Nonsense mutations in alpha-II spectrin in three families with juvenile onset hereditary motor neuropathy

Distal hereditary motor neuropathies are a rare subgroup of inherited peripheral neuropathies hallmarked by a length-dependent axonal degeneration of lower motor neurons without significant involvement of sensory neurons. We identified patients with heterozygous nonsense mutations in the alpha II-spectrin gene, SPTAN1, in three separate dominant hereditary motor neuropathy families via next-generation sequencing. Variable penetrance was noted for these mutations in two of three families, and phenotype severity differs greatly between patients. The mutant mRNA containing nonsense mutations is broken down by nonsense-mediated decay and leads to reduced protein levels in patient cells. Previously, dominant-negative alpha II-spectrin gene mutations were described as causal in a spectrum of epilepsy phenotypes

Gamma-sarcoglycanopathy (LGMD 2C) with Del 525T mutation: Report of the first familial case in Niger

We are reporting a familial case of limb-girdle muscular dystrophy (LGMD) upon 5 out of 6 siblings from parents showing no evidence of muscular dystrophy. The pedigree of the family up to five generations did not reveal any known case in the past even though consanguinity was reported. The clinical observations revealed wheelchair bound or difficulties for walking in all affected subjects, due to muscular dystrophy involving mainly the pelvic girdle. Creatine phosphoKinase (CK) was higher than normal values in both affected children and their parents. The scanning of thigh showed in all patients, an atrophy of the quadriceps with fatty conversion. Molecular analysis was carried out, first using western blot, which revealed gammasacoglycan deficiency and second, by gene screening, which showed Del 525T mutation. This mutation is most widespread in arabo-berbères tribes including Touaregs. The present cases are in our knowledge the first reported in that part of Africa, south of Maghreb. We make a focus on histological and molecular bases of the LGMD.Keywords: gamma-sarcoglycanopathy, LGMD 2C, Del 525T mutation, Nige

Pathologies musculaires liées à la titine - Un domaine en émergence

International audienceTitin-related diseases of the skeletal and cardiac muscles open a new, fruitful chapter of myology. Confined for a long time to a limited number of clinical entities, the phenotypic spectrum of titinopthies is nowadays expanding rapidly together with the discovery of many pathogenic mutations of the TTN gene. Like for many genes of large size, the fine tuning and use of high-throughput sequencing (NGS) constitutes a little revolution in the field. This powerful tool allows, although with real technical hurdles, the establishment of the definite diagnosis of titinopathy. A better knowledge of the natural history of each subtype of titinopathy enables as of now an optimized management of patients, notably when a cardiac or respiratory risk factor is identified. Research efforts in the titin-related conditions are gradually getting organized. Interactions between clinicians and geneticists are an absolute necessity. The still fragmentary knowledge of the pathogenesis of each titinopathy prevents to date to figure out any curative therapy in the very near future.Les pathologies du muscle squelettique ou du muscle cardiaque en rapport avec la titine ouvrent un chapitre nouveau et fructueux de la myologie. Longtemps confiné à quelques entités cliniques très limitées en nombre, l’éventail phénotypique des titinopathies ne cesse de croître au fur et à mesure de la découverte de nouvelles mutations pathogènes du gène TTN. Comme pour tous les gènes de grande taille de notre organisme, la mise au point et l’utilisation en routine du séquençage à haut-débit (NGS) constitue une petite révolution dans le domaine. Cet outil puissant permet, certes avec encore de réelles difficultés techniques, d’affirmer les diagnostics de titinopathie avec certitude. La meilleure connaissance de l’histoire naturelle des différentes formes de titinopathie permet dès maintenant une prise en charge optimisée des patients concernés notamment lorsqu’un facteur de risque respiratoire ou cardiaque est identifié. La recherche dans le domaine des pathologies de la titine s’organise petit à petit, l’interaction entre cliniciens et généticiens moléculaires étant une ardente nécessité. Les connaissances encore trop parcellaires de la physiopathologie de chacune des titinopathies ne permettent pas d’envisager des thérapies curatives dans un avenir très proche

Dynamin 2 mutations associated with human diseases impair clathrin-mediated receptor endocytosis.

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