Electrophysiological Characterization of C9ORF72-Associated Amyotrophic Lateral Sclerosis: A Retrospective Study

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Clinical and Molecular Landscape of ALS Patients with SOD1 Mutations: Novel Pathogenic Variants and Novel Phenotypes. A Single ALS Center Study

International audienceMutations in the copper zinc superoxide dismutase 1 (SOD1) gene are the second most frequent cause of familial amyotrophic lateral sclerosis (ALS). Nearly 200 mutations of this gene have been described so far. We report all SOD1 pathogenic variants identified in patients followed in the single ALS center of Lyon, France, between 2010 and 2020. Twelve patients from 11 unrelated families are described, including two families with the not yet described H81Y and D126N mutations. Splice site mutations were detected in two families. We discuss implications concerning genetic screening of SOD1 gene in familial and sporadic ALS

Ovarian Failure Related to Eukaryotic Initiation Factor 2B Mutations

Ovarian failure (OF) at age <40 years occurs in ∼1% of all women. Other than karyotype abnormalities, very few genes are known to be associated with this ovarian dysfunction. We studied eight patients who presented with premature OF and white-matter abnormalities on magnetic resonance imaging. Neurological signs may be absent or present after OF. In seven patients, we report for the first time mutations in three of the five EIF2B genes (EIF2B2, -4, and -5) that were recently shown to cause childhood ataxia with central nervous system hypomyelination/vanishing white-matter disease leukodystrophy. The correlation we observed between the age at onset of the neurological deterioration and the severity of OF suggests a common pathophysiological pathway

Multiexon deletions account for 15% of Congenital Myasthenic Syndrome with RAPSN mutations after negative DNA Sequencing

International audienceIntroduction: Post-synaptic congenital myasthenic syndromes (CMSs) (OMIM_ #608931) is a group of genetic disorders affecting neuromuscular transmission and due to acetylcholine receptor (AChR) deficiency in 80% of cases.[1] These autosomal recessive CMSs may be caused by mutations in genes encoding the AChR or one of the AChR-clustering or anchoring proteins, rapsyn, Dok-7 or MuSK.[1-4] Spectra of rapsyn mutations show allelic heterogeneity and suggest that the common substitution p.Asn88Lys (N88K) (variant_021217 in Q13702) results in less stable AChR clusters.[5] Until recently, all patients harbouring mutations in RAPSN are either homozygous for the p.Asn88Lys substitution or heteroallelic for p.Asn88Lys and a mutation which is in most of cases an amino acid substitution but can be also a null allele.[6] Analysis of disease severity in patients suggested that the second mutant allele may largely determine severity of the phenotype.[7] Recently, a patient with two non p.Asn88Lys in RAPSN has been described and the first chromosomal deletion event was described by Müller and colleagues.[8,9

Efficacy and safety of mexiletine in non-dystrophic myotonias: A randomised, double-blind, placebo-controlled, cross-over study

International audienceThe MYOMEX study was a multicentre, randomised, double-blind, placebo-controlled, cross-over study aimed to compare the effects of mexiletine vs. placebo in patients with myotonia congenita (MC) and paramyotonia congenita (PC). The primary endpoint was the selfreported score of stiffness severity on a 100 mm visual analogic scale (VAS). Mexiletine treatment started at 200 mg/day and was up-titrated by 200 mg increment each three days to reach a maximum dose of 600 mg/day for total treatment duration of 18 days for each cross-over period. The modified intent-to-treat population included 25 patients (13 with MC and 12 with PC; mean age, 43.0 years; male, 68.0%). The median VAS score for mexiletine was 71.0 at baseline and decreased to 16.0 at the end of the treatment while the score did not change for placebo (81.0 at baseline vs. 78.0 at end of treatment). A mixed effects linear model analysis on ranked absolute changes showed a significant effect of treatment (p < 0.001). The overall score of the Individualized Neuromuscular Quality of Life questionnaire (INQoL) was significantly improved (p < 0.001). No clinically significant adverse events were reported. In conclusion, mexiletine improved stiffness and quality of life in patients with nondystrophic myotonia and was well tolerated