GGPS1-associated muscular dystrophy with and without hearing loss

Ultra-rare biallelic pathogenic variants in geranylgeranyl diphosphate synthase 1 (GGPS1) have recently been associated with muscular dystrophy/hearing loss/ovarian insufficiency syndrome. Here, we describe 11 affected individuals from four unpublished families with ultra-rare missense variants in GGPS1 and provide follow-up details from a previously reported family. Our cohort replicated most of the previously described clinical features of GGPS1 deficiency; however, hearing loss was present in only 46% of the individuals. This report consolidates the disease-causing role of biallelic variants in GGPS1 and demonstrates that hearing loss and ovarian insufficiency might be a variable feature of the GGPS1-associated muscular dystrophy

Recent advances in french cohort of congenital myasthenic syndromes patients

International audienceCongenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of rare diseases caused by dysfonction of neuromuscular transmission and share common clinical features characterized by fluctuation of muscle weakness and fatigability. Identification of mutations in genes encoding neuromuscular junction (NMJ) proteins has intensified in recent years. However in French cohort, some of CMS patients are still genetically undiagnosed. These last years, using whole exome sequencing and sanger sequencing, we identify for the first time mutations in SLC5A7 encoding the presynaptic sodium dependant hight-affinity choline transporter 1 (CHT1) responsible of severe CMS with episodic apnea (CMS-EA) and one the other hand new mutations in GFPT1 encoding an enzyme involved in glycosylated of ubiquitous proteins causing limb-girdle CMS with tubular aggregates. In the first study, we identified 11 recessive mutations in SLC5A7 that are associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS-EA. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. In the second study, we identified 9 new GFPT1 mutations and we report the first retrospective clinical evaluation of LG-CMS individuals stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from 3 unrelated individuals demonstrates that the maintenance of NMJs is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation-reinnervation processes affecting the 3 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 extrajunctional area.His two studies highlighted that CHT1 is the second most frequent gene after CHAT responsible of CMS-EA and reinforced that GFPT1 is the primary genetic cause of ubiquitous CMS. This work has allowed to widen the genetic and clinical spectrum of CMS whose phenotypic complexity that could be only a small part of a much more extensive disease phenotype

How chromosomal deletions can unmask recessive mutations? Deletions in 10q11.2 associated with CHAT or SLC18A3 mutations lead to congenital myasthenic syndrome

International audienceA congenital myasthenia was suspected in two unrelated children with very similar phenotypes including several episodes of severe dyspnea. Both children had a 10q11.2 deletion revealed by Single Nucleotide Polymorphisms array or by Next Generation Sequencing analysis. The deletion was inherited from the healthy mother in the first case. These deletions unmasked a recessive mutation at the same locus in both cases, but in two different genes: CHAT and SLC18A3

Identification of a new splice site mutation in synaptotagmin-2 responsible for a severe and early presynaptic form of congenital myasthenic syndrome

International audienceCongenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of inherited disorders caused by defective synaptic transmission at the neuromuscular junction (NMJ) and characterized by fluctuation of muscle weakness and fatigability. Recently, many mutations encoding presynaptic and ubiquitous proteins have been identified as responsible for increasingly complex CMS phenotypes of CMS. Among them, this is the case of autosomal dominant mutations in Synaptotagmin2 (SYT2) C2B domain that have been linked to described as responsible for presynaptic CMS combined to Lambert-Eaton myasthenic syndromes and motor neuropathy forms. SYT2 is the major synaptotagmin isoform expressed at the NMJ and acts as a calcium sensor that is mediated by the presence of two tandem C2 domains. In the French cohort of CMS patients, we recently identified in a consanguineous family a new homozygote recessive intronic mutation in SYT2 causing an early and severe presynaptic CMS. Using a minigene construct we demonstrated that this intronic mutation in the donor splice site of SYT2 intron 4 leads to a SYT2 in-frame exon 4 skipping suppressing the N-terminal part of C2A domain. Morphological and functional studies revealed that defects in SYT2 C2A domain affects NMJs maintenance, synaptic transmission and triggers a decrease of SYT2 expression partially compensated by the upregulation of SYT1 expression at the NMJ. This study reports the identification of a new severe presynaptic CMS form associated to a recessive intronic mutation in SYT2 and completes the previously reported data on the dominant SYT2-related motor neuropathy and Lambert-Eaton myasthenic syndrome

Identification of a new splice site mutation in synaptotagmin-2 responsible for a severe and early presynaptic form of congenital myasthenic syndrome

International audienceCongenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of inherited disorders caused by defective synaptic transmission at the neuromuscular junction (NMJ) and characterized by fluctuation of muscle weakness and fatigability. Recently, many mutations encoding presynaptic and ubiquitous proteins have been identified as responsible for increasingly complex CMS phenotypes of CMS. Among them, this is the case of autosomal dominant mutations in Synaptotagmin2 (SYT2) C2B domain that have been linked to described as responsible for presynaptic CMS combined to Lambert-Eaton myasthenic syndromes and motor neuropathy forms. SYT2 is the major synaptotagmin isoform expressed at the NMJ and acts as a calcium sensor that is mediated by the presence of two tandem C2 domains. In the French cohort of CMS patients, we recently identified in a consanguineous family a new homozygote recessive intronic mutation in SYT2 causing an early and severe presynaptic CMS. Using a minigene construct we demonstrated that this intronic mutation in the donor splice site of SYT2 intron 4 leads to a SYT2 in-frame exon 4 skipping suppressing the N-terminal part of C2A domain. Morphological and functional studies revealed that defects in SYT2 C2A domain affects NMJs maintenance, synaptic transmission and triggers a decrease of SYT2 expression partially compensated by the upregulation of SYT1 expression at the NMJ. This study reports the identification of a new severe presynaptic CMS form associated to a recessive intronic mutation in SYT2 and completes the previously reported data on the dominant SYT2-related motor neuropathy and Lambert-Eaton myasthenic syndrome

New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani–Lenz syndrome

International audienceCongenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of rare diseases due to mutations in neuromuscular junction (NMJ) protein-coding genes. Until now, many mutations encoding postsynaptic proteins as Agrin, MuSK and LRP4 have been identified as responsible for increasingly complex CMS phenotypes. The majority of mutations identified in LRP4 gene causes bone diseases including CLS and sclerosteosis-2 and rare cases of CMS with mutations in LRP4 gene has been described so far. In the French cohort of CMS patients, we identified a novel LRP4 homozygous missense mutation (c.1820A > G; p.Thy607Cys) within the β1 propeller domain in a patient presenting CMS symptoms, including muscle weakness, fluctuating fatigability and a decrement in compound muscle action potential in spinal accessory nerves, associated with congenital agenesis of the hands and feet and renal malformation. Mechanistic expression studies show a significant decrease of AChR aggregation in cultured patient myotubes, as well as altered in vitro binding of agrin and Wnt11 ligands to the mutated β1 propeller domain of LRP4 explaining the dual phenotype characterized clinically and electoneuromyographically in the patient. These results expand the LRP4 mutations spectrum associated with a previously undescribed clinical association involving impaired neuromuscular transmission and limb deformities and highlighting the critical role of a yet poorly described domain of LRP4 at the NMJ. This study raises the question of the frequency of this rare neuromuscular form and the future diagnosis and management of these cases

JAK inhibitors are effective in a subset of patients with juvenile dermatomyositis: a monocentric retrospective study

International audienceObjectiveTo evaluate the efficacy and safety of Janus kinase inhibitors (JAKis) in JDM.MethodsWe conducted a single-centre retrospective study of patients with JDM treated by JAKi with a follow-up of at least 6 months. Proportion of clinically inactive disease (CID) within 6 months of JAKi initiation was evaluated using PRINTO criteria and skin Disease Activity Score. Serum IFN-α concentration was measured by Simoa assay.ResultsNine refractory and one new-onset patients with JDM treated with ruxolitinib (n = 7) or baricitinib (n = 3) were included. The main indications for treatment were refractory muscle involvement (n = 8) and ulcerative skin disease (n = 2). CID was achieved in 5/10 patients (two/two anti-MDA5, three/four anti-NXP2, zero/three anti-TIF1γ-positive patients) within 6 months of JAKi introduction. All responders could withdraw plasmatic exchange, immunoadsorption and other immunosuppressive drugs. The mean daily steroid dose decreased from 1.1 mg/kg (range 0.35–2 mg/kg/d) to 0.1 (range, 0–0.3, P = 0.008) in patients achieving CID, and was stopped in two. Serum IFN-α concentrations were elevated in all patients at the time of treatment initiation and normalized in both responder and non-responder. A muscle biopsy repeated in one patient 26 months after the initiation of JAKi, showed a complete restoration of muscle endomysial microvascular bed. Herpes zoster and skin abscesses developed in three and two patients, respectively.ConclusionJAKis resulted in a CID in a subset of new-onset or refractory patients with JDM and may dramatically reverse severe muscle vasculopathy. Overall tolerance was good except for a high rate of herpes zoster infection

Evidence-based, Implementable Motor Rehabilitation Guidelines for Individuals With Cerebral Palsy

International audienc

Evidence-based, Implementable Motor Rehabilitation Guidelines for Individuals With Cerebral Palsy

International audienc

Long-Reads Sequencing Strategy to Localize Variants in TTN Repeated Domains

International audienceTitin protein is responsible for muscle elasticity. The TTN gene, composed of 364 exons, is subjected to extensive alternative splicing and leads to different isoforms expressed in skeletal and cardiac muscle. Variants in TTN are responsible for myopathies with a wide phenotypic spectrum and autosomal dominant or recessive transmission. The I-band coding domain, highly subject to alternative splicing, contains a three-zone block of repeated sequences with 99% homology. Sequencing and localization of variants in these areas are complex when using short-reads sequencing, a second-generation sequencing technique. We have implemented a protocol based on the third-generation sequencing technology (long-reads sequencing). This new method allows us to localize variants in these repeated areas to improve the diagnosis of TTN-related myopathies and offer the analysis of relatives in postnatal or in prenatal screening