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 Here, we describe 11 affected individuals from four unpublished families with ultra-rare missense variants in GGPS1 and provide follow-up details from a previously reported family.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

Paroxysmal strabismus and stridor acquired in childhood: Do not overlook calcemia!

International audienceHypocalcemia is known to induce stridor but was rarely reported to cause strabismus. We report the case of a 4-year-old girl who presented with paroxysmal stridor and strabismus with diplopia, persisting for several weeks. Severe hypocalcemia (1.25 mmol/L) was finally diagnosed and was related to hypoparathyroidism, which was the first manifestation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in this patient. Strabismus and stridor both resolved after normalization of calcemia. This case report is a rare observation of paroxysmal strabismus caused by hypocalcemia and it highlights the importance of calcium monitoring in any situation of atypical neurological symptoms

Functional validation of a novel variant of the SPTAN1 gene identified in a family with distal motor myopathy with nerve involvement

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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