Expanding the phenotypic spectrum ofTRAPPC11-related muscular dystrophy: 25 Roma individuals carrying a founder variant

Abstract

BackgroundLimb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders. TRAPPC11-related LGMD is an autosomal-recessive condition characterised by muscle weakness and intellectual disability.MethodsA clinical and histopathological characterisation of 25 Roma individuals with LGMD R18 caused by the homozygousTRAPPC11c.1287+5G>A variant is reported. Functional effects of the variant on mitochondrial function were investigated.ResultsThe c.1287+5G>A variant leads to a phenotype characterised by early onset muscle weakness, movement disorder, intellectual disability and elevated serum creatine kinase, which is similar to other series. As novel clinical findings, we found that microcephaly is almost universal and that infections in the first years of life seem to act as triggers for a psychomotor regression and onset of seizures in several individuals withTRAPPC11variants, who showed pseudometabolic crises triggered by infections. Our functional studies expanded the role of TRAPPC11 deficiency in mitochondrial function, as a decreased mitochondrial ATP production capacity and alterations in the mitochondrial network architecture were detected.ConclusionWe provide a comprehensive phenotypic characterisation of the pathogenic variantTRAPPC11c.1287+5G>A, which is founder in the Roma population. Our observations indicate that some typical features of golgipathies, such as microcephaly and clinical decompensation associated with infections, are prevalent in individuals with LGMD R18.