Itai Berger

Mutations in the Fatty Acid 2-Hydroxylase Gene Are Associated with Leukodystrophy with Spastic Paraparesis and Dystonia

Myelination is a complex, developmentally regulated process whereby myelin proteins and lipids are coordinately expressed by myelinating glial cells. Homozygosity mapping in nine patients with childhood onset spasticity, dystonia, cognitive dysfunction, and periventricular white matter disease revealed inactivating mutations in the FA2H gene. FA2H encodes the enzyme fatty acid 2-hydroxylase that catalyzes the 2-hydroxylation of myelin galactolipids, galactosylceramide, and its sulfated form, sulfatide. To our knowledge, this is the first identified deficiency of a lipid component of myelin and the clinical phenotype underscores the importance of the 2-hydroxylation of galactolipids for myelin maturation. In patients with autosomal-recessive unclassified leukodystrophy or complex spastic paraparesis, sequence analysis of the FA2H gene is warranted.

Mitochondrial Complex I Deficiency Caused by a Deleterious NDUFA11 Mutation

Complex I deficiency is the most common respiratory chain defect, clinically manifesting by severe neonatal lactic acidosis, Leighs disease, or various combinations of cardiac, hepatic, and renal disorders. Using homozygosity mapping, we identified a splice‐site mutation in the NDUFA11 gene in six patients from three unrelated families. The patients presented with encephalocardiomyopathy or fatal infantile lactic acidemia. The mutation is predicted to abolish the first transmembrane domain of the gene product, thereby destabilizing the enzymatic complex. Mutation analysis of the NDUFA11 is warranted in isolated complex I deficiency presenting with infantile lactic acidemia or encephalocardiomyopathy. Ann Neurol 2008

Attitudes Toward Attention-Deficit Hyperactivity Disorder (ADHD) Treatment: Parents' and Children's Perspectives

Attitudes toward pharmacological treatment may be a major factor contributing to adherence to such treatment. In the current study, attitudes toward methylphenidate treatment among 50 children diagnosed with attention-deficit hyperactivity disorder (ADHD) and their parents were assessed. Authors of this study have found that the study population is concerned and suspicious toward methylphenidate treatment. Most participants were exposed to negative information even before treatment initiation, which caused many participants to consult other sources and postpone the treatment initiation. Although experiencing methylphenidate as safe and effective (after 23.5 months of treatment), the leading cause of negative attitudes is the concern regarding long-term effects. The single most effective factor regarding the attitude toward methylphenidate treatment is the neurologists explanation. It is concluded that the pediatric neurologist has a crucial role in affecting attitudes of children and parents toward methylphenidate treatment.

Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing.

The identification of disease causing mutation in patients with neurodegenerative disorders originating from small, non-consanguineous families is challenging. Three siblings were found to have ventriculomegaly at early gestation; postnatally, there was no acquisition of developmental milestones, and the muscles of the children were dystrophic. Plasma and CSF lactate levels were normal, but the activities of mitochondrial complex I and IV were markedly decreased. Using linkage analysis in the family, followed by whole exome sequencing of a single patient, we identified a pathogenic mutation in the AIFM1 gene which segregated with the disease state and was absent in 86 anonymous controls. This is the second report of a mutation in the AIFM1 gene, extending the clinical spectrum to include prenatal ventriculomegaly and underscores the importance of AIF for complex I assembly. In summary, linkage analysis followed by exome sequencing of a single patient is a cost-effective approach for the identification of disease causing mutations in small non-consanguineous families.

Down Syndrome and Attention-Deficit/Hyperactivity Disorder (ADHD)

Clinicians might minimize the prevalence of behavioral disorders among mentally retarded people. Decreased attention, hyperactivity, and impulsivity are frequently reported in children with Down syndrome, yet the exact prevalence of attention-deficit/hyperactivity disorder (ADHD) has not been clearly estimated in this population. The objective of this study was to estimate the prevalence of ADHD in children with Down syndrome and to emphasize the possible relationship between ADHD symptoms and the level of mental retardation and common medical comorbidity. In this study, the prevalence of ADHD among Down syndrome children was very high, reaching 43.9%. No significant correlation was found between ADHD symptoms and the level of mental retardation, but significant correlation was found with ophthalmologic problems. We conclude that children with Down syndrome are at increased risk for ADHD. When evaluating children with Down syndrome for attention deficits, psychiatric comorbidity as well as medical problems should be carefully taken into consideration.

Neonatal Seizures: Dilemmas in Workup and Management

There is a pressing need for consistent, evidence-based guidelines in the management of neonatal seizures by pediatric neurologists and neonatologists. Israeli pediatric neurologists and neonatologists completed a 20-item, self-administered questionnaire on choices of antiepileptic drugs, treatment of intractable neonatal seizures (unremitting seizures after 3 medications), treatment duration, and recommended workup. The responding 36/55 (65%) neurologists and 66/112 (59%) neonatologists made similar antiepileptic drug choices (phenobarbital as first line, phenytoin as second line, and benzodiazepines as third line). Antiepileptic treatment duration was similar for both groups, but varied considerably within them (range, 1-52 weeks). Neurologists tended to recommend longer treatment for seizures secondary to asphyxia or hemorrhage. Neurologists and neonatologists recommended different antiepileptic drugs for intractable neonatal seizures: valproic acid and topiramate by neurologists, vs lidocaine and benzodiazepines by neonatologists (P = 0.0023). Fewer neurologists recommended continuous electroencephalography monitoring after asphyxia than neonatologists (40% vs 70.5%, P = 0.013). These responses reflect both similarities and inconsistencies of the two groups in diagnosing and treating neonatal seizures. Our findings call for controlled clinical trials to establish protocols for (1) diagnosing neonatal seizures, (2) studying the efficacy and safety of new-generation antiepileptic drugs, and (3) determining optimal duration of drug administration.

Clinical Experience With Open-Label Topiramate Use in Infants Younger Than 2 Years of Age

To assess the efficacy, safety, and tolerability of topiramate in infants younger than 24 months of age, we conducted an open-label, multicenter chart review study of infants who received topiramate. Twenty-eight patients were evaluated. All had refractory epilepsy. The mean age of seizure onset was 3.8 months (range 0—10 months). Refractory infantile spasms were the most common epilepsy syndrome. Among infants without infantile spasms, complex partial seizures were the prominent seizure type in eight, followed by simple partial seizures in six. Topiramate was prescribed as add-on therapy in 25 cases and as monotherapy in 3 cases. Seven of the eight infantile spasms cases improved on topiramate therapy, attaining topiramate monotherapy in three infants. Half of the infants with other seizure types responded to topiramate. The average treatment duration among topiramate responders was 11 months. Topiramate was prescribed after a mean of 3.3 antiepilepsy drugs had been used in these infants. In no case was topiramate the first prescribed antiepilepsy drug. Adverse effects occurred only in five patients, leading to topiramate discontinuation in two patients. Topiramate was efficacious and well tolerated in infants younger than 24 months of age with refractory epilepsy. Prospective data are needed to corroborate this observation. (J Child Neurol 2003;18:258—262).

Paediatric Hashimoto encephalopathy, refractory epilepsy and immunoglobulin treatment – unusual case report and review of the literature

Background:  Hashimoto encephalopathy (HE) is a rare autoimmune disorder. It is defined as a ‘corticosteroid‐responsive encephalopathy associated with thyroiditis’.

Body Mass Index of Children With Attention-Deficit/Hyperactivity Disorder

An association between overweight and attention-deficit/hyperactivity disorder (ADHD) in children was previously suggested. We examined the prevalence of overweight, anthropometric changes, and the effect of methylphenidate treatment in 275 children with ADHD without neurological comorbidities and in controls. Data were extracted from medical charts, for up to 17 months of follow-up. Height, weight, body mass index, and their z scores did not differ between the ADHD and control groups. Prevalence of overweight and obesity was lower in the ADHD group compared with controls (19% vs 35%, P = .02, and 7% vs 16%, P = .05, respectively). During a follow-up of up to 17 months, no significant changes in height or body mass index z scores were found, including in a subgroup of overweight children. We conclude that compared with local controls, children with ADHD have rates of overweight and obesity that are lower, but that are similar to national estimates. Methylphenidate treatment did not significantly affect height, weight, or overweight status.

The Effect of Antiepileptic Drugs on Mitochondrial Activity: A Pilot Study

Mitochondria are probably a target in antiepileptic drug—induced hepatotoxicity accompanied by oxidative stress. Most studies discuss valproic acid. The information regarding other antiepileptic drugs is scarce. Most studies used in vitro methods and animal models. In this study, the authors have investigated the effect of antiepileptic drugs, other than valproic acid, on the oxidative phosphorylation process in children, by measuring mitochondrial adenosine triphosphate (ATP) production and the enzymatic activities of respiratory chain complexes II-IV in peripheral white blood cells. The results demonstrate that several antiepileptic drugs can affect the mitochondrial oxidative phosphorylation. The authors have concluded that the effect of antiepileptic drugs on the mitochondria is not limited only to valproic acid, but can affect different mitochondrial pathways and can be performed in humans by relatively simple methods, using small samples of peripheral white blood cells.