👤 J B Bouhour

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous diseases caused by mutations affecting neuromuscular transmission. Even if the first symptoms mainly occur during childhood, adult neurologists must confront this challenging diagnosis and manage these patients throughout their adulthood. However, long-term follow-up data from large cohorts of CMS patients are lacking, and the long-term prognosis of these patients is largely unknown. We report the clinical features, diagnostic difficulties, and long-term prognosis of a French nationwide cohort of 235 adult patients with genetically confirmed CMS followed in 23 specialized neuromuscular centres. Data were retrospectively analysed. Of the 235 patients, 123 were female (52.3%). The diagnosis was made in adulthood in 139 patients, 110 of whom presented their first symptoms before the age of 18. Mean follow-up time between first symptoms and last visit was 34 years [standard deviation (SD) = 15.1]. Pathogenic variants were found in 19 disease-related genes. CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%). Genotypes were clustered into four groups according to the initial presentation: ocular group (CHRNE-LE, CHRND, FCCMS), distal group (SCCMS), limb-girdle group (RAPSN, COLQ, DOK7, GMPPB, GFPT1), and a variable-phenotype group (MUSK, AGRN). The phenotypical features of CMS did not change throughout life. Only four genotypes had a proportion of patients requiring intensive care unit admission that exceeded 20%: RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%). In RAPSN and MUSK patients most ICU admissions occurred before age 18 years and in DOK7 and AGRN patients at or after 18 years of age. Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another in the same patient throughout life, particularly in AGRN, DOK7 and COLQ. At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation; 36.3% of DOK7 patients, 25% of GMPPB patients and 20% of GFPT1 patients were wheelchair-bound; most of the patients who were both wheelchair-bound and ventilated were DOK7 patients. Six patients died in this cohort. The positive impact of therapy was striking, even in severely affected patients. In conclusion, even if motor and/or respiratory deterioration could occur in patients with initially moderate disease, particularly in DOK7, SCCMS and GFPT1 patients, the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit. CHRNE-LE patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved. Show less

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders that give rise to a defect in neuromuscular transmission. We described here three patients with a characteristic phenotype of recessive CMS and presenting mutation in the gene encoding rapsyn (RAPSN). Familial analysis showed that one allelic mutation failed to be detected by direct sequencing. An allelic quantification on patient's DNA identified three novel multi-exon deletions of RAPSN. These three genomic rearrangements in RAPSN represent 15% of our CMS patients with RAPSN mutations and we emphasize that single-nucleotide polymorphism markers and a gene dosage method should be performed in addition to DNA direct sequencing analysis particularly when there is a genetic counselling issue. Show less

Little information is available on phenotype-genotype correlations in familial hypertrophic cardiomyopathy that are related to the cardiac myosin binding protein C (MYBPC3) gene. The aim of this study was to perform this type of analysis. We studied 76 genetically affected subjects from nine families with seven recently identified mutations (SASint20, SDSint7, SDSint23, branch point int23, Glu542Gln, a deletion in exon 25, and a duplication/deletion in exon 33) in the MYBPC3 gene. Detailed clinical, ECG, and echocardiographic parameters were analyzed. An intergene analysis was performed by comparing the MYBPC3 group to seven mutations in the beta-myosin heavy-chain gene (beta-MHC) group (n=52). There was no significant phenotypic difference among the different mutations in the MYBPC3 gene. However, in the MYBPC3 group compared with the beta-MHC group, (1) prognosis was significantly better (P<0.0001), and no deaths occurred before the age of 40 years; (2) the age at onset of symptoms was delayed (41+/-19 versus 35+/-17 years, P<0.002); and (3) before 30 years of age, the phenotype was particularly mild because penetrance was low (41% versus 62%), maximal wall thicknesses lower (12+/-4 versus 16+/-7 mm, P<0.03), and abnormal T waves less frequent (9% versus 45%, P<0.02). These results are consistent with specific clinical features related to the MYBPC3 gene: onset of the disease appears delayed and the prognosis is better than that associated with the beta-MHC gene. These findings could be particularly important for the purpose of clinical management and genetic counseling in familial hypertrophic cardiomyopathy. Show less

Cardiac myosin binding protein C (MyBP-C) is a sarcomeric protein belonging to the intracellular immunoglobulin superfamily. Its function is uncertain, but for a decade evidence has existed for both structural and regulatory roles. The gene encoding cardiac MyBP-C (MYBPC3) in humans is located on chromosome 11p11.2, and mutations have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy (FHC). Detailed characterization of the MYBPC3 gene is essential for studies on gene regulation, analysis of the role of MyBP-C in cardiac contraction through the use of recombinant DNA technology, and mutational analyses of FHC. The organization of human MYBPC3 and screening for mutations in a panel of French families with FHC were established using polymerase chain reaction, single-strand conformation polymorphism, and sequencing. The MYBPC3 gene comprises > 21,000 base pairs and contains 35 exons. Two exons are unusually small in size, 3 bp each. We found six new mutations associated with FHC in seven unrelated French families. Four of these mutations are predicted to produce truncated cardiac MyBP-C polypeptides. The two others should each produce two aberrant proteins, one truncated and one mutated. The present study provides the first organization and sequence for an MyBP-C gene. The mutations reported here and previously in MYBPC3 result in aberrant transcripts that are predicted to encode significantly truncated cardiac MyBP-C polypeptides. This spectrum of mutations differs from the ones previously observed in other disease genes causing FHC. Our data strengthen the functional importance of MyBP-C in the regulation of cardiac work and provide the basis for further studies. Show less