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Background: Myotonia is the main feature of both myotonic dystrophy (DM) and non-dystrophic myotonia (NDM). It is felt as stiffness, pain, fatigue, and weakness. In France, mexiletine, a non-selective voltage-gated sodium channel blocker, is approved for the treatment of myotonia in adults with NDM, and it has a temporary recommendation for use in the symptomatic treatment of DM in adults. However, it is not currently licensed for treating myotonia in children due to the lack of studies on its use in pediatrics. This has meant heterogeneous practices in its utilization and has led to prescriber reluctance, which has jeopardized accessibility. We undertook a professional practice survey of French pediatric neuromuscular centers to determine their prescribing habits for mexiletine, assessing indications, doses, efficacy, and tolerance., Methods: One medical pediatric professional from each French pediatric neuromuscular center belonging to the national neuromuscular network (FILNEMUS) was invited to complete an anonymous questionnaire., Results: In total, 34 healthcare professionals responded. Of these, 16 had already treated a child for myotonia with mexiletine. Mexiletine was prescribed in one third of pediatric patients with NDM, but it was used in only 3% of DM type 1 patients and in no DM type 2 patients. Pre-treatment assessment always included a cardiac evaluation; however, the method of introduction (inpatient vs. outpatient basis), dosage adjustment, and efficacy evaluation ranged widely. More than half of the respondents reported a high efficacy of mexiletine in their patients; only three reported moderate adverse events (dyspepsia, loss of appetite, and asthenia)., Conclusion: The findings of this first survey on mexiletine for pediatric myotonia in France lend support for the creation of future national guidelines., Competing Interests: Declaration of competing interest - Christine Barnerias and Arnaud Isapof are investigators in the following clinical study: ClinicalTrials NCT04624750 - Christine Barnerias, Catherine Sarret, Yann Pereon, Karim Wahbi, and Arnaud Isapof have participated in industrial symposia for, or have been on the scientific board of, Lupin Pharmaceuticals., (Copyright © 2025. Published by Elsevier Masson SAS.)

The molecular diagnosis of type 1 facioscapulohumeral muscular dystrophy (FSHD1) relies on the detection of a shortened D4Z4 array at the 4q35 locus. Until recently, the diagnosis of FSHD2 relied solely on the absence of a shortened D4Z4 allele in clinically affected patients. It is now established that most FSHD2 cases carry a heterozygous variant in the SMCHD1 gene. A decrease in D4Z4 DNA methylation is observed in both FSHD1 and FSHD2 patients. To refine the molecular diagnosis of FSHD2, we performed a molecular diagnosis of SMCHD1 in 54 patients with a clinical diagnosis of FSHD. All patients carry a D4Z4 array of more than 10 D4Z4 units, or a cis-duplication of the locus. Forty-eight of them carry a variant in SMCHD1 and six other cases are hemizygous for the 18p32 locus encompassing SMCHD1. Genetic and epigenetic analyses were considered to assess the pathogenicity of new SMCHD1 variants and of variants previously classified as likely pathogenic. In comparison to the healthy population and FSHD1 patients, we defined a threshold of 40% of methylation at the D4Z4 DR1 site as associated with SMCHD1 variants or SMCHD1 hemizygosity. We also showed that the number of D4Z4 on the shortest 4q allele ranges from 11 up to 35 units in these same patients. Using variant interpretation and protein structure prediction tools, we also highlight the difficulty in interpreting the impact of pathogenic variants on SMCHD1 function. Our study further emphasizes the intriguing relationship between D4Z4 methylation, SMCHD1 variants with SMCHD1 protein structure-function in FSHD., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: All individuals have provided written informed consent for the use of DNA sample for medical research and the study was done in accordance with the Declaration of Helsinki. Samples were provided by the Center for biological Resources (Department of Medical Genetics, La Timone Children’s hospital) with the AC 2011-1312 and N°IE-2013-710 accreditation numbers., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous diseases caused by mutations affecting neuromuscular transmission. Even if the first symptoms mainly occur during childhood, adult neurologists must confront this challenging diagnosis and manage these patients throughout their adulthood. However, long-term follow-up data from large cohorts of CMS patients are lacking, and the long-term prognosis of these patients is largely unknown. We report the clinical features, diagnostic difficulties, and long-term prognosis of a French nationwide cohort of 235 adult patients with genetically confirmed CMS followed in 23 specialized neuromuscular centres. Data were retrospectively analysed. Of the 235 patients, 123 were female (52.3%). The diagnosis was made in adulthood in 139 patients, 110 of whom presented their first symptoms before the age of 18. Mean follow-up time between first symptoms and last visit was 34 years [standard deviation (SD) = 15.1]. Pathogenic variants were found in 19 disease-related genes. CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%). Genotypes were clustered into four groups according to the initial presentation: ocular group (CHRNE-LE, CHRND, FCCMS), distal group (SCCMS), limb-girdle group (RAPSN, COLQ, DOK7, GMPPB, GFPT1), and a variable-phenotype group (MUSK, AGRN). The phenotypical features of CMS did not change throughout life. Only four genotypes had a proportion of patients requiring intensive care unit admission that exceeded 20%: RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%). In RAPSN and MUSK patients most ICU admissions occurred before age 18 years and in DOK7 and AGRN patients at or after 18 years of age. Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another in the same patient throughout life, particularly in AGRN, DOK7 and COLQ. At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation; 36.3% of DOK7 patients, 25% of GMPPB patients and 20% of GFPT1 patients were wheelchair-bound; most of the patients who were both wheelchair-bound and ventilated were DOK7 patients. Six patients died in this cohort. The positive impact of therapy was striking, even in severely affected patients. In conclusion, even if motor and/or respiratory deterioration could occur in patients with initially moderate disease, particularly in DOK7, SCCMS and GFPT1 patients, the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit. CHRNE-LE patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Proximal spinal muscular atrophy (SMA) is defined by a degeneration of the anterior horn cells resulting in muscle weakness predominantly in the proximal lower limbs. While most patients carry a biallelic deletion in the SMN1 gene (localized in chromosome 5q), little is known regarding patients without SMN1-mutation, and a genetic diagnosis is not always possible. Here, we report a cohort of 24 French patients with non-5q proximal SMA from five neuromuscular centers who all, except two, had next-generation sequencing (NGS) gene panel, followed by whole exome sequencing (WES) if gene panel showed a negative result. The two remaining patients benefited directly from WES or whole genome sequencing (WGS). A total of ten patients with causative variants were identified, nine of whom were index cases (9/23 families = 39%). Eight variants were identified by gene panel: five variants in DYNC1H1, and three in BICD2. Compound heterozygous causative variants in ASAH1 were identified directly by WES, and one variant in DYNC1H1 was identified directly by WGS. No causative variant was found using WES in patients with a previous panel with negative results (14 cases). We thus recommend using primarily NGS panels in patients with non-5q-SMA and using WES, especially when several members of the same family are affected and/or when trio analyses are possible, or WGS as second-line testing if available., (© 2023. The Author(s).)

Pediatric chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired immune-mediated disorder of the peripheral nervous system with a number of diagnostic pitfalls. A subset of treatment-resistant CIDP adult patients have been found with antibodies against paranodal proteins. We report the first pediatric case in a 14 year-old adolescent with a severe CIDP phenotype in whom positive anti-neurofascin 155 antibodies were found in his serum. Resistant to conventional therapies, he showed dramatic improvement when treated with Rituximab with mild to moderate functional motor disability at 24 month follow-up. In pediatric CIDP patients that remain refractory to conventional treatments, the presence of antibodies to paranodal proteins warrants investigation as it can have potential therapeutic guidance., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Facioscapulohumeral dystrophy (FSHD) is a late-onset autosomal dominant form of muscular dystrophy involving specific groups of muscles with variable weakness that precedes inflammatory response, fat infiltration, and muscle atrophy. As there is currently no cure for this disease, understanding and modelling the typical muscle weakness in FSHD remains a major milestone towards deciphering the disease pathogenesis as it will pave the way to therapeutic strategies aimed at correcting the functional muscular defect in patients., Methods: To gain further insights into the specificity of the muscle alteration in this disease, we derived induced pluripotent stem cells from patients affected with Types 1 and 2 FSHD but also from patients affected with Bosma arhinia and microphthalmia. We differentiated these cells into contractile innervated muscle fibres and analysed their transcriptome by RNA Seq in comparison with cells derived from healthy donors. To uncover biological pathways altered in the disease, we applied MOGAMUN, a multi-objective genetic algorithm that integrates multiplex complex networks of biological interactions (protein-protein interactions, co-expression, and biological pathways) and RNA Seq expression data to identify active modules., Results: We identified 132 differentially expressed genes that are specific to FSHD cells (false discovery rate < 0.05). In FSHD, the vast majority of active modules retrieved with MOGAMUN converges towards a decreased expression of genes encoding proteins involved in sarcomere organization (P value 2.63e -12 ), actin cytoskeleton (P value 9.4e -5 ), myofibril (P value 2.19e -12 ), actin-myosin sliding, and calcium handling (with P values ranging from 7.9e -35 to 7.9e -21 ). Combined with in vivo validations and functional investigations, our data emphasize a reduction in fibre contraction (P value < 0.0001) indicating that the muscle weakness that is typical of FSHD clinical spectrum might be associated with dysfunction of calcium release (P value < 0.0001), actin-myosin interactions, motor activity, mechano-transduction, and dysfunctional sarcomere contractility., Conclusions: Identification of biomarkers of FSHD muscle remain critical for understanding the process leading to the pathology but also for the definition of readouts to be used for drug design, outcome measures, and monitoring of therapies. The different pathways identified through a system biology approach have been largely overlooked in the disease. Overall, our work opens new perspectives in the definition of biomarkers able to define the muscle alteration but also in the development of novel strategies to improve muscle function as it provides functional parameters for active molecule screening., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Subtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. The disease also segregates with a specific A-type haplotype containing a degenerated polyadenylation signal distal to the last repeat followed by a repetitive array of β-satellite elements. This classification applies to most patients with FSHD. A subset of patients called FSHD2 escapes this definition and carries a mutation in the SMCHD1 gene. We also recently described patients carrying a complex rearrangement consisting of a cis -duplication of the distal 4q35 locus identified by molecular combing., Methods: Using this high-resolution technology, we further investigated the organisation of the 4q35 region linked to the disease and the 10q26 locus presenting with 98% of homology in controls and patients., Results: Our analyses reveal a broad variability in size of the different elements composing these loci highlighting the complexity of these subtelomeres and the difficulty for genomic assembly. Out of the 1029 DNA samples analysed in our centre in the last 7 years, we also identified 54 cases clinically diagnosed with FSHD carrying complex genotypes. This includes mosaic patients, patients with deletions of the proximal 4q region and 23 cases with an atypical chromosome 10 pattern, infrequently found in the control population and never reported before., Conclusion: Overall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease., Competing Interests: Competing interests: A patent application (No. EP08165310.7) on molecular combing for the diagnosis of FSHD1 and exploration of D4Z4 has been registered by Genomic Vision, University of the Mediterranean, and Public Assistance of the Hospitals of Marseille. NL is a co-inventor of the patent., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation., Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]., Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach., Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.

Objective: To genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management., Methods: Among the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed., Results: We studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce., Conclusions: The pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning., (© 2019 American Academy of Neurology.)

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder characterized by progressive motor and respiratory decline during the first year of life. Early and late-onset cases have recently been reported, although not meeting the established diagnostic criteria, these cases have been genotyped. We thus conducted a national multicenter observational retrospective study to determine the prognosis of children with SMARD1 according to their phenotype. We recorded all known French pediatric cases with mutations identified on the immunoglobulin μ-binding protein 2 gene and the presence of respiratory symptoms. Thirty centers provided 22 observations. A diaphragmatic palsy was diagnosed 1.5 months (p = 0.02) after first respiratory symptoms, and hypotonia preceded areflexia by 4 months (p = 0.02). Early onset of symptoms leading to specialist consultation before the age of 3 months was associated with a significantly worse prognosis (p < 0.01). Among the 6 patients who were still alive, all were tracheostomized. Only one case survived beyond 2 years without artificial ventilation. The remaining patients died at a median age of 7 months. Our results may help pediatricians to provide medical information to parents and improve the decision-making process of setting up life support., (Copyright © 2018 Elsevier B.V. All rights reserved.)

SCN8A encephalopathy is a newly defined epileptic encephalopathy caused by de novo mutations of the SCN8A gene. We report herein a four-year-old boy presenting with severe non-epileptic abnormal movements, of possibly antenatal onset, progressively associated with pharmacoresistant epilepsy and regression, associated with a de novo heterozygous missense mutation of SCN8A. This case shows that paroxysmal non-epileptic episodes of severe tremor and hyperekplexia-like startles and a striking vegetative component can be the first early symptoms of severe SCN8A developmental and epileptic encephalopathy. Clinicians should be aware of these symptoms in order to avoid misdiagnosis and ensure early appropriate therapeutic management. [Published with video sequences on www.epilepticdisorders.com].

Background: 18p deletion syndrome is a rare disorder caused by partial or full monosomy of the short arm of chromosome 18. Clinical symptoms caused by 18p hemizygosity include cognitive impairment, mild facial dysmorphism, strabismus and ptosis. Among other genes, structural maintenance of chromosomes flexible hinge domain containing 1 ( SMCHD1 ) is hemizygous in most patients with 18p deletions. Digenic inheritance of a SMCHD1 mutation and a moderately sized D4Z4 repeat on a facioscapulohumeral muscular dystrophy (FSHD) permissive genetic background of chromosome 4 can cause FSHD type 2 (FSHD2)., Objectives: Since 12% of Caucasian individuals harbour moderately sized D4Z4 repeats on an FSHD permissive background, we tested if people with 18p deletions are at risk of developing FSHD., Methods: To test our hypothesis we studied different cellular systems originating from individuals with 18p deletions not presenting FSHD2 phenotype for transcriptional and epigenetic characteristics of FSHD at D4Z4. Furthermore, individuals with an idiopathic muscle phenotype and an 18p deletion were subjected to neurological examination., Results: Primary fibroblasts hemizygous for SMCHD1 have a D4Z4 chromatin structure comparable with FSHD2 concomitant with DUX4 expression after transdifferentiation into myocytes. Neurological examination of 18p deletion individuals from two independent families with a moderately sized D4Z4 repeat identified muscle features compatible with FSHD., Conclusions: 18p deletions leading to haploinsufficiency of SMCHD1 , together with a moderately sized FSHD permissive D4Z4 allele, can associate with symptoms and molecular features of FSHD. We propose that patients with 18p deletion should be characterised for their D4Z4 repeat size and haplotype and monitored for clinical features of FSHD., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: In young patients with mononeuropathy who lack family history and precipitating factors, hereditary neuropathy with liability to pressure palsy (HNPP) may be a possibility. Our objective is to propose neurophysiological criteria for HNPP in patients <30 years of age., Methods: We conducted a national multicenter retrospective clinical and neurophysiological study in patients under 30 with genetically confirmed HNPP., Results: All of the 51 patients included in the study had at least 1 demyelinating pattern in 2 asymptomatic nerves, and 3 abnormalities were found in almost 90%, including slowed motor nerve conduction velocity across the elbow in at least 1 ulnar nerve (97.5%), increased distal motor latency (DML) in at least 1 fibular nerve (95.8%), and increased DML in both median nerves (89%). Age influenced DML slightly only in the fibular nerve., Discussion: Dissemination of nerve involvement in HNPP incites to perform a complete nerve conduction study. including bilateral ulnar, fibular, and median nerves. Muscle Nerve 57: 217-221, 2018., (© 2017 Wiley Periodicals, Inc.)

Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb-girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients' muscle biopsies. We report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which nine are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from three unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation-reinnervation processes affecting the three main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extra-junctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a "tubular aggregates myopathy with synaptopathy".

Guillain-Barré syndrome is a rare acute polyradiculoneuropathy. Several variants and unusual presentations have been described, particularly in pediatrics. In most cases, making an early diagnosis is challenging due to the treatments that consist in the rapid administration of intravenous immunoglobulin or plasma exchange. The authors present the case of a 7-year-old boy with an atypical and severe axonal Guillain-Barré syndrome, associated with Mycoplasma pneumonia . When he was admitted, febrile respiratory failure was the main focus, and then he presented signs of acute polyneuropathy with cranial nerve palsy and brief hyperreflexia. Mechanical ventilation was required for 48 days as well as 2 cycles of intravenous immunoglobulin. The authors describe all the medical challenges that the authors encountered. This case highlights the fact that respiratory distress can be the main clinical symptom in children. This delays the establishment of a correct diagnosis, even more so when neurological manifestations are abundant and unusual., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Dystrophinopathies, either the severe Duchenne Muscular Dystrophy (DMD) or the milder Becker Muscular Dystrophy (BMD), are X-linked recessive disorders caused by mutations in the DMD gene. DMD is one of the longest human genes. Large deletions or duplications account for 60-80% of the mutations. Remaining anomalies consist in point mutations or small rearrangements. Routinely, the molecular diagnosis is done by a Multiplex Ligation-dependent Probe Amplification (MLPA) or array Comparative Genome Hybridization (aCGH), followed, if negative, by Sanger sequencing of all exons., Methods: In this study, massive parallel sequencing (MPS) or next generation sequencing (NGS) was used to make a rapid and costless molecular diagnosis in a young boy suspected of DMD., Results: A small deletion: NM&#95;004006.2:c.2803+5&#95;2803+8del was identified. The diagnosis was performed in one single manipulation and within a week. The consequence of this intronic mutation is a skipping of exon 21 confirmed by mRNA and protein analysis., Conclusions: NGS appears to be an efficient new strategy in DMD molecular diagnosis. It highlights the major evolution of the diagnostic strategy towards high throughput technologies, where bioinformatics analysis becomes the real challenge for variations detection. This is the first study reporting in vivo impact of this intronic mutation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca(2+) sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding., (© 2014 WILEY PERIODICALS, INC.)

Background Context: Combined monitoring of muscle motor evoked potentials elicited by transcranial electric stimulation (TES-mMEP) and cortical somatosensory evoked potentials (cSSEPs) is safe and effective for spinal cord monitoring during scoliosis surgery. However, TES-mMEP/cSSEP is not always feasible. Predictors of feasibility would help to plan the monitoring strategy., Purpose: To identify predictors of the feasibility of TES-mMEP/cSSEP during scoliosis surgery., Study Design/setting: Prospective cohort study in a clinical neurophysiology unit and pediatric orthopedic department of a French university hospital., Patient Sample: A total of 103 children aged 2 to 19 years scheduled for scoliosis surgery., Outcome Measures: Feasibility rate of intraoperative TES-mMEP/cSSEP monitoring., Methods: All patients underwent a preoperative neurological evaluation and preoperative mMEP and cSSEP recordings at both legs. For each factor associated with feasibility, we computed sensitivity, specificity, positive predictive value (PPV), and negative predictive value. A decision tree was designed., Results: Presence of any of the following factors was associated with 100% feasibility, 100% specificity, and 100% PPV: idiopathic scoliosis, normal preoperative neurological findings, and normal preoperative mMEP and cSSEP recordings. Feasibility was 0% in the eight patients with no recordable mMEPs or cSSEPs during preoperative testing. A decision tree involving three screening steps can be used to identify patients in whom intraoperative TES-mMEP/cSSEP is feasible., Conclusions: Preoperative neurological and neurophysiological assessments are helpful for identifying patients who can be successfully monitored by TES-mMEP/cSSEP during scoliosis surgery., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Transcranial electric stimulation elicited muscle motor evoked potentials (TESmMEPs) is one of the best methods for corticospinal tract's function monitoring during spine and spinal cord surgeries. A train of multipulse electric stimulation is required for eliciting TESmMEPs under general anaesthesia. Here, we investigated the best stimulation parameters for eliciting and recording tibialis anterior's TESmMEPs during paediatric scoliosis surgery., Patients and Methods: Numbers of pulses (NOP), inter-stimulus intervals (ISI) and current intensities allowing the best size tibialis anterior muscle's TESmMEPs under general anaesthesia, were tested and collected during 77 paediatric scoliosis surgery monitoring procedures in our hospital. Individual pulse duration was kept at 0.5 ms and stimulating electrodes were positioned at C1 and C2 (International 10-20-EEG-System) during all the tests., Results: The NOP used for eliciting the best tibialis anterior TESmMEPs response was 5, 6, and 7 respectively in 21 (27%), 47 (61%) and 9 (12%) out of the 77 patients. The ISI was 2, 3 and 4 ms respectively in 13 (17%), 55 (71%) and 9 (12%) of them. The current intensity used varied from 300 to 700 V (mean: 448±136 V)., Conclusion: Most patients had 6 as best NOP (61%) and 3 ms as best ISI (71%). These findings support that a NOP of 6 and an ISI of 3 ms should be preferentially used as optimal stimulation settings for intraoperative tibialis anterior muscle's TESmMEPs eliciting and recording during paediatric scoliosis surgery., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: Myotonia is unusual in infants, and not well-known., Methods: We describe neonatal life-threatening features of myotonia caused by de novo mutations in the muscle sodium channel gene SCN4A., Results: Three male neonates initially displayed episodic laryngospasms, with face and limb myotonia appearing later. We found SCN4A de novo mutations in these neonates: p.Gly1306Glu in 2 unrelated cases and a novel mutation p.Ala799Ser in the third. Two patients survived their respiratory attacks and were efficiently treated by sodium channel blockers (mexiletine, carbamazepine) following diagnosis of myotonia., Conclusion: Severe neonatal episodic laryngospasm is a new phenotype caused by a sodium channelopathy, which can be alleviated by channel blockers.

Spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by homozygous inactivation of the SMN1 (Survival Motor Neuron 1) gene. The disease severity is mainly influenced by the copy number of SMN2, a nearly identical gene from which only low amounts of full-length mRNA are produced. This correlation is not absolute, suggesting the existence of yet unknown factors modulating disease progression. We identified and characterized the rare variant c.859G>C (p.Gly287Arg) in exon 7 in both SMN2 copies of a male patient affected with type III SMA, a milder form of the disease rarely associated with only two SMN2 copies. We demonstrated in vivo, in this patient and in a second unrelated patient, and ex vivo, using SMN splicing assays, that the variant induces inclusion of exon 7 into SMN2 mRNA. Moreover, we show that the c.859G>C variation is located in a composite splicing regulatory element in the centre of exon 7. The variation does not affect binding of HTra2â nor creates a novel SF2/ASF enhancer, but disrupts an hnRNP A1 binding site. The natural occurrence of enhanced inclusion of SMN2 exon 7 in milder SMA cases supports the current therapeutic strategies based on splicing modulation in SMA patients.