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PurposeIn this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes,CC2D2A.MethodsWe selected 53 patients with pathogenic variants onCC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature.ResultsDevelopmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype–phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype.ConclusionThis study contradicts previous literature stating an association betweenCC2D2A-related JS and ventriculomegaly. Our study implies thatCC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.

Duchenne muscular dystrophy (DMD) is a neuromuscular disease that inevitably leads to total loss of autonomy. The new therapeutic strategies aim to both improve survival and optimize quality of life. Evaluating quality of life is nevertheless a major challenge. No DMD-specific quality of life scale to exists in French. We therefore produced a French translation of the English Duchenne muscular dystrophy module of the Pediatric Quality of Life Inventory (PedsQLTMDMD) following international recommendations. The study objective was to carry out a confirmatory validation of the French version of the PedsQLTMDMD for pediatric patients with DMD, using French multicenter descriptive cross-sectional data. The sample consisted of 107 patients. Internal consistency was acceptable for proxy-assessments, with Cronbach's alpha coefficients above 0.70, except for the Treatments dimension. For self-assessments, internal consistency was acceptable only for the Daily Activities dimension. Our results showed poor metric qualities for the French version of the PedsQLTMDMD based on a sample of about 100 children, but these results remained consistent with those of the original validation. This confirms the interest of its use in clinical practice.

In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes,We selected 53 patients with pathogenic variants onDevelopmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype.This study contradicts previous literature stating an association between

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca2+) mishandling. Ca2+ release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca2+ release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca2+ concentration was increased, but RYR1-mediated Ca2+ release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca2+ concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca2+ concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca2+ leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.