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There is limited information on the potential effects of repeated intrathecal antisense oligonucleotide drug delivery on cerebrospinal fluid (CSF) biochemical and blood cell profiles. This study aimed to examine longitudinal changes in the biochemical components (glucose, protein) and blood cell counts in the CSF of spinal muscular atrophy (SMA) patients treated with intrathecal nusinersen.We collected and analyzed clinical and CSF parameters (cell count, protein, glucose, culture) of 50 individuals with SMA during nusinersen treatment (22 type 1, 17 type 2, and 11 type 3).The median protein concentration at baseline and during treatment was within the normal range but rose during treatment and was significantly above baseline at the time of the ninth intrathecal injection (p = 0.02, two-tailed Wilcoxon matched-pairs test, and p = 0.0015, Friedman test for repeated measures). Further analysis showed that the increase in CSF protein concentration was evident for SMA types 2 and 3 patients, but not for type 1. This observation was also demonstrated by a significant correlation between the SMN2 gene copy number and the increase in CSF protein concentration (Spearman rank correlation test).Our results demonstrate that a delayed increase in CSF protein concentration is expected during nusinersen treatment for SMA types 2 and 3. This might reflect the medication's effect and a possible therapeutic biochemical marker.

Aquaporin-4 antibody (AQP4-Ab) Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare neuroinflammatory syndrome presenting predominantly with optic neuritis and transverse myelitis. We report a case of radiologically isolated longitudinally extensive optic neuritis in an asymptomatic 12-year-old female with positive serum AQP4-Ab, with resolution of imaging changes after immune therapy. By contrast to patients with radiologically isolated syndrome, of which some will never convert to multiple sclerosis, the pathogenicity of AQP4-Ab in the context of sub-clinical disease, supported treatment in our patient. Given the severe morbidity in AQP4-Ab NMOSD, prognostic biomarkers for disease severity are required to guide optimal therapy for patients.

The objective of this study was to assess the prevalence of disordered eating behaviors (DEBs) in young individuals with idiopathic intracranial hypertension (IIH) and to identify predictors of DEBs in this population.Individuals with IIH aged eight to 25 years and their matched controls responded to a self-rating survey comprised of the Eating Attitude Test-26 for assessing the presence of DEBs and the Depression, Anxiety and Stress Scale.Fifty-three subjects with IIH and 106 healthy controls were included. DEBs were significantly more prevalent in individuals with IIH (P 0.001). Individuals with IIH and DEBs were more likely to have longer periods of treatment [odds ratio: 1.07, 95% CI: 1.02-1.41), P = 0.008] and to have lost a significant amount of weight during the course of treatment [odds ratio: 9.06 (95% CI: 1.30-62.9), P = 0.026]. Depression, anxiety, and stress were more prevalent in the IIH group than in the controls (P = 0.004) and were associated with DEBs in these individuals (P = 0.01).There is an increased prevalence of DEBs among young individuals with IIH, which persists even after disease resolution, and is associated with higher reported rates of depression, anxiety, and stress. Medical caregivers should have heightened awareness to DEBs in individuals with IIH with the aim of early identification and intervention.

OBJECTIVE: Perinatal intracranial hemorrhage (pICH) is a rare event that occurs during the fetal/neonatal period with potentially devastating neurological outcome. However, the etiology of pICH is frequently hard to depict. We investigated the role of rare genetic variations in unexplained cases of pICH. METHODS: We performed whole-exome sequencing (WES) in fetuses and term neonates with otherwise unexplained pICH, and their parents. Variant causality was determined according to the American College of Medical Genetics and Genomics (ACMG) criteria, consistency between suggested genes and phenotypes, and mode of inheritance. RESULTS: Twenty-six probands (25 families) were included in the study (9 with a prenatal diagnosis and 17 with a postnatal diagnosis). Intraventricular hemorrhage (IVH) was the most common type of hemorrhage (n = 16, 62%), followed by subpial (n = 4, 15%), subdural (n = 4, 15%), and parenchymal (n = 2, 8%) hemorrhage. Causative/likely causative variants were found in 4 subjects from 3 of the 25 families (12%) involving genes related to the brain microenvironment (COL4A1, COL4A2, and TREX-1). Additionally, potentially causative variants were detected in genes related to coagulation (GP1BA, F11, VWF, FGA, F7) (n = 4, 16%). A potential candidate gene for phenotypic expansion related to microtubular function (DNAH5) was identified in one case (4%). Fifty five percent of the variants were inherited from an asymptomatic parent. Overall, these findings showed a monogenic cause for pICH in 12% to 32% of the families. INTERPRETATION: Our findings reveal a clinically significant diagnostic yield of WES in apparently idiopathic pICH and support the use of WES in the evaluation of these cases. This article is protected by copyright. All rights reserved.

Pompe's disease occurs due to an autosomal recessive trait resulting from numerous distinctive mutations in the GAA gene. It manifests as a broad spectrum of clinical phenotypes with progressive weakness that impairs motor and respiratory functions being common for all its forms. Cardiac hypertrophy is a prominent feature of its classic infantile form. To date, the pathogenic variant c.2015G > A (p.Arg672Gln) in exon 14 of the GAA gene has been described in 10 children of different ethnic groups, with variable phenotypic presentations. This work describes three children from two unrelated families of Arab ethnicity who presented with infantile-onset Pompe's disease as a result of a c.2015G > A (p.Arg672Gln) mutation. The clinical course of the children we report was more severe than previous reports. This further emphasizes the lack of a strict genotype–phenotype correlation in regard to the unique c.2015G > A (p.R672Q) mutation that causes Pompe's disease. This information contributes to the knowledge of the phenotypic expression of the specific mutation c.2015G > A (p.Arg672Gln) that causes Pompe's disease.

The existing data on the neurodevelopmental outcome of children born with an isolated atretic cephalocele (IAC) are scant. We aimed to expand upon these data by describing our experience with affected children, as well as assist parents and clinicians in deciding how to proceed when an IAC is diagnosed prenatally. A follow-up study was conducted on nine children who were born with an IAC. Evaluations were performed by pediatric neurologists and child development specialists. Developmental outcomes were based on a global development evaluation that assessed gross and fine motor skills, receptive and expressive language levels, activities of daily living, communication skills, and social domains. Adaptive skills were estimated by the Adaptive Behavior Assessment System, Second Edition. None of the nine children (median age 4 years and 6 months) had abnormal findings on neurological examination. Six children had age-appropriate developmental milestones, two had a mild motor delay, and one had mild expressive language delay (catchup was achieved by all of the latter three by ~ 3.5 years of age). The mean general adaptive composite score was 105 ± 11.7 (normal = 100). None of the children had behavioral, social, or communication problems. Children diagnosed with an IAC with/without a falcine sinus and devoid of coexisting intracranial abnormalities seem to have a normal neurodevelopmental outcome. Continuation of pregnancy may be recommended when an IAC is detected prenatally, and reassurance if detected postnatally.

Aim To evaluate the long-term effectiveness of cannabidiol (CBD)-enriched oil for the treatment of refractory epilepsy and to assess the development of tolerance to its anti-seizure effect. Methods A prospective study of 92 consecutive patients (age 1–37 years, mean-11.8 years) with treatment resistant epilepsy who were treated with cannabis oil extract (CBD/tetrahydrocannabinol [THC] ratio of 20:1). Mean monthly seizure frequency was reported by the patients/their parents during monthly clinic visits. Tolerance was defined as either the need to increase the dose by ≥30% due to reduced treatment efficacy or as an increase of ≥30% in mean monthly seizure frequency in patients treated for at least 3 months with no change in other anti-seizure medications. Results Mean follow-up time was 19.8 ± 12.5 months (range 3–45). Mean CBD dose was 11.3 (4–38) mg/kg/day. Twenty-nine (31%) patients discontinued treatment due to lack of effect or adverse reactions, which were reported in 51% (47/87) of the patients. Overall responder rate (>50% seizures reduction) was 54%, whereas 8 patients (9%) became seizure-free. Eighty-four patients were included in the tolerance analysis. Tolerance was observed in 21 (25%) patients after a mean duration of 7.3 ± 5.4 months of CBD-enriched oil treatment. There was a negative correlation between epilepsy duration and tolerance development (p = 0.038). Conclusions We report for the first time the plausible appearance of tolerance to cannabidiol-enriched oil. This may limit treatment efficacy in the long-term clinical management of refractory epilepsy in both pediatric and adult population. Further studies are needed to investigate potential mechanisms.

Insulin-like growth factor-1 (IGF-1) is an anabolic hormone with myotrophic effects on muscle tissue. Patients with spinal muscular atrophy (SMA) sustain early-onset sarcopenia, which contributes to an increased prevalence of insulin resistance. Our aim was to determine the IGF-1 status in 5q-SMA patients and its association with insulin resistance. Real-life clinical and laboratory data of 34 patients (15 males; age 3 months-24 years) included: anthropometric measurements [weight, height/length, body mass index or weight-to-length ratio, delta-height standard deviation score (∆Ht SDS) as the difference between height/length SDS and mid-parental height (MPHt) SDS] and laboratory measurements [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and IGF-1]. HOMA-IR levels categorized patients as insulin-resistant [HOMA-IR ≥1.9 (n = 20)] or insulin-sensitive [HOMA-IR

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system which occurs predominantly in the pediatric population. Acute treatment is high-dose intravenous glucocorticoids. Alternative treatment is usually intravenous immune globulin and/or plasma exchange. Fulminant ADEM is rare in children. Only a few cases of cyclophosphamide use in refractory ADEM have been reported. Here, we report a case of a 12-year-old girl with fulminant ADEM who was comatose and improved dramatically after cyclophosphamide administration. Cyclophosphamide treatment should be considered as a therapy in children with fulminant ADEM nonresponsive to standard therapies.

Epilepsy is one of the most frequent CNS manifestations of tuberous sclerosis, and for most patients, it is the major debilitating factor. In up to 70% of the cases, the epilepsy is refractory and usually associated with significant behavioral as well as developmental consequences. Therefore, controlling seizures is one of the biggest medical and surgical challenges. Understanding the cellular mechanism involved in the disease empowered targeted research aimed toward early intervention in the epileptogenicity process. In this review, we present an update on the pharmacological treatments in tuberous sclerosis-related epilepsy.

The clinical applicability and yield of brain magnetic resonance imaging (MRI) in the setting of an inpatient pediatric department has not been investigated. The authors performed a retrospective chart review of nontraumatic/nonneurosurgical children who underwent brain MRI during their hospitalization in a general pediatric department over a 5-year period. Of the 331 children who underwent brain MRI, 148 (45%) had abnormal findings. High-risk headaches and focal seizures were significantly correlated with findings on brain MRI. Diagnostic and therapeutic yields were most significant in acute demyelinating events, acute cerebrovascular disorders, high-risk headaches when supported by neurologic and ophthalmologic findings, focal seizures with evidence of multifocal epileptic activity on an electroencephalogram and ophthalmic complaints when accompanied by cranial nerve palsy and optic nerve impairment. Since the contributions of a brain MRI in hospitalized children is pivotal in specific clinical situations, a judicious decision-making process should be done before its scheduling, in order to optimize clinical care.

The introduction of nusinersen, the first therapeutic modality for Spinal Muscular Atrophy (SMA) patients has raised hopes and led to construction of a multi-professional medical SMA service, including pediatric endocrinology. Our study aimed to provide a comprehensive description of the endocrine manifestations of SMA patients with variable degree of sarcopenia. Real-life clinical and laboratory data of 62 SMA patients (age range 3 months to 31 years, 24 type 1, 21 type 2, 17 type 3) were collected including: weight-status, self-reported information on puberty, current pubertal stage, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), basal gonadotropin and androgen levels. Precocious pubarche (mean age at onset 3.9 ± 2.8 years) was found in 24% (15/62) of the SMA cohort [45.9%(11/24) type 1 and 19%(4/21) type 2]. A higher HOMA-IR predicted precocious pubarche after adjustment for SMA type and age (OR=1.42; 95% CI, 1.05, 1.93, P = 0.025). Bilateral cryptorchidism was found in 60% of type 1 and 30% of type 2 boys; type 3 young adult males attained full puberty. Most of the young women had normal pubertal development and regular menses, regardless of degree of obesity. Our findings suggest that isolated precocious pubarche is associated with early-onset insulin resistance linked to severity of muscular atrophy.

The antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator-free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients.Thirty-four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by ≥3 or ≤0 points in the HFMSE total score were considered to be responders or nonresponders, respectively.Lower baseline levels of two muscle microRNAs (miR-206 and miR-133a-3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR-206 levels were inversely correlated with the HFMSE score.Lower miR-206 and miR-133a-3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long-term benefit.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletion or mutation of the SMN1 gene. It is characterized by a progressive loss of motor neurons resulting in muscle weakness. The disease affects 1 in 11,000 live births and before the era of treatment SMA was a leading genetic cause of mortality in infants. Recently, disease modifying therapies have been introduced in clinical practice. They include intrathecal and oral antisense oligonucleotides binding to pre-mRNA of SMN2 gene and increasing the translation of fully functional SMN protein as well as SMN1 gene replacement therapy. Onasemnogene abeparvovec uses the adeno-associated virus 9 (AAV9) vector to deliver the SMN1 gene. Phase 1 and phase 3 clinical trials showed that a single administration of onasemnogene abeparvovec resulted in improvement of motor functions in the majority of infants with SMA. Currently, phase 3 trials in SMA1 and SMA2 patients, as well as presymptomatic infants diagnosed with SMA, are ongoing. The drug was approved for medical use in the US in 2019, and in Japan and the European Union in 2020. Thus, first real-world data on efficacy and safety of onasemnogene abeparvovec in SMA patients are available.

Epilepsy is estimated to exist in approximately 40% of individuals with cerebral palsy; however, the specific features that make it drug resistant are not well defined. The main aim of this study was to determine the clinical risk factors that could predict drug-resistant epilepsy, in children with cerebral palsy. The study was performed via a retrospective chart review, analyzing clinical parameters of 118 children with cerebral palsy with either drug-resistant epilepsy or controlled epilepsy, between the years 2013 and 2018. We established a predictive model for drug-resistant epilepsy in children with cerebral palsy that is simple to apply in clinical settings and composed of the additive effect of a low Apgar score at 5 minutes, neonatal seizures, focal-onset epilepsy, and focal slowing on electroencephalogram (EEG; area under the receiver operating characteristic of 0.840). Early prediction of drug-resistant epilepsy may benefit to achieve better seizure control in children with cerebral palsy.

Several works have reported on the antiepileptic impact of cannabis-based preparations in patients with treatment-resistant epilepsy (TRE). However, current formulations suffer from low bioavailability and side effects. PTL-101, an oral formulation containing highly purified cannabidiol (CBD) embedded in seamless gelatin matrix beadlets was designed to enhance bioavailability and maintain a constant gastrointestinal transit time.This phase II, prospective study was open to pediatric patients with TRE on stable antiepileptic drugs' (AEDs) doses, who experienced ≥4 seizures within four weeks of enrolment and with a history of ≥4 AEDs failing to provide seizure control. Following a 4-week observation period, patients began a 2-week dose-titration phase (up to ≤25mg/kg or 450mg, the lower of the two), followed by a 10-week maintenance treatment period. Caregivers recorded seizure frequency, type, and severity and ranked their global impressions after 7 and 12weeks of treatment. Responders were those showing a ≥50% reduction from baseline monthly seizure frequency. Safety assessments monitored vital signs, adverse effects, physical and neurological exams, and laboratory tests.Sixteen patients (age: 9.1±3.4) enrolled in the study; 11 completed the full treatment program. The average maintenance dose was 13.6±4.2mg/kg. Patient adherence to treatment regimens was 96.3±9.9%. By the end of the treatment period, 81.9% and 73.4±24.6% (p0.05) reductions from baseline median seizure count and monthly seizure frequency, respectively, were recorded. Responders' rate was 56%; two patients became fully seizure-free. By study end, 8 (73%) caregivers reported an improved/very much improved condition, and 9 (82%) reported reduced/very much reduced seizure severity. Most commonly reported treatment-related adverse effects were sleep disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased seizure frequency, and restlessness (3 patients each (18.8%)). None were serious or severe, and all resolved.PTL-101 was safe and tolerable for use and demonstrated a potent seizure-reducing effect among pediatric patients with TRE.

Approximately 40% of young-onset multiple sclerosis (MS) patients experience breakthrough disease, which carries a high risk for long-term disability, and requires using therapies beyond traditional first-line agents. Despite the increasing use of newer disease-modifying treatments (DMTs) in this population, data are not available to guide the need for escalating DMTs and there is a scarcity of data on the effects of natalizumab in children and young adults with active disease. We performed a retrospective analysis of the rate of No Evidence of Disease Activity (NEDA), tolerability, and safety of natalizumab in a multi-center cohort of 36 children and young adults with highly active MS. All patients had active disease and initiated treatment with natalizumab. The primary endpoint was the rate of achieving NEDA-3 status, within two years of natalizumab treatment. To examine a possible effect of age on the outcome of treatment, outcomes were also analyzed by pre-pubertal (n = 13 children aged 9-13 years) and pubertal subgroups (n = 23 young adolescents aged 14-20 years). The NEDA-3 status of the pre-pubertal group was 92% in the first and second year and in the pubertal group - 96% in the first year and 92% in the second year. Natalizumab reduced the number and volume of brain lesions in both pre-pubertal and pubertal groups. Treatment was well-tolerated, only 8 patients (22.2%) had adverse events during the 2-year study period. Our analysis shows that natalizumab is effective and well-tolerated in pre-pubertal and pubertal MS patients.

Background A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study. Methods Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case. Results Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia. Conclusions We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.

Pseudotumor cerebri syndrome (PTCS) is a disorder defined by increased intracranial pressure in the absence of an intracranial space-occupying lesion. This retrospective study aimed to examine the outcomes in children with PTCS.Data was collected retrospectively from the charts of consecutive pediatric patients treated for PTCS at our hospital between 2000 and 2007 (60 patients; 36 females, 24 males).Forty-six patients (76.6%) responded well to acetazolamide therapy, with full resolution of symptoms, including papilledema (average treatment duration 1 year; range: 1 month-5 years). Of the 14 patients with no response to treatment, 9 (23.4%) required surgical intervention. Nonresponders tended to be younger at presentation (8.7 vs 11.5 years, P = 0.04). Twelve patients (26%) experienced relapse after acetazolamide was discontinued. The group that experienced relapse was significantly younger than the nonrelapsers (8.9 vs 12.1 years, P0.05).Younger age at presentation with PTCS was found to be a risk factor for treatment failure or relapse.

Background and Purpose: Postnatal progressive microcephaly, with seizures and brain atrophy (OMIM # 613668) is a rare disorder caused by a homozygous founder missense mutation c.1112T>C (p.L371P) in the MED17 gene on chromosome 11 that was identified in 2010 in Caucasus Jewish families. The present study aimed to delineate the phenotype and developmental outcomes in patients diagnosed with this mutation to date. Methods We conducted a medical charts review to collect the clinical, laboratory and neuroimaging findings in patients from several unrelated families of Caucasus-Jewish origin, who were diagnosed with the same homozygous c.1112T>C MED17 mutation. Results The study cohort, including the previously reported patients, comprised 10 males and 5 females from 11 families. All subjects had at birth a normal head circumference, which steeply declined to -6SD within a few months. None of the patients achieved developmental milestones. All patients had progressive spasticity and were wheelchair bound due to spastic quadriplegia. All of them eventually developed profound intellectual disability. Epilepsy of varied severity was present in all patients. Most patients required enteral feeding due to aspirations. Eight patients died before puberty (age range 2–13 years). Brain MRI showed marked cerebral atrophy and early prominent cerebellar atrophy (vermian > hemispheres) accompanied by pontine ventral flattening. Conclusions The founder c.1112T>C mutation in MED17 gene is expressed by a unique and homogeneous clinical phenotype with distinctive MRI findings. This mutation should be considered in patients of Caucasus-Jewish ancestry presenting with clinical features and a MRI pattern of progressive cerebral and cerebellar atrophy.

Objective: To assess the intracranial pressure in pediatric acute disseminated encephalomyelitis using spinal tap opening pressure on lumbar puncture, which is routinely performed as part of suspected acute disseminated encephalomyelitis workup. Compared to other cerebrospinal fluid parameters such as cell count, protein concentration, and presence of oligoclonal bands, cerebrospinal fluid opening pressure is infrequently recorded. Methods: A retrospective chart review of demographic, clinical, and laboratory data of children diagnosed with acute disseminated encephalomyelitis admitted to a tertiary referral hospital between 2005 and 2016. Results: Of the 36 children diagnosed with acute disseminated encephalomyelitis, 24 had the cerebrospinal fluid opening pressure documented in their records. The mean cerebrospinal fluid opening pressure was 27.6±12.6 cmH2O, range 9-55 cmH2O (95% confidence interval 21.9-33.6). Cerebrospinal fluid opening pressure in the acute disseminated encephalomyelitis group was statistically significantly higher ( P = .0013, 95% confidence interval 4.2-15.0) than the accepted upper limit in this age group (18 cmH2O). In 10 of 24 patients (42%), the opening pressure was above 28 cmH2O. Conclusions: Increased opening pressure was the most frequent cerebrospinal fluid abnormal finding in our cohort, which suggests a potential role of increased intracranial pressure in the acute disseminated encephalomyelitis pathophysiological disease mechanism. In certain cases, the opening pressure value could have monitoring and therapeutic implications, and therefore its measurement is highlighted by this study.

ObjectiveTo identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP).MethodsClinical, genetic, and functional analyses involving genome-wide linkage coupled to whole-exome sequencing in a consanguineous family with complicated HSP.ResultsA homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia.ConclusionsOur findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.

Background In 2003, several hundred Israeli infants risked thiamine deficiency after being fed a soy-based formula deficient in thiamine. Approximately 20 patients were seriously affected, and three of them died. We report the clinical presentation of acute encephalopathy in 11 children and the long-term sequelae of eight children who initially survived. Patients In the acute phase, six had bulbar signs, five had ophthalmologic signs and two had phrenic neuropathy. Three of the five patients with cardiac involvement had cardiomyopathy and died in the acute phase. One patient presented with a complete atrioventricular block. Results In the long-term, one patient, who was in a chronic vegetative state, died after 6 years. Seven children exhibited mental retardation and motor abnormalities, six developed severe epilepsy, two early kyphoscoliosis, and one patient remained with a complete atrioventricular block. Conclusions Infants who survive severe infantile thiamine deficiency have serious residual motor and cognitive sequelae as well as epilepsy.

Objective: To describe a novel pattern of magnetic resonance imaging (MRI) abnormalities as well as the associated clinical and laboratory findings. Design: The MRIs of more than 3000 patients with an unclassified leukoencephalopathy were systematically reviewed. Clinical and laboratory data were retrospectively collected. Setting: University hospital. Patients: Seven patients (3 male) shared similar MRI abnormalities and clinical features. Main Outcome Measures: Pattern of MRI abnormalities and clinical and laboratory findings. Results: The MRIs showed signal abnormalities of the deep cerebral white matter, corpus callosum, thalamus, basal ganglia, brainstem, and cerebellar white matter between the ages of 9 months and 2 years. On follow-up, abnormalities gradually improved. Clinical regression occurred in the second half-year of life with spasticity and loss of milestones. From the second year on, clinical improvement occurred. So far, no second episode of regression has happened. Lactate levels were elevated during clinical regression. Conclusion: These patients represent a single novel leukoencephalopathy, probably caused by a mitochondrial defect. Arch Neurol. 2012; 69(6): 718-722. Published online February 6, 2012. doi:10.1001/archneurol.2011.1048

Pediatric brain tumors (PBTs) are the most common solid tumors and the leading cause of cancer-related morbidity and mortality in childhood. Previous studies have shown a significant delay between the onset of symptoms and the diagnosis of these tumors. Delayed diagnosis of PBTs may lead to acute situations and irreversible neurological damage. In this study, we looked for the incidence of delayed diagnosis of PBTs in Israel. We tried to find the reasons for these delays and the associated risk factors in order to provide a feedback to the system for improved education and earlier diagnosis.We analyzed the charts of 330 consecutive children aged 0-18 years diagnosed with brain tumors, between the years 1996 and 2004. In the cases where delay in diagnosis was suspected, further information was collected from a family interview.The average "time to diagnosis" was 7.7 months (SD ± 16.7). Symptomatic deterioration from the first symptom until diagnosis was found in about 50% of the cases. Unacceptable delay in diagnosis was found in 27% of the children. The major reason for delay was "delay in indicated imaging." Symptoms that were found to be associated with delayed diagnosis were torticollis, ataxia, and motor dysfunction. Interestingly, the examination by specialists such as ophthalmologists or neurologists was also associated with delayed diagnosis.There is an unacceptable rate of delay in the diagnostic process of PBTs in Israel. Greater awareness and familiarity with signs and symptoms associated with these tumors and lowering imaging threshold might minimize this phenomenon.

SUMMARY Purpose: Benign childhood epilepsy with centrotemporal spikes (BCECTS) isthe mostcommon epileptic syndrome in childhood. The outcome is usually excellent, but there are some atypical forms of BCECTS with less favorable outcomes. The aim of this study was to delineate the frequency of these atypical features among patients with BCECTS. Methods: We conducted a retrospective chart study by retrieving the medical records of all consecutive patients with BCECTS who were evaluated in four pediatric neurology outpatient clinics in Israel between the years 1991 and 2008. Key Findings: A total of 196 patients with BCECTS were identified (78 female and 118 male; mean age at time of diagnosis 7.64 years, range 1.5‐14). The mean duration of follow-up was 4.43 years (range 2‐11). Nine patients (4.6%)developedelectricalstatusepilepticusinslowwaves sleep (ESES) during follow-up, four (2%) had Landau-Kleffner syndrome, three (1.5%) had BCECTS with frequent refractoryseizures,two(1%)hadBCECTSwithfallsatpresentation, one (0.5%) had a ‘‘classic’’ atypical variant, and one (0.5%) had oromotor dysfunction. None had rolandic status epilepticus. Sixty-one patients (31%) had attention deficithyperactivitydisorder(ADHD),43(21.9%) hadspecific cognitive deficits, and 23 (11.7%) had behavioral

This study explored the effect of thiamine deficiency during early infancy on the development of syntax and lexical retrieval. We tested syntactic comprehension and production, lexical retrieval abilities and conceptual abilities of 59 children aged 5-7 years who had been fed during their first year of life with a thiamine-deficient milk substitute. We compared them to 35 age-matched control children who were fed with other milk sources. Experiment 1 tested the comprehension of relative clauses using a sentence-picture-matching task. Experiment 2 tested the production of relative clauses using a preference elicitation task. Experiment 3 tested the repetition of various syntactic structures with various types of syntactic movement and embedding. Experiment 4 tested picture naming and Experiment 5 tested lexical substitutions in a sentence repetition task. Experiments 6 and 7 tested the children's conceptual abilities using a picture association task and a picture absurdity description task. The results indicated a very high rate of syntactic and lexical retrieval deficits in the group of children who were exposed to thiamine deficiency in early infancy: 57 of the 59 thiamine-deficient children examined had language impairment, compared with three of the 35 controls (9%). Importantly, unlike the impairment this group sustained in their language abilities, the conceptual abilities of most of the children were intact (only six children, 10%, were conceptually impaired). These findings indicate that thiamine deficiency in infancy causes severe and long-lasting language disorders and that nutrition may be one of the causes for language impairment.

Influenza is associated with a variety of neurologic complications. Although the epidemiologic and clinical characteristics of influenza A H1N1 were reviewed in depth, only brief descriptions of neurologic complications exist. We describe the neurologic complications of children hospitalized with influenza A H1N1 infection. We undertook a retrospective study of all hospitalized children with laboratory-confirmed influenza A H1N1 infection accompanied by neurologic complications during a 4-month winter period. Their demographics and clinical characteristics of neurologic presentations were reviewed. Fourteen of 74 children (19%) with laboratory-confirmed influenza A H1N1 infection presented with neurologic complications. Eleven (11/14, 79%) were previously healthy, and three exhibited chronic conditions. Ten (10/14, 71%) presented with seizures: six were febrile, and four were nonfebrile. Other complications included transverse myelitis, myositis, expressive aphasia, and syncope. Only the child with transverse myelitis required a course of rehabilitation. Neurologic complications associated with influenza A H1N1 in our patients were relatively mild. Seizures (febrile or nonfebrile) were the most common. However, the possibility of influenza A H1N1 infection should be borne in mind when diagnosing children with neurologic signs during the influenza A H1N1 season.

Limited information is available on the use of botulinum toxin type A injections for children with hereditary spastic paraplegia. This report includes 12 children with hereditary spastic paraplegia (mean age 4.8 ± 2.5 years) who underwent 1 to 6 sessions of botulinum toxin A injections to the hamstrings, adductors and gastrocnemius muscles. Patients showed both improved muscle tone (mean 1.9 ± 0.5 vs 1.18 ± 0.33, P < .001, Ashworth Scale) and motor function (75.3 ± 11.9 vs 77.7 ± 11, P < .001, Gross Motor Function Measure). The effect lasted for a mean of 6.6 ± 3.6 months. During the study period (mean 2.8 ± 1.8 years), the preinjection Gross Motor Function Measure increased (69.2 ± 14.7 vs 78.3 ± 13.5, P = .005), whereas the Ashworth Scale remained stable, suggesting a prolonged effect of botulinum toxin A on motor function. The authors conclude that botulinum toxin A injections to lower limbs of pediatric patients with hereditary spastic paraplegia result in prolonged functional improvement despite the progressive nature of the disease.

AIM The World Health Organization's International Classification of Functioning, Disability and Health adapted for children and young people (ICF-CY) is a framework for describing and classifying health and health-related states. The aim of the present study was to review literature on neurofibromatosis type 1 (NF1) using ICF-CY guidelines and to highlight findings about the quality of life of children with NF1. METHOD Electronic databases were searched to identify studies involving children with NF1. Eligible studies were classified according to ICF-CY categories. RESULTS Children with NF1 have a variety of cognitive and other deficits. However, very little information is available on the impact of these deficits on their daily life. INTERPRETATION Despite the broad range of functional and structural deficits in children with NF1, the functional assessment of these children remains largely unexplored. Future studies should aim at evaluating the participation of children with NF1 in various situations, using tools with high real-world validity.

Selective neurodegeneration accompanied by mitochondrial dysfunction characterizes neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Thiamine deficiency (TD) in rats is a model for the study of cellular and molecular mechanisms that lead to selective neuronal loss caused by chronic oxidative deficits. Neurodegeneration in TD-rats develops over a period of 12 to 14 days and can be partially reversed by thiamine administration. The aim of this study was to characterize the in-vivo progression of neurodegeneration and the neuronal rescue processes in TD using T(2) magnetic resonance mapping and diffusion tensor imaging (DTI). Each rat was scanned prior to TD induction (day 0), before the appearance of neurological symptoms (day 10), during the symptomatic stage (days 12 and 14) and during the recuperation period (days 31 and 87). Time-dependent lesions were revealed mainly in the thalamus and the inferior colliculi. Early decrease in the fractional anisotropy (FA) was found on day 10 in the inferior colliculi and to a lesser degree in the thalamus, while the earliest detectable changes in the T(2) parameter occurred only on day 12. FA values in the thalamus remained significantly low after thiamine restoration, suggesting irreversible disarrangement and replacement of neuronal structures. While T(2) values in the frontal cortex demonstrated no lesions, FA values significantly increased on days 14 and 31. An enlargement of the lateral ventricles was observed and persevered during the recovery period. This longitudinal MRI study demonstrated that in TD MRI can detect neurodegeneration and neuronal recovery. DTI is more sensitive than T(2) mapping in the early detection of TD lesions.

The aim of this study was to investigate the language development of 20 children who had been exposed to thiamine (vitamin B1) deficiency in infancy due to feeding with soy-based formula that was accidentally deficient of thiamine. In this case–control study, 20 children (12 males, eight females; mean age 31.8mo [SD 4.1], range 24–39mo) who were fed thiamine-deficient formula in infancy were compared with 20 children (12 males, eight females; mean age 32.2mo [SD 3.9], range 25–39mo) fed with other milk sources and matched for age, sex, and maternal education. Receptive and expressive language development was assessed with the Preschool Language Scale, 3rd edition. Other assessments included mental development (Bayley Scales of Infant Development, 2nd edition), evaluation for autistic spectrum disorders, and neurological examination. Motor development was compared by age at independent walking. The study and control groups differed significantly in the expressive communication (p

Epileptic negative myoclonus is an uncommon seizure type characterized by a sudden, brief loss of muscle tone that may lead to falling. It has been associated largely with benign childhood epilepsy with centrotemporal spikes (rolandic epilepsy), although it may also be a feature of other epileptic syndromes. In patients with rolandic epilepsy, epileptic negative myoclonus usually appears during the course of the disease, well after a diagnosis of the epilepsy has been established. Described here are five patients with rolandic epilepsy in which the presenting seizure was falls due to epileptic negative myoclonus. Because developmental delay or neurocognitive problems were present in three of the children, it is possible that epileptic negative myoclonus may be misinterpreted as clumsiness-related falls in some children who actually have undiagnosed rolandic epilepsy.

Objective:To report the follow-up findings of 7 children with severe epilepsy as a result of thiamine deficiency in infancy caused by a defective soy-based formula.Methods:The medical records of 7 children aged 5-6 years with thiamine deficiency in infancy who developed epilepsy were reviewed and their clinical data, EEG tracings, and neuroimaging results were recorded. The clinical course and present outcome of these children, now 5 years after exposure to thiamine deficiency, are described.Results:All infants displayed seizures upon presentation, either tonic, myoclonic, or focal. Six infants had an EEG recording at this stage and all showed slow background. Five of them had no epileptic activity and only 1 displayed focal activity. Following a seizure-free period of 1-9 months, the seizures recurred, and all 7 children displayed either myoclonic or complex partial seizures. Multifocal or generalized spike wave complexes were recorded on the EEGs of all 7 patients, and the tracings of 3 children evolved into hypsarrhythmia. The seizures were refractory to most antiepileptic drugs, and 4 children remain with uncontrolled seizures. All children have mental retardation and motor disabilities as well as symptoms of brainstem dysfunction.Conclusions:Our findings indicate that severe infantile thiamine deficiency may result in epilepsy.

The brain has a remarkable capacity for reorganization following injury, especially during the first years of life. Knowledge of structural reorganization and its consequences following perinatal injury is sparse. Here we studied changes in brain tissue volume, morphology, perfusion, and integrity in children with hemiplegia compared to typically developing children, using MRI. Children with hemiplegia demonstrated reduced total cerebral volume, with increased cerebrospinal fluid (CSF) and reduced total white matter volumes, with no differences in total gray matter volume, compared to typically developing children. An increase in cortical thickness at the hemisphere contralateral to the lesion (CLH) was detected in motor and language areas, which may reflect compensation for the gray matter loss in the lesion area or retention of ipsilateral pathways. In addition, reduced cortical thickness, perfusion, and surface area were detected in limbic areas. Increased CSF volume and precentral cortical thickness and reduced white matter volume were correlated with worse motor performance. Brain reorganization of the gray matter within the CLH, while not necessarily indicating better outcome, is suggested as a response to neuronal deficits following injury early in life. Guy’s and St Thomas’ Charity and the Marnie Kimelman Trust

A multicenter retrospective study was conducted to investigate the perinatal factors, imaging findings and clinical characteristics of hemiplegic cerebral palsy with a particular focus on children born prematurely. Our cohort included 135 patients of whom 42% were born prematurely; 16% were extreme premature infants who were born at 30 weeks or earlier. Nineteen (14%) were twins. Right hemiplegia was slightly more common and accounted for 59% of the patients. Imaging findings of intraventricular hemorrhage and periventricular leukomalacia were more prevalent in premature children whereas stroke, porencephaly, cerebral hemorrhage and cerebral atrophy were more evenly distributed in both term-born and prematurely-born children ( p < 0.01). The overall prevalence of epilepsy in the cohort was 26% with no differences in full-term compared to prematurely-born children. Regardless of the gestational birth age, intellectual deficits were more common in the presence of comorbidity of both hemiplegia and epilepsy ( p < 0.05).

The objective was to report our positive experience of using dexamethasone to treat 13 patients with symptomatic slit ventricle syndrome (SVS).Thirteen SVS patients who received dexamethasone during acute episodes were studied. The etiology for hydrocephalus was prematurity and intraventricular hemorrhage in 9 patients and neonatal meningitis, chorioamnionitis, Dandy-Walker variant, and congenital in 1 case each. The shunt was inserted at 1.8+/-1.0 months of age and SVS was diagnosed at 4.9+/-3.2 years of age.All patients reported relief and shorter duration of symptoms with dexamethasone. Surgical intervention was decided upon and carried out within 11+/-8 months of SVS diagnosis in 9 out of 13 patients. The other 4 are being monitored and continue to receive dexamethasone when needed.Dexamethasone appears to be a useful treatment in acutely increased intracranial pressure caused by SVS. It can provide temporary relief during the decision-making process of whether and when to perform surgery.

Intrauterine growth retardation plays a significant role in neurodevelopmental outcome. The assessment of general movements during the first 20 weeks is a new method for early detection of brain dysfunction. General movements in 31 infants with asymmetric intrauterine growth retardation and their appropriate for gestational age—matched controls were examined. General movements were scored as normal or abnormal by sequential videotape recordings in the writhing (term to 2 weeks), early fidgety (9—11 weeks), and late fidgety (14—16 weeks) periods. Scores were compared between the groups and correlated with neurodevelopmental outcome at 2 years. The incidence of normal general movements was lower in the intrauterine growth retarded infants than in the controls ( P < .001). Significant correlations were found between general movement quality and neurodevelopmental scores in the intrauterine growth retarded group. The fidgety movements were the most sensitive and specific for prediction of neurologic outcome. The general movement assessment can, therefore, serve as an additional tool for examining the neurologic status of the preterm and term intrauterine growth retarded infant. ( J Child Neurol 2004;19:14—18).

Neuroplasticity studies examining children with hemiparesis (CH) have focused predominantly on unilateral interventions. CH also have bimanual coordination impairments with bimanual interventions showing benefits. We explored neuroplasticity following hand-arm bimanual intensive therapy (HABIT) of 60 hours in twelve CH (6 females, mean age 11 ± 3.6 y). Serial behavioral evaluations and MR imaging including diffusion tensor (DTI) and functional (fMRI) imaging were performed before, immediately after, and at 6-week follow-up. Manual skills were assessed repeatedly with the Assisting Hand Assessment, Children’s Hand Experience Questionnaire, and Jebsen-Taylor Test of Hand Function. Beta values, indicating the level of activation, and lateralization index (LI), indicating the pattern of brain activation, were computed from fMRI. White matter integrity of major fibers was assessed using DTI. 11/12 children showed improvement after intervention in at least one measure, with 8/12 improving on two or more tests. Changes were retained in 6/8 children at follow-up. Beta activation in the affected hemisphere increased at follow-up, and LI increased both after intervention and at follow-up. Correlations between LI and motor function emerged after intervention. Increased white matter integrity was detected in the corpus callosum and corticospinal tract after intervention in about half of the participants. Results provide first evidence for neuroplasticity changes following bimanual intervention in CH. This project was funded by grants from Guy’s and St Thomas’ Charity, Marnie Kimelman Trust and ILAN, the Israeli Association for Disabled children. Beit Issie Shapiro funded and provided the camp venue. D. Green was supported by a grant from the Department of Immigration and Absorption during 2010-2011.

The purpose of this study was to characterize the sleep patterns of children with intrauterine growth retardation, known to be at risk for neurodevelopmental disorders, and seek a possible correlation with behavior, concentration, and attention problems. The sleep patterns of 26 children with intrauterine growth retardation aged 4 to 7 years were compared with those of 47 control children using activity monitors (actigraphs). In addition, data were collected from the parents regarding sleep habits, behavior, concentration, and attention. Children with intrauterine growth retardation aged 4 to 7 years were found to have a tendency toward poorer quality of sleep than their matched controls. This inclination was statistically significant only for one sleep measure, the true sleep time. A tendency toward increased fragmentation of sleep, prolonged waking, and decreased sleep efficiency, although not statistically significant in this study, was demonstrated. Our results showed that 58% of the children with intrauterine growth retardation, compared with 40% of the children in the control group, could be defined as “poor sleepers” (sleep efficiency lower than 90% or three or more waking episodes per night). This disturbed sleep profile is probably an integral part of the neurodevelopmental profile typical of these at-risk children. No significant correlations were found between sleep quality and behavior, concentration, and attention problems. ( J Child Neurol 2002;17:872—876).

In a community-based study of 4,309 children with neurodevelopmental disabilities who were referred to the Institute for Child Development, Tel Aviv, Israel, 62 (1.4%) had macrocephaly (head circumference above the ninety-eighth percentile for age), of whom 42 (1%) had macrocephaly not associated with hydrocephalus. With the exception of neonatal respiratory distress the incidence of perinatal complications was not different from that in other children referred to the Institute for Child Development. In children with developmental disabilities, macrocephaly was a significant risk factor for febrile seizures (odds ratio = 3.1, P < 0.001) and epilepsy (odds ratio = 7.7, P < 0.001), but not for mental retardation (odds ratio = 1.1, P = 0.78) or cerebral palsy (odds ratio = 1.3, P = 0.67). Children with macrocephaly had a high rate of comorbid diagnosis. We conclude that in children with developmental disabilities the presence of macrocephaly even when not associated with hydrocephalus is associated with an increased risk of seizures.

The aim of this study was to determine the features of pseudotumor cerebri or idiopathic intracranial hypertension in prepubertal and pubertal children. We retrospectively reviewed patient charts of those 16 years and younger, diagnosed with pseudotumor cerebri/idiopathic intracranial hypertension. Our study group consisted of 27 patients; the mean age was 10.9 years, and there was a male-to-female ratio of 13 to 14. In the prepubertal group ( n = 13), the male-to-female ratio was 8 to 5; in the pubertal group, ( n = 14), the ratio was 5 to 9. Overweight or obesity was found in 16 (59%) patients. Outcome was favorable except for one who remained symptomatic. Pseudotumor cerebri/idiopathic intracranial hypertension in children is rare. Its characteristics differ from adults. We found the prepubertal group to be a distinct group since pseudotumor cerebri/idiopathic intracranial hypertension did not occur predominantly in females and was not associated with obesity. ( J Child Neurol 2002;17:745—748).

We sought markers for predicting a favorable outcome of botulinum toxin A injected to the lower-extremity muscles of 26 children with hemiplegic or diplegic cerebral palsy. Clinical assessment preceding and 1 month following injection included gross motor function measure, a modified Ashworth scale, and evaluation of range of motion of knee extension and ankle dorsiflexion. Response to treatment was classified based on a parent questionnaire. The 19 children (73%) considered by their parents as being good responders were compared to the 7 (27%) considered as being poor responders. In the good responders, the preinjection Ashworth scale (spasticity) was significantly higher (P < .05) and gross motor function measure scores (function) were lower (P < .05). Sixty-eight percent of the good responders were nonindependent walkers compared to 14% of the poor responders (P < .05). There were no differences in age, type of cerebral palsy, and dose of injection. An Ashworth scale indicating increased muscle tone, lower gross motor function measure scores, and nonindependent ambulatory status were predictive for a favorable response to botulinum toxin A injections and can guide patient selection and expectations of treatment outcome. (J Child Neurol 2002;17:272-277).

BACKGROUND AND PURPOSE: Brain MR imaging is recommended in children with cerebral palsy. Descriptions of MR imaging findings lack uniformity, due to the absence of a validated quantitative approach. We developed a quantitative scoring method for brain injury based on anatomic MR imaging and examined the reliability and validity in correlation to motor function in children with hemiplegia. MATERIALS AND METHODS: Twenty-seven children with hemiplegia underwent MR imaging (T1, T2-weighted sequences, DTI) and motor assessment (Manual Ability Classification System, Gross Motor Functional Classification System, Assisting Hand Assessment, Jebsen Taylor Test of Hand Function, and Children's Hand Experience Questionnaire). A scoring system devised in our center was applied to all scans. Radiologic score covered 4 domains: number of affected lobes, volume and type of white matter injury, extent of gray matter damage, and major white matter tract injury. Inter- and intrarater reliability was evaluated and the relationship between radiologic score and motor assessments determined. RESULTS: Mean total radiologic score was 11.3 ± 4.5 (range 4–18). Good inter- (ρ = 0.909, P < .001) and intrarater (ρ = 0.926, P = < .001) reliability was demonstrated. Radiologic score correlated significantly with manual ability classification systems (ρ = 0.708, P < .001), and with motor assessments (assisting hand assessment [ρ = −0.753, P < .001]; Jebsen Taylor test of hand function [ρ = 0. 766, P < .001]; children's hand experience questionnaire [ρ = −0. 716, P < .001]), as well as with DTI parameters. CONCLUSIONS: We present a novel MR imaging–based scoring system that demonstrated high inter- and intrarater reliability and significant associations with manual ability classification systems and motor evaluations. This score provides a standardized radiologic assessment of brain injury extent in hemiplegic patients with predominantly unilateral injury, allowing comparison between groups, and providing an additional tool for counseling families.

This article describes the neurologic presentations of children with mitochondrial disorders. The charts of 42 children with highly suspect mitochondrial disorders were reviewed. Thirty-seven children were diagnosed as having definite mitochondrial disorders based on a suggestive clinical presentation and at least one accepted criteria, while in five patients the diagnosis remained probable. All patients had nervous system involvement, but it was the presenting symptom in 28 of 42. Eighteen children had normal intelligence and 24 had mental retardation or developmental delay at the onset of their disease. Twenty-five patients had either an acute regression or a progressive encephalopathy. The most frequent neurologic manifestations were abnormal tone, seizures, extrapyramidal movements, and autonomic dysfunction. The eyes were involved in 11 children. Nerve deafness was found in seven patients. Myopathy was found in only six patients. In conclusion, a complex neurologic picture, especially with other organ involvement, warrants a full mitochondrial evaluation. (J Child Neurol 2000; 15:44-48).