LGMD2S is an autosomal recessive disorder characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, ... LGMD2S is an autosomal recessive disorder characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay (summary by Bogershausen et al., 2013). For discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy (LGMD), see LGMD2A (253600).
Bogershausen et al. (2013) reported a consanguineous Syrian family in which 3 girls had progressive proximal muscle weakness resulting in impaired ambulation. The girls were 16, 20, and 26 years of age at the time of the report, ... Bogershausen et al. (2013) reported a consanguineous Syrian family in which 3 girls had progressive proximal muscle weakness resulting in impaired ambulation. The girls were 16, 20, and 26 years of age at the time of the report, but the symptoms began in childhood. The younger girls had fatigue and muscle pain, whereas the older patient was more severely affected with an inability to climb stairs. The shoulder girdle muscles were less severely affected than the hip girdle muscles. Other features included hip dysplasia, scoliosis, and increased serum creatine kinase. Two patients had myopia, 1 had mild cataracts, and another had strabismus. One had slight enlargement of the right cardiac ventricle and another had moderate restrictive pulmonary function. The oldest had mild intellectual disability. - Clinical Variability Bogershausen et al. (2013) reported 2 Hutterite families with an autosomal recessive neuromuscular disorder. Affected individuals had early-onset psychomotor delay and evidence of a hyperkinetic movement disorder characterized mainly by choreiform movements of the trunk, limbs, and head, although athetoid movements, tremor, and dystonic posturing were also noted. All had truncal ataxia resulting in gait instability, mild muscle weakness, and increased serum creatine kinase. One patient had generalized seizures, and 2 had abnormal EEG. Neuroimaging showed mild cerebral atrophy in 2 patients. The families shared a common ancestor from the 1790s.
By whole-exome sequencing combined with linkage analysis of a Syrian family with LGMD, Bogershausen et al. (2013) identified a homozygous mutation in the TRAPPC11 gene (G980R; 614138.0001). The same technique revealed a different homozygous mutation in the TRAPPC11 ... By whole-exome sequencing combined with linkage analysis of a Syrian family with LGMD, Bogershausen et al. (2013) identified a homozygous mutation in the TRAPPC11 gene (G980R; 614138.0001). The same technique revealed a different homozygous mutation in the TRAPPC11 gene (Ala372_Ser429del; 614138.0002) in affected members of 2 Hutterite families with a slightly different phenotype, but including neuromuscular dysfunction. The G980R mutation occurred in the gryzun domain, whereas the deletion occurred in the foie gras domain. Patient cells showed increased fragmentation of the Golgi apparatus and decreased amounts of the mutant proteins. Studies in yeast suggested that the mutant missense protein lost the ability to interact properly with other TRAPP proteins. Patient cells also showed altered protein transport along the secretory pathway, with a delayed exit from the Golgi and a defect in the formation and/or movement of late endosomes/lysosomes. The findings suggested that altered membrane trafficking is the underlying molecular mechanism of this disease spectrum.