Neurologic complications of thiamine (B1) deficiency following bariatric surgery in adolescents.

BACKGROUND: The prevalence of obesity among children and adolescents is rising and poses a major health concern. Bariatric surgery is well established in adults and has become an option for adolescents. Thiamine (B1) deficiency is common following bariatric surgery in adults. It may present as Beri-Beri, Wernicke encephalopathy, or Korsakoff psychosis. OBJECTIVE: Our aim was to describe the clinical features, diagnosis, and treatment of adolescents who presented with B1 deficiency after bariatric surgery at one center, and to summarize the data from the literature. PATIENTS: Three adolescents with morbid obesity (two boys and one girl, aged 15.5 to- 17-years-old), presented at Schneider Children's Medical Center of Israel with progressive lower limb pain and weakness 2-3 month following a bariatric procedure (sleeve gastrectomy or narrowing of a bariatric band). The girl also had upper limb involvement and cerebellar signs. All three were non-compliant with micronutrient supplementation. After admission, they received intravenous B1 and oral multivitamin supplementation, and their symptoms improved considerably. CONCLUSIONS: Micronutrient supplementation following bariatric surgery is crucial to prevent deficiencies. In adolescents, compliance with micronutrient supplementation should be assessed before and after such surgery. Thiamine deficiency may cause polyneuropathy, among other symptoms. Treatment reduces the severity of neurological complications.

Real-Life Outcome After Gene Replacement Therapy for Spinal Muscular Atrophy: A Multicenter Experience.

BACKGROUND: Onasemnogene abeparvovec-xioi (OA) has been available since 2019 as a gene replacement therapy for individuals with spinal muscular atrophy (SMA) under age two years. We aim to expand upon the sparse knowledge about its safety and clinical efficacy. METHODS: The clinical outcome data of all the individuals with SMA who were treated with gene therapy in four tertiary hospitals in Israel were retrieved and analyzed. RESULTS: The study participants included 25 individuals who received the gene therapy between age 11 days and 23 months and whose median follow-up duration was 18.0 (interquartile range [IQR], 12.4 to 18.3) months. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores increased by a median (IQR) of 13 (8 to 20) points at the last follow-up compared with baseline. None of the patients experienced regression in motor abilities after gene therapy, which was generally well tolerated. There was gradual improvement in motor function, especially among presymptomatic patients (P ≤ 0.001) whose disease duration was shorter (≤8 months) before receiving gene therapy (P ≤ 0.001) and who did not experience recurrent infections and illnesses in the months following treatment (P ≤ 0.001). CONCLUSIONS: OA was well tolerated and led to favorable functional motor outcomes at six to 24 months after treatment initiation. Better progress in motor function was observed in individuals who received OA earlier and who were presymptomatic, irrespective of the SMN2 copy number or type. Our results further strengthen the clinical efficacy of OA and reinforce the importance of early recognition of SMA via newborn screening programs.

Evaluation of sputum cultures in children with spinal Muscular atrophy.

BACKGROUND: Spinal Muscular Atrophy (SMA) is a severe neuromuscular disorder. Despite increased survival due to novel therapies, morbidity from respiratory complications still persists. We aim to describe these patients' sputum cultures as an expression of chronic infectious airway disease. METHODS: Retrospective review of medical records of all children with SMA followed at the multidisciplinary respiratory neuromuscular clinic at Schneider Childrens' Medical Center of Israel over a 16-year period. Sputum cultures were obtained during routine visits or pulmonary exacerbations. RESULTS: Sixty-one SMA patients, aged 1 month to 21 years, were included in this cohort. Of these, sputum cultures were collected from 41 patients. Overall, 288 sputum cultures were obtained, and 98 (34%) were negative for bacterial growth. For the first culture taken from each patient, 12 out of 41 (29%) were sterile. The most common bacteria were pseudomonas aeruginosa (PSA) (38%) and staphylococcus aureus (19.6%). PSA was found in SMA type I patients more frequently than in type II patients (15/26 = 58% vs 4/13 = 31%, p < 0.001). PSA infection was positively associated with noninvasive ventilation, recurrent atelectasis, recurrent pneumonias, swallowing difficulties, but no significant association was found with cough assist machine usage. The incidence of positive cultures did not differ between those treated with Onasemnogene abeparvovec or Nusinersen compared to those without treatment, but the age of first PSA isolation was slightly older with Nusinersen treatment (p = 0.01). CONCLUSIONS: Airway bacterial colonization is common in SMA type I patients and is not decreased by Onasemnogene abeparvovec or Nusinersen treatment.

Pulmonary function tests for evaluating the severity of Duchenne muscular dystrophy disease.

AIM: In Duchenne muscular dystrophy (DMD), lung disease contributes significantly to morbidity and mortality. This study aimed to assess the usefulness of various pulmonary function tests in evaluating DMD severity. METHODS: This retrospective study analysed lung function tests of patients with DMD-treated in the multidisciplinary respiratory neuromuscular clinic at Schneiders' Children Medical Center of Israel. Data were analysed according to age, ambulatory status and glucocorticoid treatment. RESULTS: Among 90 patients with DMD, 40/63 (63.5%) ambulatory patients and 22/27 (81.5%) nonambulatory patients successfully performed spirometry. Significant annual declines were demonstrated among nonambulatory patients, in percentile predicted forced vital capacity (3.8%) and in total lung capacity (5.5%) per year. The decline correlated with age and loss of ambulation but not with steroid treatment. Peak cough flow values were randomly distributed and did not correlate with age, ambulation or treatment. In nonambulatory patients, transcutaneous carbon dioxide measurement correlated significantly with age (r = 0.55, p = 0.02). CONCLUSION: Forced vital capacity, total lung capacity and transcutaneous carbon dioxide correlated with the clinical severity of disease in children with DMD. These measures may be useful in follow-up and clinical trials. A comparable correlation was not found for peak cough flow.

Adeno-associated virus serotype 9 antibody titers in patients with SMA pre-screened for treatment with onasemnogene abeparvovec -routine care evidence.

Spinal muscular atrophy (SMA) is characterized by progressive weakness of skeletal and respiratory muscles. This study aimed to evaluate the prevalence of pre-existing anti adeno-associated virus serotype 9 antibody (AAV9-Ab) titers among infantile-onset SMA diagnosed infants pre-screened for treatment with AAV9-based onasemnogene abeparvovec, and to explore whether clinical and/or demographic characteristics are correlated with AAV9 Ab test results. This is a retrospective multicenter study of children diagnosed with 5q SMA younger than two years of age. The obtained data included demographic data, SMA type, SMN2 gene copy number, onset date, and results of AAV9-Ab test and of SMA prior treatments. Thirty-four patients were enrolled; six patients had positive results of AAV9-Ab (titer > 1:50) in the initial screening, 15 patients were re-tested for AAV9-Abs, of whom, three patients had seroreverted [1.5-4.5 months] between the two AAV9-Abs tests. One patient had seroconverted (5.5 months after the first AAV9-Abs test). The remaining 11 patients presented matching titer results in the two tests. No demographic/clinical factors were correlated to high AAV9-Abs titers (P > 0.05).We recommend AAV9-Ab re-tests to be performed until the age of 8 months, or, if 1.5 months or more have passed after the initial AAV9-Abs test.

Clinical improvement of a toddler with COVID-19 focal cerebral arteriopathy possibly due to intra-arterial nimodipine.

Pediatric stroke is considered an infrequent complication of COVID-19. Focal cerebral arteriopathy (FCA) is one of the most common causes of arterial ischemic stroke in a previously healthy child. The present report describes a toddler with FCA most likely induced by SARS-CoV-2 infection who showed significant clinical improvement that may be related to injection of intra-arterial nimodipine. To our knowledge, this is the first reported use of nimodipine in this setting.

Muscle microRNAs in the cerebrospinal fluid predict clinical response to nusinersen therapy in type II and type III spinal muscular atrophy patients.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The Utility of Early Brain MRI for Patients with Neurofibromatosis Type 1 and Optic Pathway Glioma: A Long-Term Follow-Up in a Tertiary Referral Hospital.

Screening studies have shown detection of optic pathway gliomas (OPGs) in 8 to 31% of children with neurofibromatosis type 1 (NF1). Many of those affected show prolonged indolent phases, but others develop vision disturbances even before diagnosis and treatment. We assessed the clinical presentation at diagnosis, location, natural progression, and risk factors for impaired vision of OPG. The clinical database of the NF1 multidisciplinary clinic of Schneider Children's Medical Center of Israel was reviewed for all patients diagnosed and followed with NF1 during 2007 to 2019. OPG was diagnosed by hyperintensity and thickening along the optic pathway on T2-weighted brain magnetic resonance imaging (MRI), with or without contrast enhancement. Of 257 children with NF1 who underwent MRI, 57 (22%) were diagnosed with OPG; 31 (54%) were females. Twenty-five (44%) had familial NF1. Fifteen (26%) who exhibited tumor progression and worsening in ophthalmic examinations required treatment. Post-chiasmatic glioma was a predictive factor for treatment (p < 0.05), whereas MRI done later and female gender were not significant. Four patients who eventually needed therapy had normal ophthalmic examinations at least 1 year prior to their first MRI. For 6 (40%) of the patients treated, vision continued to worsen. Our findings demonstrate that normal ophthalmic examinations do not always exclude OPG in children with NF1. Early brain MRI before age 36 months may detect OPG, lead to better follow-up and early treatment, and help improve vision outcome.

Impairments in communication and social interaction in children with neurofibromatosis type 1: Characteristics and role of ADHD and language delay.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a multisystem neurocutaneous disorder with increased risk of tumor formation and higher incidence of autism spectrum disorder (ASD) than the general population. The aim of the study was to assess the presence of ASD symptoms in young children with NF1 and to examine their potential association with attention deficit hyperactivity disorder (ADHD) and speech delay. METHODS: The cohort included 30 patients with NF1 attending the multidisciplinary NF1 clinic of a tertiary pediatric medical center from September 2015 through September 2016. The parents/caregivers completed the Social Communication Questionnaire (SCQ) and the Vineland Adaptive Behavior Scales (VABS II). RESULTS: Sixteen patients (53%) had a previous diagnosis of ADHD. There was a positive association between the presence of ADHD and a low score on the VABS II interpersonal relationships subscale of the Socialization domain. Language delay, documented in 12 children (40%), also correlated with a low interpersonal relationships score. CONCLUSIONS: ADHD appears to be more a marker than an actual independent risk factor of ASD in NF1. The early evaluation of children with NF1 for interpersonal communication problems and ASD, especially those with a speech delay or ADHD, will alert clinicians to initiate appropriate and timely treatment.

COVID-19 in advanced Duchenne/Becker muscular dystrophy patients.

Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy. As a result of progressive muscle weakness, pulmonary function decreases during the second decade of life and lung disease contributes significantly to morbidity and mortality in these patients. Corticosteroids are the current standard of care for patients with DMD, despite known adverse effects such as obesity and immunosuppression. Over the past year (2020), the novel coronavirus (COVID-19/SARS-CoV2) outbreak has caused a global pandemic. Restrictive lung disease due to low lung volumes, chronic immunosuppressive treatment with corticosteroids, and obesity are potential risk factors that may contribute to a more severe course of the disease. Out of 116 Duchenne/Becker muscular dystrophy patients treated in our tertiary neuromuscular center, six patients with DMD and one with advanced Becker muscular dystrophy were found to be positive for COVID-19 infection. Two of the DMD patients were admitted for hospitalization, of whom one was dependent on daily nocturnal non-invasive ventilation. All patients recovered without complications despite obesity, steroid treatment and severe restrictive lung disease.

Impact of a national population-based carrier-screening program on spinal muscular atrophy births.

Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease. Population carrier screening for SMA was introduced in Israel in 2008 through health-care services' insurance plans and expanded to the entire Israeli population in 2013 by a national health program. The aim of the study was to evaluate the impact of carrier screening on reducing the rate of birth of infants with SMA. All cases of prenatal and postnatal diagnosis of SMA in 2008-2017 were identified from databases of relevant government organizations, genetic laboratories in medical centers, and health care systems in Israel. Since 2013, screening was performed in 309,352 individuals, of whom 5741 were found to be carriers (carrier rate 1:54). Given an average of 180,000 live births annually, the predicted rate of SMA diagnosis was 15 cases per year. Prior to 2013, the average rate of prenatally diagnosed SMA was 4.66 cases per year, compared with 7.75 cases per year following population-wide provision of screening. The annual rate of postnatally diagnosed cases remained steady since 2008, with an average of 7- 7.25 cases per year. Screening has been effective in increasing prenatal detection of SMA but has had no effect on the rate of confirmed postnatal diagnoses. We speculate that screening rates may be affected by social, cultural, and religious factors.

Prognostic Parameters of Acute Transverse Myelitis in Children.

Acute transverse myelitis is a rare and disabling disorder. Data on the imaging features in children are sparse. The aim of this study was to describe the clinical and magnetic resonance imaging findings characteristic of pediatric idiopathic acute transverse myelitis and to identify those with prognostic value. The database of a tertiary pediatric medical center was retrospectively reviewed for patients aged less than 18 years who were diagnosed in 2002-2017 with acute transverse myelitis that was not associated with recurrence of a demyelinating autoimmune event. Data were collected on clinical, laboratory, and imaging findings and outcome. A total of 23 children (11 male, 12 female) met the study criteria. Mean age at disease onset was 10 years, and mean duration of follow-up was 6 years 10 months. Spinal cord and brain magnetic resonance imaging scans were performed on admission or shortly thereafter. The most common finding was cross-sectional involvement, in 16 patients (70%). The mean number of involved spinal segments was 8. The most frequently involved region was the thoracic spine, in 17 patients (74%). Clinical factors predicting good prognosis were cerebrospinal fluid pleocytosis, absence of tetraparesis, and prolonged time to nadir. In conclusion, most children with acute transverse myelitis appear to have a good outcome. Prompt diagnosis and treatment are important. Further research is needed in a larger sample to evaluate the predictive value of imaging features.

Evolution of EEG Findings in Pontocerebellar Hypoplasia Type 2A: Normal EEG in the First Few Months followed by Abnormal Tracing over the Years.

Pontocerebellar hypoplasia (PCH) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by cerebellar and pontine hypoplasia, progressive microcephaly, and developmental delay. Ten types of PCH have been described; PCH type 2A (PCH2A) due to a mutation in TSEN54 is the most frequent. Seizures have been reported in the large majority of patients. The probability of epilepsy developing increases with age, along with difficulties in differentiating seizures from dyskinetic movements. The aim of the present report was to describe the clinical symptoms and electroencephalogram (EEG) changes over time in three patients of Israeli Arab origin with PCH2A. All three, including two siblings and their first cousin, were homozygous for the TSEN54 p.A304S mutation. The patients demonstrated profound psychomotor retardation, severe spasticity and contractures, choreoathetoid movements, and seizures. The magnetic resonance imaging (MRI) scans and EEGs were reviewed by an experienced neuroradiologist and epileptologist, respectively. The MRI scans revealed a dragonfly-like cerebellar pattern in all patients. Despite the normal early EEG findings, all patients had characteristic features of epilepsy, with tonic seizures starting in the first days to months followed by focal to bilateral tonic-clonic seizures in early childhood which continued to adolescence. In conclusion, patients with PCH2A due to the missense mutation p.A304S in TSEN54 exhibit profound psychomotor delay, movement disorders, and intractable epilepsy. An evolution of EEG abnormalities and seizure semiology occurs over time. Similar to several other genetic epileptic encephalopathies, the normal early EEG tracing does not rule out the later occurrence of epilepsy.

Small-fiber neuropathy associated with autoinflammatory syndromes in children and adolescents.

INTRODUCTION: Small-fiber neuropathy is rare in children. It has been associated with several autoimmune disorders, but there are no reports of an autoinflammatory etiology. METHODS: The data of four children/adolescents presenting with erythromelalgia and neuropathic pain from 2014 to 2019 were collected retrospectively from the electronic database of a pediatric medical center. RESULTS: Results of clinical and/or electrophysiological evaluation excluded large nerve fiber involvement. Skin biopsy results confirmed small-fiber neuropathy. According to genetic analysis, two patients were heterozygous and one was homozygous for mutations in the familial Mediterranean fever (MEFV) gene. Behcet disease was diagnosed in the fourth patient. Treatment with anti-interleukin-1 agents, intravenous immunoglobulin, and glucocorticoids was beneficial. DISCUSSION: The diagnosis of small-fiber neuropathy should be considered in children/adolescents presenting with erythromelalgia. A thorough investigation is required to reveal the underlying disorder. Clinicians should be alert to the peripheral neurological manifestations of autoinflammatory syndromes because effective treatments are available.

Handwriting in children with Attention Deficient Hyperactive Disorder: role of graphology.

BACKGROUND: Handwriting difficulties are common in children with attention deficient hyperactive disorder (ADHD). The aim of our study was to find distinctive characteristics of handwriting in children with ADHD by using graphology to analyze physical characteristics and patterns, and to evaluate whether graphological analysis is an effective ADHD diagnostic tool for clinicians. METHOD: The cohort included 49 children aged 13-18 years attending a tertiary neurology and epilepsy center in 2016-2017; 22 had a previous DSM-IV/V diagnosis of ADHD. The children were asked to write a 10-12-line story in Hebrew on a blank sheet of paper with a blue pen over a 20-min period. The samples were analyzed by a licensed graphologist blinded to the clinical details of the children against a predetermined handwriting profile of individuals with ADHD. Each ADHD characteristic identified in each sample was accorded 1 point, up to a total of 15 points. Patients with a graphology score of 9-15 were considered to have ADHD. RESULTS: There were 21 boys (43%) and 28 girls (57%) in the cohort; 15 boys (71.4%) and 7 girls (25%) had a DSM-IV/V diagnosis of ADHD. The mean graphology score was significantly higher in the children who had a DSM-IV/V diagnosis of ADHD than in the children who did not (9.61 + 3.49 vs. 5.79 + 4.01, p = 0.002, respectfully). Using a score of 9 as the cutoff, in the girls, graphology had a specificity of 80% (95% CI 59.2-92.8) and a of sensitivity 71.4% for predicting ADHD. Corresponding values in the boys were 75.0 and 76.2%. CONCLUSION: The handwriting of children with ADHD has specific characteristics. Graphology may serve as a clinically useful tool in the diagnosis of ADHD.

Atypical Clinical Presentations of Pediatric Acute Immune-Mediated Polyneuropathy.

Guillain-Barré syndrome (GBS) is the most common cause of acute flaccid paralysis in children. During the acute phase, the disorder can be life-threatening by involving the respiratory muscles and the autonomic nervous system. Nevertheless, the prognosis is good, and most children achieve full recovery. The aim of this study was to characterize the clinical and electrophysiologic findings in children with Guillain-Barré syndrome referred to a tertiary center in Israel. A retrospective database review from 2009 to 2015 identified 39 children. Data on clinical presentation, respiratory complications, and long-term neurologic outcomes were collected. Atypical clinical findings at admission included asymmetric weakness in 23%, nonascending weakness in 30%, and normal deep tendon reflexes in 28%. Eight children were later diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Electrophysiologic findings, available in 12 patients with Guillain-Barré syndrome, revealed acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in 4 (33.5%), AIDP with secondary axonal changes in 3 (25%), and acute motor axonal neuropathy (AMAN) subtype in 4 (33.5%); 8% had no abnormal findings. On follow-up, 71% of the children with Guillain-Barré syndrome fully recovered compared to 14% of the children with CIDP. Corresponding rates of neurologic sequelae were 29% and 86%. Clinicians should be alert to the atypical presenting symptoms of Guillain-Barré syndrome, which occur in a significant proportion of children.

Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy.

Histidyl-tRNA synthetase (HARS) ligates histidine to cognate tRNA molecules, which is required for protein translation. Mutations in HARS cause the dominant axonal peripheral neuropathy Charcot-Marie-Tooth disease type 2W (CMT2W); however, the precise molecular mechanism remains undefined. Here, we investigated three HARS missense mutations associated with CMT2W (p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly). The three mutations localize to the HARS catalytic domain and failed to complement deletion of the yeast ortholog (HTS1). Enzyme kinetics, differential scanning fluorimetry (DSF), and analytical ultracentrifugation (AUC) were employed to assess the effect of these substitutions on primary aminoacylation function and overall dimeric structure. Notably, the p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly HARS substitutions all led to reduced aminoacylation, providing a direct connection between CMT2W-linked HARS mutations and loss of canonical ARS function. While DSF assays revealed that only one of the variants (p.Val155Gly) was less thermally stable relative to wild-type, all three HARS mutants formed stable dimers, as measured by AUC. Our work represents the first biochemical analysis of CMT-associated HARS mutations and underscores how loss of the primary aminoacylation function can contribute to disease pathology.

Thick Corpus Callosum in Children.

BACKGROUND AND PURPOSE: A thick corpus callosum (TCC) can be associated with a very grave outcome in fetuses, but its clinical presentation in older children seems to be markedly different. METHODS: The corpus callosum (CC) was defined as thick based on observations and impressions. We reviewed cases of children who were diagnosed as TCC based on brain magnetic resonance imaging (MRI) studies. The pertinent clinical data of these children were collected, and their CCs were measured. RESULTS: Out of 2,552 brain MRI images, those of 37 children were initially considered as showing a TCC. Those initial imaging were reviewed by an experienced neuroradiologist, who confirmed the diagnosis in 34 children (1.3%): 13 had neurofibromatosis-1 (NF-1), 9 had epilepsy, 3 had macrocephaly capillary malformation (MCM) syndrome, 3 had autistic spectrum disorder, 1 had a Chiari-1 malformation, and 1 had increased head circumference. No specific neurologic disorder could be defined in seven children. The measured thickness of the CC in these children was comparable to those published in the literature for adults. CONCLUSIONS: A TCC is a rare brain malformation that can be found in neuropathologies with apparently diverse pathognomonic mechanisms, such as NF-1 and MCM. It is not necessarily associated with life-threatening conditions, instead being a relatively benign finding, different in nature from that reported in fetuses.

Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome.

We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is crucial for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1lew/lew mice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1 homozygous mutations as a cause of presynaptic CMS. Ann Neurol 2017;81:597-603.

Congenital myasthenic syndrome in Israel: Genetic and clinical characterization.

The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND, CHAT, GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ, RAPSN, and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected.