G>A is the most mutation, which was detected in 5 of 15 alleles. The c.482G>A was found in two late-onset patients.
 

Conclusion:

It is common for methylmalonic acidemia with homocystinemia, cblC type in China. The clinical symptoms of patients are variety. In this study, MMACHC gene mutations were mostly in exon 4. The c.609G>A may be the hotspot mutation. The c.482G>A is probably related to late-onset patients. The c.658_660delAAG was only found in Chinese till now.

P11 THE PROGNOSIS OF THE EPILEPSY WITH ORGANIC ACIDEMIA

Takako Fujita1, Yukiko Ihara1, Yuko Tomonoh1, Hiroshi Ideguchi1, Takahito Inoue1, Sawa Yasumoto1, Shinichi Hirose1
1Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan

Objectives:

As for clinical symptoms of congenital metabolic disease, there are various symptoms such as vomiting, headache, seizure, and the developmental delay. The report is few about the prognosis of epilepsy with congenital metabolic syndrome. Therefore, we report the prognosis of the organic acidemia in our hospital.
 

Method:

We experienced seven cases of organic acidemia and the clinical course and the prognosis of epilepsy were analysed in the cases with seizure.
 

Results:

We experienced four methylmalonic acidemia, one propionic acidemia, one glutaric aciduria type Ⅱ and one isovaleric acidemia. One case affected with seizure, two cases hypotonia/developmental delay and four cases vomiting/respiratory disturbance. Three cases had seizure problems; one being febrile seizure, the other two being epilepsy. Prognosis of epilepsy was good in both cases. They had various degrees of developmental delay.
 

Conclusion:

The half of cases had seizure, but a few cases complicated epilepsy. The prognoses of epilepsy were good. It was suggested that early diagnosis and treatment of the metabolic diseases take part in preventing the complication of the epilepsy and poor prognosis.

P12 ELECTROENCEPHALOGRAM AND TRANSCRANIAL DOPPLER ULTRASONOGRAPHY IN NEONATAL CITRULLINEMIA

Inn-Chi Lee1,2,3, Pen-Hua Su2,3, Jui-Ming Hu2,3, Yan-Yan Ng2,3, Jia-Yuh Chen2,3, Yung-Jung Chen4
1Department of Pediatric Neurology, Chung Shan Medical University Hospital, Taichung, Taiwan
2Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan
3 School of Medicine, Chung Shan Medical University, Taichung, Taiwan
4Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan

Objectives:

We studied a first-reported case with genotype of argininosuccinate synthetase (ASS1) mutations, c.380G>A (p.R127Q)/ c.380G>A (p.R127Q) in two alleles by a series of electroencephalograms and real-time transcranial Doppler ultrasonography.
 

Patient and Methods:

The newborn presented with status epilepticus and coma at 3 days old. The laboratory data showed hyperammonemia and marked lactic acidosis in the blood and cerebral spinal fluid.
 

Results:

An electroencephalogram on day 3 showed severe suppression of cerebral activity and focal paroxysmal volleys of slow and sharp waves (< 1 Hz) over the left hemisphere, which returned to normal after blood exchange transfusion and peritoneal dialysis at 15 days of age. Real-time transcranial Doppler ultrasonography showed a brain edema at day 3, high peaked systolic and low diastolic flows in basal, anterior, and middle cerebral arteries, which registered lower systolic and higher diastolic flows immediately after a blood exchange transfusion. The resistance indices were significantly different (mean resistance indices of 0.58 vs. 0.37; P = 0.01)
 

Conclusion:

Electroencephalogram and transcranial Doppler ultrasonography can be used to monitor the efficacy of a blood exchange transfusion at the metabolic crisis and neurological status, showed a significant improvement in blood flow after half a dozen full-volume blood-exchange transfusions.

P13 USING NEONATAL CONTINUOUS HAEMODIALYSIS TO PREVENT HYPERAMMONAEMIC ENCEPHALOPATHY

Ryutaro Kinoshita1, Makoto Tsutsumi1, Eiji Ohta1, Masatoshi Nakamura1, Sawa Yasumoto1, Shinichi Hirose1, Yoshitugu Shirakawa2, Hayato Matsumoto2
1ivision of Neonatology, Center for Maternal Fetal and Neonatal Medicine, Fukuoka University Hospital, Fukuoka, Japan
2Division of Pediatrics and Neonatology, Fukuoka Shin Mizumaki Hospital, Onga, Japan

Objectives:

We record EEG and MRI findings for a hyperammonemia patient and report his neurological development.
 

Case report:

The patient is a male born at 35 weeks with a low birth weight of 2,254g. On his second day after birth he was in poor condition and was hospitalized with apnea. Laboratory examinations showed hyperammonemia (NH3 >2480ug/dl) and metabolic acidosis. GC/MS and MS/MS tests indicated his orotic acid was normal, an unexpected result when an organic acid metabolism disorder is suspected. Our diagnosis was CPS (carbamoyl phosphate synthetase) deficiency. After hospitalization, the patient began convulsing and we performed an EEG, which showed a suppression-burst pattern indicating a severe abnormality. As a treatment for hyperammonemia, we did an exchange blood transfusion, but it was ineffective. We then began continuous haemodialysis (CHD), and normalized the patient’s ammoniacal value. After four days of CHD, there were no subsequent hyperammonemia attacks. One month later, a head MRI indicated no abnormalities; similarly, an EEG done at two months showed neither paroxysms nor suppression-bursts. At 18 months, the boy’s neurological development was normal, without convulsions or EEG irregularities.
 

Conclusion:

Electroencephalogram and transcranial Doppler ultrasonography can be used to monitor the efficacy of a blood exchange transfusion at the metabolic crisis and neurological status, showed a significant improvement in blood flow after half a dozen full-volume blood-exchange transfusions.

P14 A CASE OF GLYCOGEN STORAGE DISEASE SIMILAR TO MELAS

Young Ok Kim1, Young Jun Son1, Young Jong Woo1, Si Un Lee1, Eun Young Kim2, Young Il Roh3
1Department of Pediatrics, Chonnam National University Medical School, Gwangju, Korea
2Department of Pediatrics, Gwangju Christian Hospital, Gwangju, Korea
3 Department of Pediatrics, Chosun University Hospital, Gwangju, Korea

Objectives:

Lactic acidosis with mental confusion in children who had failure to thrive and similar family history can resulted in suspicion of inherited disorders such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and glycogen storage disease type Ia (GSD Ia).
 

Methods:

A 12-year-old girl was admitted in stuporous mental state following dyspnea. Her height and weight were both below 3 percentile. Physical examination revealed hepatomegaly and multiple old bruise on lower extremities. Her older brother also had easy brusing tendency, frequent epistaxis, short stature and hepatomegaly.
 

Results:

Laboratory exam in blood revealed increased lactate (over 12 mmol/L) and lactate versus pyruvate ratio (49.5); anemia; increased total/LDL-cholesterol (295/121 mg/dL) and triglyceride (1314 mg/dL); and uric acid (10.5㎎/㎗) in addition to proteinuria. The brain CT showed bilateral multifocal calcifications in basal ganglia, thalami, cerebellum and cerebral subcortical white matter. Evaluation for her brother also showed similar abnormalities. Glucose-6-phosphatase catalase unit gene was analyzed in two sibilings, which showed the same heterozygous mutation (P178A and G222R).
 

Conclusion:

We reported a case of GSD Ia in need of differential diagnosis with MELAS, because she had similar presenting findings with MELAS (encephalopathy, lactic acidosis, short stature, and basal ganglia calcification). But she and her brother had different characteristics from MELAS: hepatomegaly, easy bruise, frequent epistaxis, hyperuricemia, and marked increased level of triglyceride. She and her brother had got treatment of dietary therapy and allopurinol medication. And then, they were transferred to other hospital for liver transplantation.

P15 EFFECTIVENESS OF MODIFIED ATKINS DIET FOR 5 PATIENTS WITH GLUT1 DEFICIENCY SYNDROME

Yasushi Ito1, Hirokazu Oguni1, Susumu Ito1, Miyako Oguni1, Makiko Osawa1
1Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan

Objectives:

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a treatable metabolic encephalopathy resulting from impaired glucose transport into the brain. We investigated the effectiveness of modified Atkins diet (MAD) for 5 patients with GLUT1-DS.
 

Methods:

MAD was tried for 5 male patients with GLUT1-DS. Ages at starting MAD ranged from 7y4m to 16y9m. Duration of MAD treatment ranged from 1 to 33 months (mean; 15 months). In two patients, MCT-ketogenic diet (2:1) was changed to MAD because the latter was less restricted in total proteins and calories. The seizure frequency, neurological status, EEG background activities were compared before and after the introduction of MAD. This study was approved by the Ethics Committee of Tokyo Women's Medical University and informed consent was obtained from all patients.
 

Results:

All patients produced 2+ to 3+ urinary ketosis by ketostick test checking in the morning before breakfast. Epileptic seizures either decreased remarkably in number or ceased completely in all patients. The interictal EEG examination showed improvement of the background activity, and a disappearance of epileptic discharges. Although other neurological manifestations such as ataxia, spasticity, dysarthria and dystonia were not sufficiently improved, their aggravation mostly observed before meals disappeared after the introduction of MAD. Along with an increased vigilance level, motivation and cognitive function appeared to be better. There was no significant side effect.
 

Conclusion:

As compared to the conventional ketogenic diet, MAD is less restrictive to the total protein and calories, and palatable. The effectiveness of MAD was comparable to that of conventional one. Therefore, MAD is very acceptable for patients and their family to continue for a long time.

P16 WHITE MATTER ABNORMALITIES IN GLUT1 DEFICIENCY SYNDROME: A DIFFUSION TENSOR IMAGING STUDY WITH SPM

Tomohiko Nakata1, Jun Natsume1, Tatsuya Fukasawa1, Yoshiteru Azuma1, Tamiko Negoro1, Keiko Yanagihara2, Kazuyoshi Watanabe3
1Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
2Department of Developmental Infectious Disease, Osaka Medical Center and Research Institute for Material and Child Health, Osaka, Osaka, Japan
3 Faculty of Medical Welfare, Aichi Shukutoku University, Nagoya, Aichi, Japan

Objectives:

GLUT1-DS (glucose transporter type 1 deficiency syndrome) is a disorder of brain energy metabolism and leads to seizures with infantile onset, a movement disorder, mental impairment. Although neuroimaging is considered uninformative in GLUT1-DS, some case reports have indicated its white matter abnormalities. We attempted to determine whether diffusion tensor imaging (DTI) can detect fine white matter abnormalities in a patient with GLUT1-DS.
 

Methods:

We studied a 3-year-old girl who exhibited seizure at 2 months of age and was diagnosed GLUT1-DS at 3 years of age based on her clinical features, hypoglycorrhachia and reduced erythrocyte glucose uptake. Fractional anisotropy (FA) map was created from DTI and compared with those from 10 normal controls by using statistical parametric mapping (SPM). A significant cluster was defined as a cluster with a height p=0.005 and an extent threshold 50 voxels.
 

Results:

This patient showed delayed myelination on T2-weighted images at 12 months of age and high T2-signal of left parietal subcortical white matter at the age of 3 years. Analysis with FA map revealed decreased FA values in bilateral posterior limbs of internal capsules, deep white matter lesion around lateral cerebral ventricles and genu of corpus callosum.
 

Conclusion:

Analysis with FA map pointed out white matter abnormalities that conventional MRI images failed to detect. This finding suggests that a disorder of brain energy metabolism may relate to white matter abnormalities in the structure or myelination extending beyond the conventional MRI-visible lesion.

P17 FDG-PET IN GLUT1 DEFICIENCY SYNDROME: COMPARISON OF PATIENTS WITH AND WITHOUT DECREASED ERYTHROCYTE GLUCOSE UPTAKE

Jun Natsume1, Yoshiteru Azuma1, Hirokazu Kurahashi1, Tomohiko Nakata1, Naoko Ishihara1, Akihisa Okumura2, Keiko Yanagihara3, Kazuyoshi Watanabe4
1Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
2Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan
3 Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan
4Aichi Shukutoku University, Aichi, Japan

Objectives:

Glucose transporter type 1 deficiency syndrome (Glut1-DS) is diagnosed by reduced CSF glucose level (hypoglycorrhachia) and impaired glucose uptake into erythrocytes. However, we have experienced patients with hypoglycorrhachia and normal erythrocyte glucose uptake. We performed FDG-PET in patients with hypoglycorrhachia, and compared the PET in patients with and without decreased erythrocyte glucose uptake to assess the difference of metabolic patterns in these two conditions.
 

Methods:

We studied 5 patients with hypoglycorrhachia, who were suspected to have Glut1-DS. Erythrocyte glucose uptake was reduced in 3 of 5 patients. We divided the patients into 2 groups: patients with decreased erythrocyte glucose uptake (Group 1) and patients with normal erythrocyte glucose uptake (Group 2). FDG-PET was performed and analysis was carried out using SPM to compare the PET image of each patient with 11 controls. A significant cluster was defined as a cluster with a height p = 0.001 and an extent threshold 100.
 

Results:

Decreased uptake in bilateral thalami was observed in all patients of Group 1 and one of two patients in Group 2. Relatively increased uptake in bilateral basal ganglia was seen in all patients of Group 1 and Group 2. Cortical abnormalities were variable.
 

Conclusion:

Similar cerebral glucose uptake pattern was seen in patients with or without decreased erythrocyte glucose uptake. It suggests that patients without decreased erythrocyte glucose uptake may also have deficiency of Glut1 in central nervous system.

P18 WEST SYNDROME ASSOCIATED WITH NEONATAL HYPOGLYCEMIC BRAIN INJURY

Sawa Yasumoto1, Noriko Nakamura1, Yuko Tomonoh1, Yukiko Ihara1, Hiroshi Ideguchi1, Takahito Inoue1, Toshiko Mori1, Shinichi Hirose1
1Fukuoka University, Fukuoka, Japan

Objectives:

We herein report a case of West syndrome associated with neonatal hypoglycemic brain injury.
 

Methods:

We report the clinical features of a 9-month-old boy and analyze his MRI and EEG findings since neonatal period.
 

Results:

Clinical features show the patient born from a mother with toxemia at term. One day after birth, he suffered from neonatal seizures and intractable hypoglycemia (<10mg/dl), caused by hyperinsulinemia. It took over 24 hours to normalize blood glucose. From birth to the age of 9 months, he developed psychomotor retardation with visual disturbances. After that, he suffered from tonic spasms which appeared daily in a series. When the patient was two weeks old, MRI showed T2 prolongation in the white matter of bilateral parieto-occipital lobes. EEG showed hypsarrythmia with occipital paroxysms. Clonazepam combined with zonisamide was effective for tonic spasms and improved his psychomotor development. However epileptic seizures increased after he was 1 year old and EEG findings worsened. His family did not want the ACTH therapy and gabapentin was added on the previous medication. At two year of age, he had left severe psychomotor retardation, though clinical seizures had decreased.
 

Conclusion:

Burns et al (2008)reported twelve patients developed epilepsy caused by neonatal hypoglycemic brain injury. Three cases of them had infantile spasms. Severe neonatal symptomatic hypoglycemia with cerebral lesions is a risk factor for West syndrome.

P19 THREE AUTOPSY CASES OF UNIQUE BRAIN ANOMALY SUFFERING FROM REPETITIVE HYPOGLYCEMIC ATTACKS

Naho Miwa1, Naoyuki Tanuma1, Masaharu Hayashi2
1Department of Pediatrics, Tokyo Metropolitan Fuchu Medical Center for the Disabled, Tokyo, Japan
2Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan

Objectives:

In the patients with developmental brain disorders, attacks of hypoglycemia (HG), indiscernible from epileptic seizures, can occur in the absence of pancreas disorders and congenital metabolic errors occasionally. In order to clarify pathogenesis of such HG attack, we examined three autopsy cases of unique brain anomaly showing repetitive HG attacks.
 

Methods:

Case 1 of diffuse cortical dysplasia, a 42-year-old male, developed generalized convulsion in infancy, and suffered from repetitive HG attacks between the ages of 27 and 38. Endocrine and metabolic tests failed to demonstrate abnormalities. Case 2 of megalencephaly and hydrocephalus, a 4-year-old boy, had a reduced subcutaneous adipose tissue, growth failure and frequent HG attacks. He lacked epileptic seizures, and endocrine and metabolic tests failed to demonstrate abnormalities. Case 3 of Arima syndrome with molar tooth sign on MRI, an 11-year-old female, suffered from renal failure at 9 years, but she did not show epileptic seizures. She developed HG attacks before death, which vanished after replacement of carnitine.
 

Results:

Three cases demonstrated no abnormalities in the pancreas, liver, endocrine organs including the hypophysis or hypothalamus at autopsy, although the pancreas was not examined in case 3.
 

Conclusion:

HG seemed to be caused by the reduction of carnitine in case 3. On the other hand, the cause of HG was not determined even by pathological analysis in cases 1 and 2. Interestingly HG attacks occurred for a limited period in case 1. The further immunohistochemical study will be performed in the pancreas, endocrine organs and hypothalamus in cases 1 and 2.

P20 GENOTYPIC PHENOTYPIC CHARACTERISTIC OF GALACTOSEMIA IN THE POST NEONATAL AGE IN INDIA

Harshuti Shah1, Zachary Grinspan2
1Rajvee Child Neuro Hospital, Ahmedabad, India
2Department of Child Neurology, Columbia University, New York, United States

Summary:

Classical Galactosemia is an inborn error of metabolism, which manifests in neonatal age group. Treatment with galactose free diet in neonatal age group, leads to symptom free outcome. In developing countries, lack of compulsory neonatal screening programmme and lack of awareness leads to delay in diagnosis resulting in permanent neurological handicap
 

Abstract:

Classical Galactosemia is an inborn error of galactose metabolism caused by a deficiency of the enzyme Galactose-1-phosphate uridyl transferase leading to significant neurological impairment. In Indian population, incidence, phenotypic characteristics are less known .The present study shows the current phenotypes in Indian population with striking findings because of delayed diagnosis associated with neurological impairment. They were followed up for one year or more with galactose free diet. We describe a cohort of 21 patients diagnosed by assay of galactose -1-phosphate uridyl transferase. Age at diagnosis was 6 months to 14 years with male preponderance. 20 patients demonstrated delay in developing motor milestones.18 had hypotonia and 2 had hypertonia. 4 had extra pyramidal movements. 13 patients failed to develop language, 5 had dysarthria. 9 patients had epilepsy. 9 patients had neurobehavioral problems, 16 patients had a history of prolonged neonatal jaundice with or without sepsis. Of 7 patients who underwent MRI, five had abnormalities. The EEG tracings of 9 patients showed epileptiform abnormalities. Of 18 patients convinced for identifying mutation, 14 were diagnosed to have identifiable mutation. 9 patients were identified of having LA variant of GALT enzyme and rest were durate variant. All patients of galactosemia maintained on galactose free diet were followed for 1 year or more but there was no significant neurological improvement. Our observation reminds us of the severe consequences of treatable metabolic disorders due to delayed diagnosis and futility of galactose free diet for neurological outcome once the damage has set in.

P21 A CASE OF A CHILD WITH CARNITINE DEFICIENCY

Ung Ninh Thi1
1National Hospital of Pediatrics, Hanoi, Viet Nam

Objective:

To report a case of carnitine deficiency in a girl aged 26 months.
 

Methods:

Case study.
 

Results:

A 26-month girl is the second child with a past history of preterm 38 weeks gestation, 2200 gram at birth. The first child boy is also preterm and development delay. Patient presented with developmental delay, central nervous system dysfunction, hypotonia, and progressive proximal weakness. Metabolic decompensation was triggered by viral illness with rigid neck, right orbicularis weakness, hyperreflexia, failure to thrive. Cerebrospinal fluid biochemistry, microbiology and cytology, and MRI of the brain were normal. Other laboratory findings included: glycemia 4,6mol/L, lactic acid 4 mmol/L, NH3 110Mmol/L, LDH 361 u/L, AST: 43U/L, and ALT: 27U/L.Tandem mass spectrometry analyses showed a decrease in free carnitine. Total acylcarnitine was also decreased. 3-OH isobutyrate was elevated slightly, and glycerol and glycerate were also elevated. Metabolic decompensation was progressive with apnea and coma.
 

Conclusion:

A girl of carnitine deficiency with onset at early 26 months presented with encephalopathy, myopathy with motor delay.

P22 CLINICAL CHARACTERISTICS OF EPILEPSY WITH HUNTER SYNDROME

Kenjiro Kikuchi1,3, Shin-ichiro Hamano1, Reiko Koichihara1, Manabu Tanaka1, Motoyuki Minamitani1, Tomotaka Oritsu1,3, Hiroshi Mochizuki2, Hiroyuki Ida3
1Division of Neurology, Saitama Children’s Medical Center, Saitama, Japan
2Division of Endocrinology and Metabolism, Saitama Children’s Medical Center, Saitama, Japan
3Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan

Objective:

There are few reports concerning epilepsy in Hunter syndrome. The aim is to evaluate the clinical characteristics of epilepsy in Hunter syndrome.
 

Methods:

The study included 17 patients with Hunter syndrome. We divided the patients into two groups: epilepsy group (4 patients) and non-epilepsy group (13 patients). Two groups were compared about clinical manifestations, and we described the clinical course of epilepsy in epilepsy group.
 

Results:

Mental retardation was found in three of four patients (75%) in epilepsy group, whereas in 5 of 13 (46.2%) in non-epilepsy group, but there was no statistical difference (p=0.24). The ratio of using wheeled chair in epilepsy group was higher than in non-epilepsy group (p<0.05). There were no differences about cardiac manifestation, respiratory disability, deafness. Patients of the epilepsy group had seizures at the age of 13.1 ± 3.3 (average ± SD) years old, and they had died at the age of 17.5 ± 1.8 (average ± SD) years old. Three of them had tonic seizures which were controlled well by within 2 anticonvulsants, but one had refractory myoclonic seizure. Abnormal MRI findings were not observed except hydrocephalus.
 

Conclusion:

The frequency of epilepsy in Hunter syndrome was higher than previous reports, and was associated with using wheeled chair. We could not found the relationship between epilepsy in Hunter syndrome and mental retardation. Epileptic seizures in the patients with Hunter syndrome were tended to be controlled by a few anticonvulsants.

P23 A GROSS DELETION OF ARYLSULFATASE B IDENTIFYING IN A TAIWANESE PATIENT WITH MUCOPOLYSACCHARIDOSIS TYPE VI

Wei-De Lin1, Yu-Yuan Ke2, Chung-Shing Wang3, Fuu-Jen Tsai3,4, I-Ching Chou3,5
1Department of Medical Research, China Medical University, Taichung, Taiwan
2Department of Pediatrics, Changhua Christian Hospital, Changhua, Taiwan
3Children's Medical Center, China Medical University Hospital, Taichung, Taiwan
4Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan
5Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan

Objective:

Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome) is an autosomal recessive lysosomal storage disease induced by a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase (arylsulfatase B, ARSB). The deficiency of ARSB leads to an accumulation of dermatan sulfate (DS) in lysosomes and gross excretion in the urine. The diagnosis is usually made in early childhood when organomegaly, corneal clouding, coarse features, enlarged tongue, frequent respiratory illness or otitis media, and joint stiffness are all apparent. Other complications include hearing loss, chronic respiratory tract infections, sleep apnea, pulmonary hypertension, hydrocephalus, rapid-onset blindness, and cardiac valve insufficiency or stenosis. In this study, an unusual ARSB gene deletion mutation type in a Taiwanese MPS VI patient was demonstrated.
 

Methods:

To validate the patient’s type of MPS, urine mucopolysaccharide was defined by two-dimensional electrophoresis and leukocyte ARSB activity was determined by fluorogenic assay. One MPS VI Taiwanese patient was investigated. Direct sequencing was used to identify any mutation in the patient’s ARSB gene. Total RNA isolated from the patient’s blood sample and performed reverse transcription-polymerase chain reactions (RT-PCR) to identify exon deletion.
 

Results:

Abnormal excretion of DS and low leukocyte ARSB activity was observed in the urine sample of the patient studied. No mutation was found after direct sequencing of her ARSB gene except exon 4 region which could not be amplified by PCR. The result of RT-PCR revealed that her exon 4 of ARSB was deleted mutation in mRNA level.
 

Conclusion:

The results of this study suggest that an unusual ARSB gene mutation exist in Taiwanese MPS VI patients. Therefore, ARSB gene profiling may be useful in genetic counseling for families affected by MPS VI.

P24 A METACHROMATIC LEUKODYSTROPHY (MLD) PATIENT’S LONG-TERM FOLLOW UP: NEUROLOGIC AND EXTRA- NEUROLOGIC COMPLICATIONS

Takahito Inoue1, Michitaka Yonekura1, Takako Fujita1, YukikoIhara<1, Sawa Yasumoto1, Shinichi Hirose1, Shiho Kodama2, Sachio Takashima3
1Department of Pediatrics, Fukuoka University, School of Medicine, Fukuoka, Japan
2Department of Pathology, Fukuoka University, School of Medicine, Fukuoka, Japan
3 International University of Health and Welfare Graduate School, Fukuoka, Japan

Objective:

To describe complications in a metachromatic leukodystrophy (MLD) patient’s long-term follow up. Background: MLD is a demyelinating genetic disorder characterized by the absence of the enzyme arylsulfatase A (ASA); this absence causes the toxin sulfatide to accumulate in the cells, especially in the nervous system. We report here on an MLD patient receiving home care.
 

Case:

The patient is a 12 year old girl who developed status epilepticus (diagnosed by brain imaging and ASA measurement); at age four, she began having convulsive attacks which caused psycho-motor deterioration. During the next year, she presented progressive difficulty in walking and developed leg stiffness; she was unable to sit or stand. In addition, she developed hypertonia, and this gradually affected her respiratory system, gastroesophageal reflux and nutritional intake. For the next five years, a slowly progressing visual impairment and auditory and speech disorders made communication difficult. At age ten, she was in a vegetative state and was given emergency surgical treatment to puncture her tumorous gallbladder and remove fluids from it. She died two years later at age 12. Death was caused by an intestinal obstruction which resulted from the developing tumors in the gallbladder and by multiple organ dysfunction.
 

Results:

Convulsive attacks, hypertonia, and gallbladder involvement (neurologic and extra-neurologic complications) in an MLD patient’s long-term follow up not only increased the suffering of patient, but also added to the burden of caregiver, particularly by causing repeated hospitalization and discharge.
 

Conclusion:

Convulsive attacks, hypertonia and gallbladder involvement in MLD cause serious problems and should be recognized as important MLD complications. For the convulsive attacks and hypertonia, early stage drug therapy is indispensable and early surgical treatment is essential for the gallbladder involvement, as later, invasive procedures, endanger the weakened patient. These therapeutic procedures will contribute to an improved quality of living for the MLD patient.

P25 LATE-ONSET KRABBE’S DISEASE WITH HYPOPHOSPHATEMIC RICKETS AND FOCAL STATUS EPILEPTICUS

Derrick Wei-Shih Chan1, Ee-Shien Tan2, Maureen Cleary2,4, Fabian Kok-Peng Yap3
1Neurology Service, KK Women’s and Children’s Hospital, Singapore
2Metabolic Service, KK Women’s and Children’s Hospital, Singapore
3Endocrine Service, KK Women’s and Children’s Hospital, Singapore
4Great Ormond Street Hospital, London, United Kingdom

Objective:

Krabbe’s disease is a lysosomal storage disorder with neurological regression and leukodystrophy on MRI brain. The late-onset variant is rarer (10-15%) and has a clinically heterogenous phenotype. We report a child with late-onset Krabbe’s disease and hypophosphatemic rickets who developed focal status epilepticus and subsequent focal epilepsy.
 

Methods:

This is a retrospective case report.
 

Results:

We describe a child with underlying hypophosphatemic rickets who presented aged 6 years old with progressive motor and cognitive regression. Magnetic resonance imaging of the brain showed leukodystrophy and analysis of galactosylceramidase GALC supportive of Krabbe’s disease.
 

Conclusion:

Late-onset Krabbe’s disease and hypophsophatemic rickets are individually rare. This is the first description of a patient with both clinical entities. Focal status epilepticus and seizures are recognised in Krabbe’s disease and can be medically intractable.

P26 PROGRESSIVE MYOCLONUS EPILEPSY DUE TO GAUCHER DISEASE TYPE 3 WITHOUT HEPATOSPLENOMEGALY

Norimichi Higurashi1,2, Shin-ichiro Hamano2, Hiroyuki Ida2, Asako Tajima3, Toya Ohashi3
1Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan
2Division of Neurology, Saitama Children’s Medical Center, Saitama, Japan
3Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan

Objective:

Gaucher disease type 3 (GD3) is characterized by progressive myoclonus epilepsy and prominent hepatosplenomegaly. GD3 without hepatosplenomegaly has been rarely reported.
 

Methods:

To extend phenotypic spectrum of GD3, we report a female patient with GD3 who did not present hepatosplenomegaly.
 

Results:

This patient was born to nonconsanguineous parents suffered a convulsion at age one year. EEG and brain CT showed normal results. Her growth and psychomotor development were normal before onset of typical absence seizures at age five years six months. Although absences disappeared on multiple antiepileptic agents at age seven years 11 months, diffuse spike-waves and focal (poly-)spikes frequently appeared on interictal EEG. Generalized tonic-clonic seizures developed at age nine, and action tremor, ataxia, erratic myoclonus, and ophthalmoplegia at 12. These symptoms were progressively aggravated. Somatosensory evoked potential test at age 14 showed giant reactions. Although neither hepatosplenomegaly nor cherry-red spot were noted, lipid-accumulated bone-marrow macrophages were identified at age 16. Detailed examinations revealed reduction of leukocyte beta-glucosidase activity (less than 17 percent of normal control) and missense mutations in each allele of beta-glucosidase gene. One mutation, N188S, had been previously reported as a causative mutation for GD3, despite 67 percent of residual enzyme activity. The other was a novel mutation, G199D, later revealed to be null mutation. Even when she was admitted to our hospital at age 18 because of aggravation of seizures, hepatosplenomegaly was not observed.
 

Conclusion:

It is of clinical importance to consider GD3 when patients present progressive myoclonus epilepsy even without hepatosplenomegaly.

P27 A CASE OF TAY-SACHS DISEASE WITH CLUSTERS OF SUBCLINICAL SEIZURES

Motomasa Suzuki1, Koichi Maruyama1, Hirokazu Kurahashi1, Toshiyuki Kumagai1, Kazuyoshi Watanabe2
1 Department of Pediatric Neurology, Aichi Welfare Center for Persons with Developmental Disabilities, Kasugai, Japan
2Aichi Shukutoku University, Aichi, Japan

Background:

We report a 22–month-old boy with Tay-Sachs disease, who showed clusters of electrical seizures without clinical manifestation. Although seizures almost invariably occur after 1-year-of-age in patients with Tay-Sachs disease, clusters of subclinical seizures have not been reported.
 

Case report:

He appeared normal at birth. He visited our hospital because of developmental delay when he was 15 months old. Physical examination revealed hypotonia, loss of head control, exaggerated startle response to sound. His hypotonia progressed and his fundus examination revealed cherry red spot. His cranial MRI showed high intensity in the bilateral basal ganglia, irregular high intensity area in bilateral thalamus and high intensity areas in deep white matter on T2-weighted imaging. He was diagnosed with Tay-Sachs disease because of deficiency of hexosaminidase A (20.1 nmol/mg P/hr, normal range of 153-371 nmol/mg P/hr). He developed the first febrile seizure at 13-month-old-of-age and the first afebrile seizure at 16-months-old-of-age. Seizures were characterized by twitchings of eyelids and clonic movements of limbs lasting for about 30 seconds. Phenobarbital was started. His EEG at 19-month-old showed repetitive bilateral anterior-temporal spikes without ictal discharges. His EEG at 22-month-old revealed ictal discharges of rhythmic sharp wave bursts originating from the left frontal/anterior-temporal or posterior-temporal region. Although some of ictal discharges were associated with staring eyes with eyelid twitchings, most of them were electrical seizures without clinical manifestations. The dosage of phenobarbital was increased.
 

Conclusion:

We presented the first report of a patient with Tay-Sachs disease with clusters of subclinical seizures. Although it remains unknown whether electrical seizures without clinical manifestations are common in patients with Tay-Sachs disease, it can be useful to record EEG to detect subclinical seizures, even if they do not display any apparent clinical seizures.

P28 SERIAL MR IMAGING AND 1H-MR SPECTROSCOPY IN MONOZYGOTIC TWIN WITH MILD INFANTILE TAY - SACHS DISEASE

Asuka Iwai1, Atsushi Imamura1, Ryosuke Miura1, Atsushi Terazawa1, Reiko Ito1, Koji Orii1,2
1Department of Pediatrics, Gifu Prefectural General Medical Center, Gifu, Japan
2Orii Clinic, Gifu, Japan

Objectives:

Tay-Sachs disease is an autsomal recessive neurodegenerative disorder of ganglioside metabolism with a deficiency of hexosaminidase A (Hex A), an enzyme involved in the metabolism of gangliosides, causes an accumulation of GM2 ganglioside in neurons and impairment of neuronal function. We have performed serial MR imaging (MRI) and 1H-MR Spectroscopy (1H-MRS) in monozygotic siblings with early onset Tay-Sachs disease manifesting a mild phenotype, and discuss the evaluation of neuronal damage in these two cases.
 

Cases:

Five-year-old monozygotic female twin who neurological deterioration and visual agnosia were appeared at 2 years of age. Biochemical measurements of lysosomal enzyme activity with leucocytes showed decreased Hex A in them, therefore, they were diagnosed as having infantile Tay-Sachs disease. The sister showed similar slowly progressive clinical symptoms and deterioration; however the younger sister also demonstrated intractable seizure in the right leg. Head circumference was not enlarged in them. MRI demonstrated bilateral hyperintense signal changes in the periventricular white matter on T2-weighted and FLAIR weighted images, however no signal changes in the basal ganglia in either twin. The ratio of N-acetylaspartate (NAA)/creatine (Cr) was decreased in the both white matter lesions and corpus striatum. The lactate peak was seen in left basal ganglia of the younger sister. Serial MRI and 1H-MRS were performed at three times, 2, 3 and 4 years of age, respectively. Brain atrophy was progressed and the ratio of NAA/Cr was gradually decreased in the twin. They were bed-ridden at 30 months; however they need neither tracheotomy nor hospitalization, even now. They had a putative Gln390Pro mutation; however another mutation had not been identified in Hex A gene.
 

Conclusion:

Changes in metabolites on 1H-MRS were closely linked to the clinical features of the twin. Serial study by 1H-MRS is useful for the metabolic evaluation of neuronal tissue in children with Tay-Sachs disease.

P29 LONG-TERM PROGNOSIS FOR A CASE OF NEURONAL CEROID-LIPOFUSCINOSIS WITH EPILEPSY AND SICK SINUS SYNDROME

Yukiko Ihara1, Yuko Tomonoh1, Noriko Nakamura1, Takako Fujita1, Hiroshi Ideguchi1, Takahito Inoue1, Sawa Yasumoto1, Shinichi Hirose1
1Department of Pediatrics, Fukuoka University, Faculty of Medicine, Fukuoka, Japan

Objectives:

We report a rare case of juvenile neuronal ceroid-lipofuscinosis (JNCL, CLN3) with epilepsy and sick sinus syndrome (SSS) to show that NCL lipopigment accumulates within neurons and other cells, suggesting a multisystemic distribution. NCL is characterized by progressive loss of vision, seizures, and loss of cognitive and motor functions, but it is rarely associated with arrhythmia, SSS.
 

Case report:

The patient is a 33-year-old male with a history of visual disturbances beginning when he was six. At that age, his bilateral optic nerves showed atrophy and he had chronic seizures and myoclonus. At eight, he began antiepileptic drug treatments. His EEG showed irregular diffuse high voltage spikes and waves; his head MRI revealed diffuse high intensity areas in the bilateral insular cortex, and ventricles marked by diffuse dilatation. Skin and muscle biopsy revealed variations in fiber size and increased acid phosphatase positive granules. We diagnosed ceroid-lipofuscinosis. The patient also showed progressive mental retardation and retrogression. At 24, his face was pallid and he suffered from loss of appetite, consciousness disturbances, and bradycardia. An ECG showed complete A-V block and sinus bradycardia; echocardiography showed his wall motion was not asynergic, and that there were no organic changes. We performed emergency pacing and pacemaker implantation. After that, he had no cardiac problems, but he is unable to communicate and cannot perform daily tasks without assistance now.
 

Conclusion:

Hoffman IL et al. (2001) reported a heart pathology revealed at autopsy by myocardial and valvular storage of lipopigments which were observed histologically and confirmed ultrastructually. We suggest a similar mechanism (valvular storage of lipopigments) as the origin of our patient’s SSS mechanism.

P30 CLINICAL EVALUATION OF LEIGH ENCEPHALOPATHY IN 4 PEDIATRIC CASES

Reiko Koichihara1, Shin-ichiro Hamano1, Manabu Tanaka1, Kenjiro Kikuchi1, Tomotaka Oritsu1, Motoyuki Minamitani2
1Department of Neurology, Saitama Children's Medical Center, Saitama, Japan
2Department of Development and Health Care, Saitama Children’s Medical Center, Saitama, Japan

Objectives:

To report clinical and imaging characteristics of phenotype of epilepsy, EEG and neuroradiological findings in Leigh syndrome diagnosed in early childhood.
 

Methods:

We reviewed the clinical, EEG and neuroradiological features of the patients diagnosed with Leigh syndrome in Saitama Children’s Medical Center from 2003 to 2009.
 

Results:

The 4 children (1 male and 3 female) were enrolled in this period. The mean age of onset was 6.25 months (range: 4-8months). They are diagnosed by clinical criteria based on the combination of neurological features and elevated lactic concentration with characteristic MRI features in basal ganglia. The 8993T>G mtDNA mutation was detected in two patients. Epilepsy was observed in three patients. Two of them demonstrated infantile spasms with hypsarrhythmia with focal epileptic discharge on EEG and their brain MRI showed signal changes on bilateral lenticular nucleus and brain stem. One case showed signal changes on subcortical gray matter of frontal and occipital lobes in MRI and hypoperfusion of frontal lobe in SPECT. Another case without infantile spasms showed partial and myoclonic seizures with thalamus signal changes on MRI without basal ganglia abnormalities.
 

Discussion:

Previous reports suggested an important role of focal cortex, lenticular nucleus and brain stem in pathogenesis of infantile spasm through their PET results. In our study, the patients with infantile spasms demonstrated abnormal MRI signal changes on lenticular nucleus and brain stem, and their focal cortical lesions were also suggested from the results of EEG, MRI or SPECT.

P31 A CASE OF NEONATAL CONVULSION WITH PERSISTENT HYPERLACTATEMIA: LEIGH SYNDROME WITH HETEROPLASMIC MUTATION FOR MT-ND5 GENE

Bosco Chan1, Kwak Yin Chan1, Kin Cheong Yau1, Kam Ming Au2, Yuet Ping Yuen2, CM Mak2, PLS Chen2, Che Kwan Ma3
1 Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China
2 Department of Chemical Pathology, Princess Margaret Hospital, Hong Kong, China
3 Department of Paediatrics and Adolescent Medicine, United Christian Hospital, Hong Kong, China

Case History:

A 19-day-old full term baby girl who was previously well was admitted to neonatal unit because of convulsion. Physical examination was unremarkable. Investigations included sepsis screening, CT brain and EEG were normal. She was noted to have persistent metabolic acidosis and hyperlactatemia with serum lactate level over 7mmol/L. CSF lactate was 4.6mmol/L and lactate-to-pyruvate ratio was elevated to 35. Clinically there was no recurrence of seizure and the patient was neurologically normal until 5 months of age, she developed poor suck, generalized hypotonia and developmental delay. At 7 months, she had bilateral ptosis, nystagmus and ophthalmoplegia. MRI brain / MR spectroscopy showed symmetrical abnormal signals in brainstem and internal capsule. The presence of high lactate peak was suggestive of mitochondrial encephalopathy. Leigh syndrome was suspected based on clinical, biochemical and radiological findings. She was treated with mitochondrial cocktail therapies including riboflavin, thiamine, coenzyme Q10, ascorbic acid and levocarnitine. Muscle biopsy was refused by her parents. She was then referred for genetic analysis in particular searching for mitochondrial disorders. A stepwise approach targeting the common mutations was adopted. Initial study for hotspot mutations in mitochondrial DNA including nucleotides of m.8993T>G or C, m.3243A>G, m.8344A>G by PCR-restriction enzyme study were negative. Subsequent mutation screening for PHDA1 (pyruvate dehydrogenase E1A), PC (pyruvate caboxylase) and SURF-1 genes (for Leigh Syndrome) by PCR-direct sequencing was also negative. Heteroplasmic mutation for MT-ND5 gene at m.13094T>C (p.Val253Ala) was detected and confirmed by PCR-direct sequencing, PCR-restriction enzyme study and amplification refractory mutation system (ARMS). It was also recently reported to be the disease-causing mutation in a patient with mitochondrial encephalomyopathy (reference 1), and the pathogenic effect of this mutation on complex I activity has been demonstrated. She was found to have downhill clinical course despite medical treatments with persistent elevated serum and CSF lactate level. At 11 months, she developed apnea and had central hypoventilation and was now ventilator-dependent. CT brain performed at 12 months showed disease progression, with symmetrical hypodense lesions over bilateral thalami and midbrain and evolving cerebral atrophy.
 

Conclusion:

Neonatal convulsion with persistent elevated serum lactate level is highly suggestive of primary neurometabolic disorder. Stepwise approach in the investigations of this patient confirms the diagnosis of mitochondrial disorder. This is the first reported case of Leigh syndrome with MT-ND5 gene mutation identified in our locality.

Reference: 1. Valente et al. Biochim Biophys Acta. 2009;1792:791-5

P32 EPILEPSIES IN MELAS SYNDROME

Wen-Kan Feng1, Kun-Long Hung1, Jia-Woei Hou1
1 Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan

Objectives:

Neurologic signs such as seizures, muscle weakness, headache with vomiting are often leading to the diagnostic workup for the mitochondrial encephalopathies. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a disease characterized by recurrent headache and epilepsy. The onset of symptoms has been referred to as stroke-like episodes that caused by mitochondrial dysfunction in small cerebral blood vessels. This study is performed to define the clinical features including the epilepsy occurring in MELAS patients in a medical center in Taiwan.
 

Methods:

Retrospective review of six patients with diagnosis of MELAS was conducted with clinical, neuroradiologic, biochemical and electrophysiologic analysis.
 

Results:

By biochemical studies, all of the patients had lactic acid elevation during glucose loading test. MELAS was suspected initially when MRI revealed abnormal signal intensity at cortex or basal ganglion that revealed cerebral atrophy and infarction. Genetic testing from peripheral blood confirmed an A3243G transition in 4 patients and T3291C transition in one patient. Seizures occurred in 4 cases (66%) and mean age of onset was seven years . We also evaluated EEG for 5 patients included 4 seizure cases and one non-seizure case. Their EEGs showed focal or multifocal epileptiform activities and regional cortical dysfunction in four cases (80%) including the non-seizure one. Besides seizures, there were recurrent headache and vomiting in two cases (33%) and muscle weakness in one case as the early manifestations. Other features revealed short stature and failure to thrive (66%), visual field defect (50%), cognitive impairment (66%), and cardiac involvement (33%).
 

Conclusion:

This study emphasizes that epileptic seizures are common in MELAS but not the earliest presenting sign. However EEG studies usually showed abnormal results as focal or multi-focal spikes and cortical dysfunction. Epileptic seizure in MELAS seems difficult to control leading to frequent attacks in some patients.

P33FOCAL EPILEPSY AND MELAS IN A SINGAPORE PAEDIATRIC HOSPITAL

Wendy Kein Meng Liew1, DWS Chan1, Tchoyoson Lim2, SKH Tay3
1 KK Women's and Children's Hospital, Singapore
2National Neuroscience Institute, Singapore
3National University Hospital, Singapore

Objectives:

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is characterized by sudden onset of stroke-like episodes, usually presenting before the age of 20, and accompanied by migraine-like headaches, seizures, cognitive decline and progressive deafness. It is caused by mitochondrial DNA mutations, the most common being A3243G. Seizures may be generalized or focal. We report 2 patients with MELAS and their seizure semiology, neuroimaging and EEG findings.
 

Methods:

We retrospectively studied cases of MELAS in a tertiary paediatric hospital. Data on diagnosis, clinical signs and symptoms, electroencephalogram (EEG) and anti-epileptic medications were collected and analyzed.
 

Results:

Two patients, both females aged 8 years and 10 years old respectively, with MELAS were identified. One patient presented with headache, unsteady gait and vomiting. The other presented with recurrent episodes of encephalopathy with ataxia, dysphasia and visual hallucinations. Both developed focal seizures and one had non-convulsive focal status epilepticus. Comparison of EEG and MRI findings showed concordance between the seizure foci and the stroke-like lesions. Both patients required anti-epileptic medications to control seizures.
 

Conclusion:

Initial seizures in MELAS occur during acute decompensations and often have focal semiology. Later multifocal symptomatic epilepsy develops in association with accumulating chronic structural lesions in the brain. Focal seizures show correlation between electrographic abnormalities and lesions on MRI brain and respond well to anticonvulsant therapy. Non-convulsive focal status epilepticus can occur in MELAS.

P34 EPILEPSY IN METABOLIC MYOPATHY WITH RAGGED-RED FIBERS

Tai-Heng Chen1,2, Tze-Kiong Er1,2, Wen-Chen Liang1,3, Yuh-Jyh Jong1,2
1Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
2Kaohsiung Medical University, Kaohsiung, Taiwan
3National Institute of Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan

Objectives:

Mitochondrial disorders (MDs) consist of a heterogeneous group of multisystem disorders. The pictures of metabolic myopathy, as lipid accumulation or ragged-red fibers (RRF), are common in MDs because the muscle is highly dependent on oxidative metabolism; however, concomitances of epilepsy are rare. We reviewed the epilepsy occurring in patients with muscle biopsy presenting suggestive of metabolic myopathy in MDs.
 

Methods:

We retrospectively reviewed muscle biopsies from patients with clinical pictures of metabolic myopathy, followed from 1986 to 2009 in Kaohsiung Medical University Hospital. Clinical histories of epilepsy and electroencephalography (EEG) were reviewed; furthermore, neuroimaging, metabolic surveys, serum creatine kinase (CK) level, and genetic analysis have been performed in several cases.
 

Results:

We enrolled ten patients, aged 10-33 years (male : female = 2 : 8), whose muscle biopsies revealed lipid accumulation and RRF. Their CK level ranged from 2,000 to 31,000 IU/L. Seven patients had epilepsy associated with epileptogenic EEG findings and five of them had abnormal neuroimaging. All seven epileptic patients were finally diagnosed mitochondrial encephalomyopathy confirmed by genetic analysis: three of them were myoclonus epilepsy with RRF (MERRF) with A8344G mtDNA mutation and four were mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with one had rare mtDNA 3271T>C mutation and three had mtDNA 3243A>G mutation. Three patients without epilepsy were diagnosed multiple acyl-CoA dehydrogenase deficiency (MADD) with mutations at electron-transferring-flavoprotein dehydrogenase (ETFDH) gene.
 

Conclusion:

In addition to mitochondrial encephalomyopathy, rare metabolic myopathies, such as MADD, might share the common myopathic pictures of lipid accumulation and RRF. Especially in those with no epileptic phenotypes and no proved mitochondrial genetic defect, MADD should be put in the list of differential diagnosis since its hotspot mutations (p.A84T) in Taiwanese can be readily identified recently.

P35 SEVERE MYOCLONİC SEIZURES IN PEROXISOMAL D-BIFUNCTIONAL PROTEIN DEFICIENCY

Tai-Heng Chen1,2, Tze-Kiong Er1,2, Wen-Chen Liang1,3, Yuh-Jyh Jong1,2
1Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
2Kaohsiung Medical University, Kaohsiung, Taiwan
3National Institute of Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan

Objectives:

Mitochondrial disorders (MDs) consist of a heterogeneous group of multisystem disorders. The pictures of metabolic myopathy, as lipid accumulation or ragged-red fibers (RRF), are common in MDs because the muscle is highly dependent on oxidative metabolism; however, concomitances of epilepsy are rare. We reviewed the epilepsy occurring in patients with muscle biopsy presenting suggestive of metabolic myopathy in MDs.
 

Methods:

We retrospectively reviewed muscle biopsies from patients with clinical pictures of metabolic myopathy, followed from 1986 to 2009 in Kaohsiung Medical University Hospital. Clinical histories of epilepsy and electroencephalography (EEG) were reviewed; furthermore, neuroimaging, metabolic surveys, serum creatine kinase (CK) level, and genetic analysis have been performed in several cases.
 

Results:

We enrolled ten patients, aged 10-33 years (male : female = 2 : 8), whose muscle biopsies revealed lipid accumulation and RRF. Their CK level ranged from 2,000 to 31,000 IU/L. Seven patients had epilepsy associated with epileptogenic EEG findings and five of them had abnormal neuroimaging. All seven epileptic patients were finally diagnosed mitochondrial encephalomyopathy confirmed by genetic analysis: three of them were myoclonus epilepsy with RRF (MERRF) with A8344G mtDNA mutation and four were mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with one had rare mtDNA 3271T>C mutation and three had mtDNA 3243A>G mutation. Three patients without epilepsy were diagnosed multiple acyl-CoA dehydrogenase deficiency (MADD) with mutations at electron-transferring-flavoprotein dehydrogenase (ETFDH) gene.
 

Conclusion:

In addition to mitochondrial encephalomyopathy, rare metabolic myopathies, such as MADD, might share the common myopathic pictures of lipid accumulation and RRF. Especially in those with no epileptic phenotypes and no proved mitochondrial genetic defect, MADD should be put in the list of differential diagnosis since its hotspot mutations (p.A84T) in Taiwanese can be readily identified recently.

P36 RAPID ESTIMATION OF THE EFFICACY OF ORAL PYRIDOXINE FOR WEST SYNDROME: INTRAVENOUS ADMINISTRATION OF PYRIDOXINE UNDER EEG MONITORING

Kenji Sugai1, Hitoshi Sakuma1, Hirofumi Komaki1, Yoshiaki Saito1, Eiji Nakagawa1, Masayuki Sasaki1
1Department of Child Neurology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan

Objectives:

Some patients with West syndrome (WS) respond to pyridoxine (V.B6), however, it is unknown how long the patients should take it to judge its efficacy, and it often causes vomiting and liver dysfunction. We studied on the rapid estimation of its efficacy for WS.
 

Methods:

Thirty-five patients with WS were given intravenous administration (IV) of V.B6. IV V.B6 was done by approximately 10 mg/kg every 5 minutes to prevent vomiting, up to a total of 30-50 mg/kg, and EEG were recorded for every 5 minutes (min) before IV V.B6, just after IV, and 15 min, 30min, 45 min, and 60 min. after IV. Following this evaluation, V.B6, 30-50 mg/kg, was orally given to the patients. Twenty out of 35 patients, 5 cryptogenic and 15 symptomatic cases, completed both IV and oral administration of V.B6.
 

Results:

By IV V.B6, hypsarrhythmia on EEG completely disappeared and did not recur within 30 min after IV (IV-Good) in 4 cases, transiently disappeared but recurred in 15 min (IV-Fair) in 4 cases, and did not disappear (IV-Poor) in 12 cases. Infantile spasms disappeared in three cases of IV-Good by oral V.B6 at 30-40 mg/kg. These three cases were symptomatic, including lissencephaly, porencephaly caused by intracranial hemorrhage, and tuberous sclerosis. Infantile spasms decreased by >50% in another one case of IV-Good with microcephaly and cerebral palsy. Oral V.B6 was ineffective in all IV-Good and IV-Poor patients.
 

Conclusion:

IV V.B6 under EEG monitoring can rapidly estimate the efficacy of oral V.B6 for WS.

P37 A NORMAL PTH HYPOCALCEMIC NEONATAL CONVULSION REVEALING MATERNAL NORMOCALCEMIC HYPERPARATHYROIDISM

Lung-Chang Lin1, Rei-Cheng Yang1
1Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
Neonatal hypocalcemia is an important cause of neonatal convulsion. We reported a rare case of normal PTH hypocalcemic neonatal convulsion with maternal normocalcemic hyperparathyroidism who had severe seizures after ten-day-old. The laboratory investigations at diagnosis showed as followings: blood sugar 53 mg/dl, WBC 8,100/μL, Hb 14.9 g/dl, total calcium (Ca) 4.6 mg/dl (reference value,8.4-10.2), magnesium (Mg) 1.6 mg/dl (reference value, 1.8-2.5), phosphorus 11.3 mg/dl (reference value, 2.5-4.6), ionized Ca 2.05 mg/dl (reference value, 4.0-5.5) , alkaline-phosphatase (ALP) 301 IU/L (reference value, 145-420), sodium 138 m mol/L (reference value, 136-145), potassium 4.0 m mol/L (reference value, 3.5-5.1), lactate 1.4 m mol/L (reference value, 0.5-2.2 ), ammonia 50 μg/dl (reference value < 70), 25-OH-D 4.3 ng/ml (reference value, 5.30-27.7), 1.25-(OH)-D 33.8 pg/ml (reference value, 1.67-17.3), parathyroid hormone (PTH) 26.78 pg/ml (reference value, 11-62). The blood biochemistry study was performed at the same time in his mother, although she did not show any clinical manifestations. Results demonstrated as followings: serum total calcium 9.5 mg/dl, Mg 2.1 mg/dl, phosphorus 3.3 mg/dl, PTH 91.74 pg/ml. Since elevated PTH level was observed in his mother, neonatal hypocalcemia with maternal hyperparathyroidism was diagnosed. After calcium gluconate supply, the seizure stopped. He was on 1.25-(OH) D 0.125 μg, and calcium carbonate 1000 mg therapy for six months and then stopped medication. Thereafter, he was free of any symptoms for 3 months with normocalcemia (ionized Ca 5.29 mg/dl). It is important to screen maternal calcium, and PTH levels in unexplained late neonatal hypocalcemia.

P38 SEIZURE LIKE TREMORS OF 6 WILSON DISEASES IN TWO FAMILIES

Won Seop Kim1, Keon Su Lee2, Ho Jin Park3
1Department of Pediatrics, Chungbuk National University, Cheongju, Korea
2Department of Pediatrics, Chungnam National University, Daejeon, Korea
3Department of Pediatrics, Eulji University, Daejeon, Korea

Objectives:

Wilson disease is an autosomal recessive disorder with a genetic mutation recently localized on chromosomal 13. The primary defect is impaired biliary excretion of copper, leading to its accumulation in the liver, brain, and other tissue (kidney, eye, etc.).
 

Methods:

We have experienced 6 cases of Wilson disease developed in 2 families.
 

Results:

In all patients, Kayser-Fleischer ring, mild elevated SGOT/SGPT with negative HBsAg, decreased serum ceruloplasmin and eleveted 24hours urine copper are observed, and neurologic symptoms are noted in 2 cases. Other familial members are negative in laboratory test for Wilson disease. In 2 cases, they had seizure like tremors and acute fulminant hepatitis developed in one, so he died despite of aggressive management such as D-penicillamine, albumin and pyridoxine administration, and intravenous hyperalimentaion. In other case, tremors and laboratory findings are improved after carbamazepine, D-penicillamine and pyridoxine administration.
 

Conclusion:

We experienced seizure like tremors with Wilson disease in 2 families.

P39 EPILEPSY IN MENKES DISEASE

Muneaki Matsuo1, Toshiyuki Maeda1, Kazuya Sasaki1, Katsunori Tsuchiya1, Kousuke Tsuji1, Yuhei Hamasaki1
1Department of Pediatrics, Saga University, Saga, Japan

Objectives:

To characterize the epilepsy in Menkes disease.
 

Methods:

Based on clinical charts, we retrospectively analyzed the clinical features of four patients with Menkes disease.
 

Results:

Three of the four patients had their initial seizures before the age of six months (two months to six months). One patient received early copper treatment (within two weeks of age) and had his first seizure at eleven months. The initial seizures were infantile spasms (two cases), generalized clonic seizures, and tonic seizures. Brief tonic seizures and myoclonus were the main seizure type after the late infancy. One patient had prolonged breath holding spells which caused cardiac arrest twice. The diagnosis of Menkes disease was delayed in two patients (two months and seven months after the initial seizures). The initial EEG showed posterior predominant polyspikes and polyspike-waves in two cases, hypsarrhythmia, and diffuse irregular high-voltage slow bursts with spikes. The MRI/MRA findings showed diffuse brain atrophy and tortuous vessels. Subdural hematoma was detected on either CT or MRI in two cases. ACTH was not used because of the risk of subdural hemorrhage and infection. Partial seizure control was obtained after late infancy in all patients. Although zonisamide was effective, two out of three patients who used zonisamide developed urolithiasis.
 

Conclusion:

The risk of intracranial hemorrhage and urolithiasis should be carefully taken into consideration when treating patients with epilepsy in Menkes disease.

P40 LOW SERUM URIC ACID IS AN IMPORTANT EARLY CLUE TO THE DIAGNOSIS OF MOLYBDENUM COFACTOR DEFICIENCY AS THE CAUSE OF NEONATAL SEIZURES – A CASE REPORT

Hian-Tat Ong1,2, Denise Li Meng Goh1,2, Karen Lim2
1University Children's Medical Institute, National University Health System, Singapore
2Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Objectives:

Neonates with refractory seizures and epileptic encephalopathy as a result of molybdenum cofactor deficiency are often reported to have poor prognosis, with early demise or severe global developmental delay. Abnormally low serum uric acid is an important early clue towards the diagnosis of this condition as the neurometabolic workup to determine the cause of neonatal seizures is often extensive and time-consuming.
 

Methods:

A female neonate, who is the second child of non-consanguineous parents, presented with neonatal seizures and encephalopathy at day 2 of life. She had metabolic acidosis due to the refractory seizures, which recurred almost hourly. The neonatal electroencephalogram (EEG) showed diffuse low voltage record (<20µV) punctuated only by frequent EEG seizures, which only responded transiently to repeated intravenous boluses of phenobarbitone (PB) and later midazolam infusion. There was no benefit from two doses of intravenous pyridoxine 50mg, as well as megadoses of vitamin cocktail, coenzyme Q and carnithine supplements. Early investigations quickly excluded central nervous system infection and cerebral malformation as the cause. While awaiting the results of more extensive neurometabolic studies sent overseas, the only clue was the abnormally low serum uric acid level of less than 30 µmol/L (below the detection limit of the assay).
 

Results:

The neonate passed away on day 14 due to the refractory seizures. The diagnosis was confirmed soon after from the markedly raised ratio of S-sulphocysteine to creatinine in the urine, and the presence of peaks of S-sulphocysteine in the plasma and cerebrospinal fluid aminogram.
 

Conclusion:

Serum uric acid is an easy but important test in the workup of neonatal epileptic encephalopathy towards the diagnosis of molybdenum cofactor deficiency. Early diagnosis may allow a trial of therapeutic dietary intervention with restriction of methionine and supplementation of cysteine. Nevertheless, the age of presentation remains the most important prognostic factor.

P41 NATIONWIDE EPIDEMIOLOGICAL STUDY OF PEDIATRIC NEUROTRANSMITTER DISEASES IN JAPAN (1ST REPORT)

Haruo Shintaku1, Masaya Segawa2, Mitsuhiro Kato2, Shinji Saitoh2, Shin-ichiro Hamano2, Masaya Kubota2, Jun Tohyama2, Jun Natsume2, Yoshihiro Maegaki2, Toyojiro Matsuishi2, Hideji Hattori2, Shuhei Ide2, Yasusi Itoh2, Hiroki Fujioka2, Yoshiko Nomura2
1 Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan
2PND Study Group, Osaka, Japan

Objectives:

Pediatric neurotransmitter disease (PND) is a relatively new concept in medical science. PNDs, which are induced by genetic disorders that affect the regulation of neurotransmitters in children, include dopamine-/serotonin-related diseases and GABA-related diseases. Left untreated, PNDs can lead to severely compromised neurological function in patients. However, diagnosing these diseases has been difficult. Thus, it is assumed that many of those patients were not diagnosed accurately and they did not receive appropriate treatments. We investigated the numbers and the distributions of patients with these diseases in Japan.
 

Methods:

We sent a questionnaire to pediatricians or neurologists of 1622 Japanese hospitals in 2009. The data were analyzed statistically.
 

Results:

We received replies from 60.3% of those hospitals (969 of 1608 hospitals). Fourteen hospitals were excluded from this study because they had no pediatrician or neurologist. In dopamine- /serotonin- related diseases, 116 patients of Segawa disease (autosomal dominant guanosine triphosphate cyclohydrolase I (GTPCH) deficiency) were reported from 44 hospitals. Those patients were in every 10 region of Japan. The prevalence rate of Segawa disease was calculated as 0.96 patients/ million. Three patients of aromatic-L-amino acid decarboxylase (AADC) deficiency, another dopamine- /serotonin- related PND, were also reported from 2 hospitals. No patient with tyrosine hydroxylase (TH) deficiency or sepiapterin reductase (SR) deficiency was reported in this study. In GABA-related disease, 3 patients of succinic semialdehyde dehydrogenase (SSADH) deficiency were reported from 3 hospitals.
 

Conclusion:

The prevalence rate of Segawa disease in this study was similar to that of a previous report by Nyggard et al. in 1993 (0.5-1.0 patients/ million). This is the first report of a nationwide epidemiological investigation of PND in Japan.

P42 AROMATIC L-AMINO ACID DECARBOXYLASE (AADC) DEFICIENCY: CLINICAL FEATURES AND FOLLOW-UP IN A CASE

Hueng-Chuen Fan 1, Shyi-Jou Chen 1, Wang-Tso Lee 2, Wuh-Liang Hwu 2, Ruey-Meei Wu 3
1Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2Department of Pediatrics, Taipei, Taiwan
3 Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan

Objectives:

Aromatic L-aminoacid decarboxylase (AADC) deficiency is a neurotransmitter defect leading to a combined deficiency of catecholamines and serotonin. Affected individuals are usually detected in infancy due to severe developmental delay, oculogyric crises and extrapyramidal movements. In the beginning, all these clinical symptoms are hard to differentiate from neonatal or infantile seizure. In the end, no patient can achieve a complete recovery from neurological symptoms.
 

Methods:

We report an AADC deficiency case of male infant presented with limbs involuntary movement, developmental delay, muscular hypotonia, dystonia, oculogyric crises, sleep disturbance and additional extraneurological symptoms. The results of EEG, brain MRI, and repeated newborn screens and CSF study were all negative. Analysis of CSF biogenic amines, including HVA, 5-HIAA, and DOPA proved AADC deficiency at his age of one year. His dystonia and oculogyric crisis had partial response to the treatment with L-Dopa, bromocriptine, and MAO inhibitors.
 

Results:

The level of CSF catecholamine metabolites (HVA and 5-HIAA) were nondetectable and DOPA was elevated. Motor fatiguability, dystonia and sleep pattern partially improved with the use of L-dopa, bromocriptine, and MAO-I.
 

Conclusion:

Only the levels of CSF catecholamine metabolites and DOPA can confirm the diagnosis of AADC deficiency, and the prognosis is usually grave. Medications including L-dopa, bromocriptine, and MAO-I are of limited benefit to this case.

P43 TWO CASES OF TYROSINE HYDROXYLASE (TH) DEFICIENCY MIMICKING IDIOPATHIC CEREBRAL PALSY AND EPILEPSY

Eric Kin Cheong Yau1, Kwok Yin Chan1, Bosco Chan1, Hencher Lee2, Chloe Mak2, Albert Yan Wo Chan2, Ching Wan Lam3
1Department of Paediatrics & Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China
2 Department of Pathology, Princess Margaret Hospital, Hong Kong, China
3 Department of Pathology, The University of Hong Kong, Hong Kong, China

Objectives:

Cerebrospinal fluid (CSF) neurotransmitter analysis and molecular genetic studies revealed TH deficiency as the underlying cause of two children with developmental delay and suspected epilepsy.
 

Methods:

Case report.
 

Results:

Patient 1 presented with hypotonia and global developmental delay at 3-month-old and subsequently developed intermittent convergent squint and prolonged limbs dystonia without impairment in consciousness. Examination revealed truncal hypotonia but spastic limbs and brisk tendon reflexes. She was wheelchair-bound and could not communicate verbally. Blood tests including creatine kinase, ammonia, lactate/pyruvate and urine for amino acids/organic acids were normal. Nerve conduction study/electromyography, muscle biopsy and brain MRI showed no abnormality. Electroencephalogram performed during dystonic attack revealed no epileptiform activity. At 10-year-old, CSF study revealed very low homovanillic acid (HVA), low 5-hydroxyindoleacetic acid (5-HIAA), reduced HVA/HIAA ratio and normal neopterin, biopterin and 3-O-methyldopa levels. Diagnosis was further confirmed with mutational analysis of TH gene showing compound heterozygous mutation (p.G216S and p.G377R). Complete resolution of dystonic attack/intermittent squint with improvement in fine motor functions and speech were achieved after levodopa (2.3mg/kg/day). Patient 2, with uneventful perinatal history, was noted to have hypotonia since 3-month-old and later with repeated generalised dystonia and eye staring. Examinations revealed truncal hypotonia, limbs dystonia and hyperreflexia. Extensive investigations including brain MRI again showed no abnormality. Therapy with levodopa (2.9mg/kg/day) resulted in marked reduction in dystonic attack, improvement in voluntary hand functions and speech. The diagnosis was confirmed by genetic test (p.G263R and c.1163+5G>C) at 11-year-old.
 

Conclusion:

TH, which catalyses the hydroxylation of L-tyrosine to L-Dopa, is the rate-limiting step in catecholamines synthesis. Broad spectrum of symptoms including developmental delay, hypotonia, rigidity, abnormal posturing and involuntary eye movement with variable severity was reported in patient with TH deficiency. Our patients were misdiagnosed as idiopathic cerebral palsy and epilepsy initially. Significant improvement in neurological symptoms and developmental achievement were noted after levodopa.

P44 A STUDY OF CEREBROSPINAL FLUID NEUROTRANSMITTERS ASSAY IN CHILDREN WITH UNDIAGNOSED NEUROLOGICAL DISEASES IN HONG KONG

Cheuk Wing Fung1, Grace Poon1, Anne Kwok1, Pik-To Cheung1, Louis Low1, Nenad Blau2, Simon Siu3, Chloe Mak3, S Tam3, Virginia Wong1
1Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong, China
2 Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, Zurich, Switzerland
3Division of Clinical Biochemistry, Queen Mary Hospital, Hong Kong, China

Background:

Paediatric neurotransmitter diseases (PND) are a group of disorders with a wide clinical spectrum of presentations including neonatal seizures, unexplained movement disorders such as dystonia, rigidity or ataxia, eye abnormalities including oculogyric crises, convergence spasm, ptosis or other intermittent ocular movement abnormalities, and autonomic symptoms like sweating, temperature instability, hypoglycaemia and hypothermia.
 

Methods:

From 2004 to 2009, 114 children, aged 2 days to 33 years, with undiagnosed neurological diseases underwent lumbar puncture. Patients had symptoms more than or equal to one of the followings: movement disorders, mental retardation / cognitive decline, epilepsy and spasticity which might be suggestive of disorders of biopterin, catecholamine and serotonin metabolism or cerebral folate deficiency. Extensive workup was unrevealing which included neuroimaging, cytogenetic studies, preliminary blood and urine for metabolic investigations. From 2004 to 2007, cerebrospinal fluid (CSF) was sent to the Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, Switzerland for neurotransmitters assay. From 2007 onwards, the analysis was performed in the Division of Clinical Biochemistry, Queen Mary Hospital, Hong Kong.
 

Results:

The presenting features of our cohort included various combination of clinical symptoms such as dystonia / rigidity, epilepsy which could be intractable, cognitive regression, global developmental delay / mental retardation, oculogyric crises, spasticity and hypotonia. 10 patients (8.8%) had abnormal neurotransmitters profile compatible with 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency (n=5), tyrosine hydroxylase (TH) deficiency (n=2), idiopathic cerebral folate deficiency (CFD) (n=2), aromatic L-amino decarboxylase deficiency (AADC) deficiency (n=1). Ultimate diagnosis was confirmed by genetic study in all patients with PTPS deficiency, TH deficiency and AADC deficiency. 2 patients with CFD showed elevated autoantibodies against folate receptor (FR) confirming the diagnosis. Treatment was commenced in all 10 patients. 1 patient with PTPS deficiency revealed complete resolution of a parkinsonism state after replacement with tetrahydrobiopterin and L-dopa with normal intelligence. Another patient with PTPS deficiency only showed resolution of hyperphenylalaninaemia biochemically without obvious clinical improvement with significant generalized dystonia and moderate mental retardation. The remaining 3 patients with PTPS deficiency showed no neurological signs but with mild learning problem. One patient with TH deficiency demonstrated marked improvement in her dystonia and oculogyric crises after treatment with L-dopa and significant developmental progress. Another patient with TH deficiency did not reveal definite improvement and developed drug-induced dyskinesia. The child with CFD showed no more regression in cognitive and motor functions after replacement with folinic acid. His younger brother, who was nearly asymptomatic except mild spasticity over both lower limbs, did not have further deterioration in neurological functions after treatment. The patient with AADC deficiency was just started on bromocriptine and vitamin B6 treatment.
 

Conclusion:

PND, a group of potentially treatable neurometabolic diseases, should be considered in any child with unexplained neurological symptoms including movement disorder, cognitive regression, oculogyric crises and spasticity. Early identification and treatment will improve morbidity and mortality.

P45 SLC25A13 GENE TARGETED MUTATION ANALYSIS IN DIRECT BILIRUBIN ELEVATED JAUNDICE PATIENTS

Shu-Li Chen1, Jian-Xiang Liao1, Peng-Qiang Wen1, Guo-Bing Wang1, Dong Cui1, Quan Yuan1, Ping Song1, Yu-Hui Hu1, Cheng-Rong Li1
1Shenzhen Children's Hospital, Shenzhen, China

Objectives:

In order to confirm how many neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in direct bilirubin elevated jaundice patients.
 

Methods:

Applied PCR and PCR-RFLP to analyze SLC25A13 gene hotspot mutation, including 851del4、1638ins23、IVS6 + 5G>A 、IVS16ins3kb and IVS11 + 1G>A in 44 direct bilirubin elevated jaundice patients.
 

Results:

In the present study, we have identified 9 NICCD in 44 direct bilirubin elevated jaundice patients. The ratio is 20.5%. 5 patients were 851del4 heterozygotes, 2 patients were 851del4 homozygotes and 2 patients were heterozygote of 1638ins23/ IVS6 + 5G>A. The major mutation type was 851del4 which accounted for 69.2%(9/13)in total mutation. 1638ins23 and IVS6+5>A accounted for 15.4%(2/13). IVS16ins3kb and IVS11 + 1G>A were not detected.
 

Conclusion:

NICCD is very common in direct bilirubin elevated jaundice patients.

P46 EFFECTS OF PROGESTERONE ON EXPRESSIONS OF INTERLEUKIN-18 IN CEREBRAL CORTEX OF NEONATAL RATS WITH SEIZURE INDUCED WITH TRIFLUOROMETHYLETHER

Ding-An Mao1, Jun-Chao Chen,1, Tao Bo1, Li-qun Liu1, Jian Li1
1Department of Pediatrics, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China

Objectives:

To investigate the effects of recurrent seizures on internleukin-18 expressions in immature and mature rat cerebral cortex; By giving progesterone,investigate the change of internleukin-18 in cerebral cortex of neonatal rat which was submitted to recurrent seizures, to determine whether progesterone protects the neurons from the damage of seizures by the change of internleukin-18.
 

Methods:

96 7-day-old(PN-7d) Sprague-Daweley rats were divided randomly into three groups:The first group was a control group of rats grown naturally.the second group was the seizure group,the rats were administered chemoconvulsant drug Trifluoromethyl ether(one time per day, the convulsion sustained for 30 min.) in this group. The third group was the intervention group; rats of this group were administered progesterone(16mg/kg) after given trifluoromethyl ether; ARS-13d, ARS-15 days, ARS-19 days, PN-75 days later, the rats were killed and their brains processed for localization of neuron plasma antigen.The expression of interleukin-18 protein in the cortex were detected by immunohistochemistry and Western-blot methods on ARS-1d(PN-13d), ARS-3d(PN-15d),ARS-7d(PN-19d) and PN-75d.
 

Results:

①IL-18 could be detected in the endochylema of rats cerebral cortex. The results of immunohistochemistry indicated: Compared with the control groups, the expression of IL-18 was significantly higher in the seizure groups (P<0.05). The level of IL-18 in seizure groups rise on ARS-1d, and the level of IL-18 reached the peak on ARS-7d, then declined. But on the PN-75d the expression of IL-18 in the seizure groups also more than control groups. The intervention groups (rats were given progesterone), compared with the seizure groups, the expression of IL-18 in cortex was significantly reduced(P<0.05).②The results of Western-blot methods: The expression of IL-18 in cerebral cortex on the ARS-1d and ARS-3d couldn't be detected, on the ARS-7d and PN-75d. Compared the seizure groups with control group, the levels of IL-18 in the seizure groups significantly higher(P<0.05).Compared the seizure groups with the intervention groups, the levels of IL-18 were significantly reduced in the latter(P<0.05).
 

Conclusion:

Recurrent seizures in neonatal rats raise the expression of IL-18 in cerebral cortex of rats. The progesterone could reduce the levels of IL-18 in cerebral cortex of the seizure rats. This phenomenon indicates progesterone could have anti-inflammatory effect on seizure severity. Progesterone can protect brain from injury induced by seizures in the infant rats.

P47 CUSHING’S DISEASE WITH EPILEPSY: A ROLE OF OVERACTIVITY OF THE HPA SYSTEM

Mariko Maezawa1, Youichi Doumoto2, Kouichi Tamada2, Masao Miyazaki2, Satomi Sonoda2, Satoshi Kimiya3, Akiko Kamiishi3, Hirohiko Ozaki4
1Department of Dental Hygiene, Tsurumi University, Yokohama/ Kanagawa, Japan
2 Ise Keiyu Hospital , Ise/ Mie, Japan
3Shimada Ryouiku Center, Tama/ Tokyo, Japan
4HIratsuka Kyousai Hospital, Hiratsuka/Kanagawa, Japan

Objectives:

Epilepsy can induce hypercortisolism. We report a ACTH-dependent Cushing`s syndrome with epilepsy and discuss the role of GABAergic systems and overactivity of the HPA systems.
 

Methods:

We report a patient who followed up more than five years as epilepsy combined with Cushing’s disease.
 

Results:

A 24-year-old woman with EEG abnormality (diffuse 2.5-3c/s spike and wave, duration: more than 7 seconds) was referred to Ise Keiyu Hospital. She had unconscious episodes twice and already diagnosed as Cushing’s disease. She had been born to non-consanguineous, healthy parents and weighed 2720g at 39 weeks gestation. Development was delayed and her IQ test at 24 years of age was 20. She already tried carbamazepine by the other hospital but failed. MRI finding showed the remarkable dilatation of posterior horn of the lateral ventricles. Her BMI shows 31.1 recently. Before the initiation of AEDs, we respected mother’s opinion and selected zonisamide as treatment for her epilepsy. After the therapy of ZNS, her QOL had been well .
 

Conclusion:

Epilepsy can induce hypercortisolism secondary to altered temporolimbic modulation of the hypothalamopituitary secretion of ACTH. (Herzog AG. 1998) We would like to discuss overactivity of the HPA , GABAergic systems and NMDA-antagonistic systems about epilepsy with Cushing’s disease.

P48 EVOLUTION OF EPILEPSY IN A CASE OF ADENYLOSUCCINATE LYASE DEFICIENCY: VIDEO-EEG AND RESPONSE TO TREATMENT

Jeremy Freeman1,2, Joy Lee1,2,3, Michiel van Werkhoven2,3, James Pitt3,4, John Duley5,6
1 The Royal Children's Hospital, Melbourne, Victoria, Australia
2Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
3 Victorian Clinical Genetics Service, Melbourne, Victoria, Australia
4Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
5Mater Children's Hospital, Brisbane, Queensland, Australia
6 School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia
  Adenylosuccinate lyase (ADSL) deficiency is a rare disorder of the purine biosynthesis pathway associated with epilepsy, intellectual impairment and autism. Epilepsy syndromes reported in ADSL deficiency include early infantile epileptic encephalopathy, West syndrome and symptomatic epilepsy with both focal and generalized seizure types. We describe a boy with this disorder in whom focal seizures developed in the first week of life, then evolved into infantile spasms at 3 months. Treatment with high dose oral prednisolone, phenobarbitone and topiramate was ineffective, but vigabatrin was effective from 7 months until 12 months of age, when episodes of tonic upgaze associated with electroclinical absences manifest and were controlled by treatment with sodium valproate. Video-EEG findings at 3 and 12 months of age are presented.

Suspicion of ADSL deficiency was raised at 3 months of age when urine metabolic screening by tandem mass spectrometry showed elevated levels of succinyladenosine (S-Ado). Purine concentrations measured by HPLC confirmed increased levels of S-Ado and succinylaminoimidazole carboxamide riboside (SAICAr) in urine. The patient was given a trial of oral S-adenosylmethionine (SAMe) to act as an adenosine donor from 5 months of age. However, levels of S-Ado and SAICAr in urine did not change and there was no clinical response to SAMe treatment over 20 months. At 30 months of age he has the development of a 10-month-old infant and there are some features of autism. His epilepsy is well controlled with sodium valproate alone.

P49 A FEMALE CASE OF SEVERE INFANTILE SPASMS WITH RETT SYNDROME-LIKE PHENOTYPE

Kazuhiro Muramatsu1, Noriko Sawaura1, Yoko Urano1, Yasunori Okada1, Hirokazu Arakawa1
1 Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan

Objectives:

To assess the clinical characteristics of early onset severe infantile spasms with Rett syndrome-like phenotype.
 

Case:

The patient, a 16-month-old female, started developing infantile spasms at age of 3 months. The spasms were considered to be atypical for first 6 months, because spasms did not occur in clusters and frequency was very low. She showed stereotypic midline hand movements and could not develop purposeful her hand skills at age of 7 months. Her development began to regress at age of 9 months. Furthermore, her parents had noticed several symptoms such as poor smile, loss of head control or reaching ability and loss of eye contact. She developed recurrent generalize tonic seizures at age of 11 months and was admitted to hospital for seizure control.
 

Results:

Since her EEG showed generalized changes in forms of multiple spikes and slow waves, similar to hypsarrhythmia, anticonvulsant agents, VPA, VitB6 and NZP were administrated. However, her EEG was worsened, and she was transferred to our hospital for ACTH therapy. ACTH therapy was very effective, and resulted in amelioration of spasms and disappearance of hypsarrhythmic pattern. However, she again developed spasms after 1 month, and EEG was worsened. Since therapy with ZNS, CZP and CLB was not effective, we administrated ACTH again along with VitB6 and TPM.
 

Conclusion:

She showed refractory infantile spasms and symptoms associated with Rett syndrome-like phenotype. Recently, X-linked cyclin-dependent kinase-like 5 (CDKL5) gene mutations have been reported in patients with neurodevelopmental disorders characterized by infantile spasms, psychomotor impairment, and Rett syndrome-like phenotype. In future we intend to analyze CDKL5 gene in this case.

P50 THREE CASES OF INFANTILE CONVULSION CHOREOATHETOSIS SYNDROME (ICCA SYNDROME)

Bosco Chan1, Kwok Yin Chan1
1 Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Hong Kong, China

Objectives:

Infantile convulsion choreoathetosis (ICCA) syndrome is a clinical entity derived from the association between benign infantile convulsion and the subsequent development of paroxysmal dyskinesia. We report our cohort of patients with ICCA syndrome and study their clinical characteristics..
 

Methods:

We retrospectively reviewed our patients with the diagnosis of paroxysmal kinesigenic dyskinesia (PKD) and history of infantile convulsion that were followed up at our department over a five-year period.
 

Results:

Three male Chinese patients were identified. Two patients had onset of infantile convulsions at four months of age, and one at nine months. All patients presented with generalized tonic-clonic seizures and had good response to phenobarbitone. Electroencephalograms showed no ictal discharges. Medications were stopped at age of three and there were no recurrence of seizure attacks. All patients had normal psychomotor developments and attended normal schools. The mean age of onset of PKD was 8.7 years (range 7-11 years). Two had positive family history of PKD. They all had good responses to low dose carbamazepine (100mg daily).
 

Discussion:

Benign infantile convulsion is a seizure disorder occurring in the infancy period, usually 3 to 12 months after birth. It is inherited as an autosomal dominant trait with incomplete penetrance and phenotype variability. Linkage of the ICCA syndrome to the periocentromeric region of chromosome 16 has been reported in previous studies including Chinese and Japanese families. Despite the existence of several genetic foci, the search for the PKD or ICCA gene is hampered by the complicated genomic architecture of the highly duplicated DNA sequences. Patients with this syndrome have normal psychomotor developments and favourable outcomes. PKD is a rare but benign neurological disorder which is commonly being misdiagnosed or overlooked. We report our cohort of Chinese patients with benign infantile convulsions with subsequent development of paroxysmal kinesigenic dyskinesia. The history of benign infantile convulsion, together with the higher male preponderance rate and positive family history of PKD should alert both physicians and parents about the potential development of PKD.

P51 THE CLINICAL AND LABORATORY FEATURE OF TWO CASES EPIDERMAL NEVUS SYNDROME

Zhihong Zhuo1, Huaili Wang1
1 Department of Pediatrics, the First Teaching Hospital of Zhengzhou University, Zhengzhou, China

Objectives:

To study the clinical feature of epidermal nevus syndrome and improve the recognition to this disease.
 

Methods:

Clinical, radiological and histopathological data of two children were analyzed, and literature was reviewed.
 

Results:

Two patients both had typical epidermal nevus with abnormality of cerebral radiology, and associated to mental retardation, epilepsy, language and movement retardation. One of the two patients was combined to ocular tumor. All of these appeared at birth or soon after birth. Histopathological analysis of biopsy specimens obtained from the epidermal nevus revealed squamate epidermis papilliform proliferation.
 

Conclusion:

The disease may affect every other organ system exclusive cutaneous lesion, including the central nervous system, and influence severely mental and life quality of patients. Early diagnosis and therapy can help improve the life quality.

P52 CLINICAL FEATURES OF BENIGN INFANTILE CONVULSIONS ASSOCIATED WITH MILD GASTROENTERITIS

Hui Xiong2, Weiping Xiang1
1 Department of Pediatrics, Tian Jin Fifth Central Hospital, Tian Jin, China
2 Department of Pediatrics, Beijing University First Hospital, Beijing, China

Objectives:

Clinical manifestations and outcomes of hospitalized children with afebrile seizures following mild gastroenteritis were evaluated and analyzed.
 

Methods:

A retrospective study and a follow-up over 12 months were conducted on patients who were admitted to our hospital during November 2006~November 2008, who were diagnosed as mild rotavirus gastroenteritis with afebrile seizure but without previous seizure disorders or family history of febrile convulsion or epilepsy, dehydration, electrolyte imbalances or hypoglycemia.
 

Results:

Out of the 31 patients, 17 were male and 14 were female. The age at the disease onset ranged from 8 months old to 29 months old (mean, 14 months). Six patients (19.4%) reported two or more episodes of seizures. All patients suffered from seizures, generalized tonic clonic seizure lasting 0.5 ~2 min, after 24~68 hours of onset of GI symptoms. No status epilepticus was observed. Neurological examination showed normal. Only 3 of the 28 patients showed abnormal interical electroencephalogram (EEG) findings with a little more slow wave, which reverted to normal during follow-up. Cranial imaging, blood biochemical profiles and cerebrospinal fluid (CSF) testing did not show any abnormalitis in any of the cases. No antiepileptic medications were prescribed as the seizures stopped spontaneously. Rotavirus antigen test was positive in 25(80.6%) children. During the follow-up, all displayed normal psychomotor development without recurrence of seizures.
 

Conclusion:

Benign infantile convulsions associated with mild gastroenteritis (BICE) has the following clinical features: most children occur at the age of 1-2 years old; The convulsions usually happen at the first several days after the onset in a generalized type; No significant changes in blood biochemical profiles, CSF, brain imaging and interictal EEG; Antiepileptic medication may not be necessary after seizure cessation.

P53 JUVENILE HUNTINGTON'S DISEASE WITH REPETITIVE STATUS EPILEPTICUS AND PERIODIC SHARP WAVE COMPLEXES ON EEG: A CASE REPORT

Ryutaro Kira1, Natsumi Isobe1, Yoshito Ishizaki1, Hiroyuki Torisu1, Masafumi Sanefuji1, Toshiro Hara1
1 Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Objectives:

Juvenile Huntington disease (JHD) is defined as having an age of onset of younger than 20 years. The clinical symptoms of JHD are different from that of adult-onset HD. Adult HD usually presents with chorea and personality changes, whereas juvenile HD is far less common and presents with parkinsonism, dystonia, dementia, and seizures. We describe a patient with juvenile HD presenting rapid regression after repetitive status epilepticus and periodic sharp wave complexes (PSWC) on EEG.
 

Case report:

The patient was a 14-year-old woman. Her father had died of HD. Her developmental milestones were normal until the onset of JHD. At the age of 5 years, she fell down on many occasions. Brain MRI showed bilateral atrophy of caudate and putamen. We performed the genetic study for HD and found a CAG trinucleotide repeat expansion of 95-100 repeats. She had afebrile seizures at the age of 8 years. Anticonvulsant therapy was started. Thereafter, abnormal neurological signs including intellectual decline and involuntary movements gradually developed. Epileptic seizures frequently occurred. EEG showed continuous generalized high voltage spike and wave complexes. When she was 13 years old, two episodes of status epilepticus occurred at a 6-month interval. After the episodes, she developed severe mental regression and was in a semi-comatose state. EEG revealed lower voltage of background activity and continuous PSWC.
 

Conclusion:

The EEG of JHD are known to show bursts of (poly-)spike and wave, focal epileptic discharges, and diffuse intermittent delta waves. To our knowledge, there have been no reports of PSWC associated with JHD. The periodic EEG pattern might be an indication of diffuse cerebral impairment in a severe type of JHD.

P54 THE EARLY CLINICAL PICTURE, NEUROPHYSIOLOGICAL AND MRI INVESTIGATIONS IN 4 PATIENTS WITH MONOCARBOXYLATE TRANSPORTER 8 (MCT8) DYSFUNCTION (ALLAN–HERNDON–DUDLEY SYNDROME)

Masaya Kubota1, Reiko Horikawa2, Hideki Hoshino1, Hirofumi Kashii1, Akiko Koyama1, Mari Imamura3, Ichiro Kuki4, Nobuhiko Okamoto5
1 Division of Neurology, National Center for Child Health and Development , Tokyo, Japan
2 Division of Endocrinology, National Center for Child Health and Development , Tokyo, Japan
3 Department of Pediatrics, Oshima Hospital , Kagoshima, Japan
4 Division of Chlid Neurology, Osaka City General Hospital , Osaka, Japan
5 Osaka Medical Center and Research Institute for Maternal and Child Health , Osaka, Japan

Objectives:

To delineate the early clinical, neurophysiological and neuroimaging aspects in patients with monocarboxylate transporter 8 (MCT8) dysfunction (Allan–Herndon–Dudley syndrome).
 

Patients and Methods:

Four patients with Allan–Herndon–Dudley syndrome (genetically proven) were included in this study. The mean age was 1 year and 11 months. All patients showed high free triiodothyronine (T3) and low free T4 levels in serum. They showed no seizure. L-T4 treatment has been unsuccessful for modifying neurological symptoms. Neurological examination, electroencephalography (EEG), evoked potentials (somatosensory evoked potentials (median nerve SEP), auditory brainstem respnses (ABR) and visual evoked potentials (VEP)) and MRI (T1WI, T2WI and FLAIR sequences) were performed at around 1 year of age.
 

Results:

Inadequate head control, marked truncal hypotonia, persistent primitive reflexes, rigid extremities with dyskinesic postures and severe mental delay were observed in all patients. Delayed N20 (the first cortical potential of the primary sensory cortex) in SEP, delayed wave I in ABR and unclear P100 deflection in VEP were evident. All patients’ MRI showed hypomyelination and thin corpus callosum. In EEG study, no paroxysmal discharge was observed.
 

Conclusion:

All the findings obtained by clinical, neurophysiological and MRI studies seem to reflect the delayed myelination and the early neuronal dysfunction in the cerebrum and the brainstem. The neuronal localization of MCT8 in brain regions critically involved in motor control and mental development. The correlation between detailed clinical phenotypes and longitudinal neurophysiological findings should be followed.

P55 A CLINICAL OBSERVATION FOR THE EFFICACY AND SAFETY OF LEVETIRACETAM MONOTHERAPY IN CHILDREN WITH EPILEPSY

Zhi-Sheng Liu1, Fang-Lin Wang1, Ge-Fei Wu1, Jia-Sheng Hu1
1Department of Neurology, Wuhan Children’s Hospital, Wuhan, China

Objectives:

To evaluate the efficacy and safety of levetiracetam (LEV) monotherapy in children with epilepsy.
 

Methods:

Forty-one children (M 26, F 15) with epilepsy between the ages of 7 months and 13 years were treated with LEV as monotherapy. These patients were from Neurology Department of Wuhan Children’s Hospital in 2007-2009. The starting dosage of LEV was 8.9-18.6mg/kg per day of tablet twice daily, and its objective dosage was 15.3-45.8mg/kg per day of tablet twice daily in children with epilepsy. This LEV monotherapy was investigated by a self-controlled and open-label research, and the follow-up period ranged from 6 months to 2 years.
 

Results:

The effective rate (at least 50% reduction in seizures) was found in 68.3% (28/41), with 39.0% (16/41) achieving seizure freedom in LEV monotherapy of children with epilepsy. Thirteen patients (31.7%) had poor efficacy (less than 50% reduction in seizures) in reduction of seizures, with seven patients (17.1%) discontinuing LEV monotherapy due to either an inadequate seizure control or aggravated seizures. Fifteen patients (36.6%) had the therapy-related adverse events in LEV monotherapy of children with epilepsy, including gastrointestinal dysfunction, dizziness, somnolence and irritability, etc. The adverse effects appeared in 2-4 weeks of early LEV therapy and were spontaneously disappeared in 1 week to 1 month of continuing therapy.
 

Conclusion:

The LEV monotherapy is effective and safe for the control of partial and generalized seizures in children with epilepsy. LEV appears to be a broad-spectrum, first-line anti-epileptic drug in treatment of children with epilepsy.

P56 A CLINICAL ANALYSIS AND STUDY OF 120 CHILDREN WITH VIRAL ENCEPHALITIS

Fuyong Jiao1, Jing Lin1
1Department of Pediatrics, Shaanxi Provincial People's Hospital of Xian Jiaotong University, Xian, China

Objectives:

To explore the characteristics and the treatments of the viral encephalitis.
 

Methods:

A total of 120 patients, clinically diagnosed with Encephalitis in the pediatric wards, between July 2001 and September 2007. The independent variables defined for each patient were age, sex, clinical symptoms, seizure type, presence of SE or refractory status epilepticus (RSE), initial electroencephalogram (EEG) finding, neuroimaging study, cerebrospinal fluid (CSF) and outcome.
 

Results:

Between July 2001 and September 2007, there were 120 encephalitis patients. The male to female ratio was 1.6:1. The most common symptoms were fever (100%), upper respiratory symptoms (65.5%) and altered level of consciousness (35.2%). The initial seizure type was categorized as focal (21.5%), generalized (37.2%), primary focal and secondary generalized (39.4%). Abnormal EEGs were 76.2 %. Six cases died, and 24 cases developed epilepsy and/or neurologic deficits.
 

Conclusion:

Our results support that appropriate symptomatic therapy and support, especially for treating convulsions, and traditional Chinese medicine should be recommended to reduce the mortality and improving.