Prise en charge des syncopes aux urgences (un nouvel outil pour une meilleure orientation ?)

La syncope est un motif fréquent de consultation aux urgences et d admission hospitalière. Il n existe pas d évaluation standardisée concernant la prise en charge des syncopes. L objectif de notre étude était de comparer l orientation aux urgences des patients admis pour syncopes sans et avec l utilisation d un logiciel d aide à la décision médicale. Il s agissait d une étude observationnelle rétrospective qui incluait les sujets adultes s étant présentés aux urgences du CHU Grenoble pour malaise avec perte de connaissance entre le 1er janvier et le 31 mai 2011. Notre critère de jugement principal était qu il existait un faible accord entre l orientation des patients prise par les médecins des urgences et l orientation proposée par le logiciel. Parmi les 22297 patients ayant consulté aux urgences, 1,36% avaient un diagnostic de syncope. Notre échantillon d étude portait sur 287 patients. A l issue de leur passage aux urgences, 147 patients sont rentrés à domicile, 60 sont sortis avec la consigne de voir un spécialiste et 80 ont été hospitalisés. Les patients hospitalisés avaient un âge médian supérieur à celui des patients rentrés à domicile, avaient plus de facteurs de risque cardiovasculaire, avaient plus souvent une cardiopathie et un ECG anormal. Les orientations préconisées par le logiciel auraient été 155 retours à domicile, 11 explorations complémentaires, 121 hospitalisations. L accord observé entre l orientation des patients prise par le médecin des urgences et celle proposée par le logiciel était de 56%, soit un accord modéré. Le logiciel peut être une aide pour les médecins travaillant aux urgences mais ne se substitue pas à leur jugement clinique.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Novel CAPN3 variant associated with an autosomal dominant calpainopathy

International audienceAimsThe most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies.MethodsThrough our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance.ResultsWe identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice.ConclusionsWe confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in‐frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well‐documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re‐assessing other myopathies for which the inheritance is considered as strictly autosomal recessive

Autosomal Recessive Cerebellar Ataxia Type 3 Due to ANO1O Mutations: Delineation and Genotype-Phenotype Correlation Study

IMPORTANCE ANO1O mutations have been reported to cause a novel form of autosomal recessive cerebellar ataxia (ARCA). Our objective was to report 9 ataxic patients carrying 8 novel ANO1O mutations to improve the delineation of this form of ARCA and provide genotype-phenotype correlation. OBSERVATIONS The ANO1O gene has been sequenced in 186 consecutive patients with ARCA. The detailed phenotype of patients with ANO1O mutations was investigated and compared with the 12 previously reported cases. The mean age at onset was 33 years (range, 17-43 years), and the disease progression was slow. Corticospinal tract signs were frequent, including extensor plantar reflexes and/or diffuse tendon reflexes and/or spasticity. No patient in our series had peripheral neuropathy. Magnetic resonance imaging of the brains of our patients revealed marked cerebellar atrophy. The most frequent mutation, a mononucleotide expansion from a polyA repeat tract (c.132dupA) that causes protein truncation, was never observed in homozygosity. Only 2 truncating mutations were reported in homozygosity, one of which (c.1150-1151del) was associated with juvenile or adolescent onset and mental retardation, whereas we show that the presence of at least 1 missense or in-frame mutation is associated with adult onset and slow progression. CONCLUSIONS AND RELEVANCE An ANO1O mutation is responsible for ARCA that is mainly characterized by cerebellar atrophy and lack of peripheral neuropathy. We therefore suggest naming this entity autosomal recessive cerebellar ataxia type 3 (ARCA3)

SMCHD1 is involved in de novo methylation of theDUX4-encoding D4Z4 macrosatellite

International audienc

SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite

International audienceThe DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which account for the majority of methylated CGs. DNA methyla-tion is altered in a number of diseases including those linked to mutations in factors that modify chro-matin. Among them, SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain Containing 1) has been of major interest following identification of germline mutations in Facio-Scapulo-Humeral Dys-trophy (FSHD) and in an unrelated developmental disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS). By investigating why germline SMCHD1 mutations lead to these two different diseases, we uncovered a role for this factor in de novo methylation at the pluripotent stage. SMCHD1 is required for the dynamic methylation of the D4Z4 macrosatellite upon reprogramming but seems dispensable for methy-lation maintenance. We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD. These findings open new questions as to what is the true aetiology for FSHD, the epige-netic events associated with the disease thus calling the current model into question and opening ne

Neurology

OBJECTIVE: To describe the clinical characteristics and outcomes of COVID-19 among patients with MG and identify factors associated with COVID-19 severity in MG patients. METHODS: The CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS network (between March 1, 2020, and June 8, 2020), including MG patients with a confirmed or highly-suspected diagnosis of COVID-19. COVID-19 was diagnosed based on a polymerase chain reaction (PCR) test from a nasopharyngeal swab and/or SARS-CoV-2 serology, thoracic computed tomography (CT-scan), or typical symptoms. The main outcome was COVID-19 severity based on location of treatment/management (home, hospitalized in a medical unit, or in an intensive care unit). We collected information on demographic variables, general history, and risk factors for severe COVID-19. Multivariate ordinal regression models were used to identify factors associated with severe COVID-19 outcomes. RESULTS: Among 3,558 MG patients registered in the French database for rare disorders, 34 (0.96%) had COVID-19. The mean age at COVID-19 onset was 55.0 ±19.9 years (mean MG duration: 8.5 ± 8.5 years). By the end of the study period, 28 patients recovered from COVID-19, 1 remained affected, and 5 died. Only high Myasthenia Gravis Foundation of America (MGFA) class (≥IV) before COVID-19 was associated with severe COVID-19 (p=0.004); factors that were not associated included gender, MG duration, and medium MGFA classes (≤IIIb). The type of MG treatment had no independent effect on COVID-19 severity. CONCLUSIONS: This registry-based cohort study shows that COVID-19 had a limited effect on most patients, and immunosuppressive medications and corticosteroids used for MG management are not risk factors for poorer outcomes. However, the risk of severe COVID-19 is elevated in patients with high MGFA classes [odds ratio: 102.6 (4.4; 2,371.9)]. These results are important for establishing evidence-based guidelines for the management of MG patients during the COVID-19 pandemic

SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite

The DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which account for the majority of methylated CGs. DNA methylation is altered in a number of diseases including those linked to mutations in factors that modify chromatin. Among them, SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain Containing 1) has been of major interest following identification of germline mutations in Facio-Scapulo-Humeral Dystrophy (FSHD) and in an unrelated developmental disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS). By investigating why germline SMCHD1 mutations lead to these two different diseases, we uncovered a role for this factor in de novo methylation at the pluripotent stage. SMCHD1 is required for the dynamic methylation of the D4Z4 macrosatellite upon reprogramming but seems dispensable for methylation maintenance. We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD. These findings open new questions as to what is the true aetiology for FSHD, the epigenetic events associated with the disease thus calling the current model into question and opening new perspectives for understanding repetitive DNA sequences regulation