Belaya et al. (2012) reported 5 patients from 4 families of European origin with limb-girdle congenital myasthenic syndrome with tubular aggregates on muscle biopsy. The age at onset ranged from 0.5 to 7 years. Presenting symptoms included difficulty ... Belaya et al. (2012) reported 5 patients from 4 families of European origin with limb-girdle congenital myasthenic syndrome with tubular aggregates on muscle biopsy. The age at onset ranged from 0.5 to 7 years. Presenting symptoms included difficulty walking and frequent falls, but younger patients showed hypotonia and poor head control. Proximal limb muscles were predominantly affected, although some distal muscle groups were also involved. There was minimal involvement of facial, ocular, and bulbar muscles, and only 1 patient had mild ptosis. Two developed scoliosis. Electrophysiologic studies indicated a disorder of the neuromuscular junction, including a decrement on 3-Hz repetitive nerve stimulation and jitter and blocking on single-fiber EMG. All patients benefited from anticholinesterase medication, and 2 showed a response with 3,4-diaminopyridine, which increases acetylcholine release from the nerve terminal. One of the patients had previously been reported by Slater et al. (2006). Muscle biopsy showed structural and functional abnormalities of the neuromuscular junction, including decreased acetylcholine receptor (AChR) binding sites and decreased postsynaptic folding, consistent with a loss of endplate AChR. All patients reported by Belaya et al. (2012) had tubular aggregates on muscle biopsy, characterized as long membranous tubules packed with different misfolded and aggregated membrane proteins.
In 5 patients from 4 families with limb-girdle congenital myasthenic syndrome with tubular aggregates, Belaya et al. (2012) identified 7 different mutations in the DPAGT1 gene (see, e.g., 191350.0002-191350.0006). All mutations were in the compound heterozygous state. The ... In 5 patients from 4 families with limb-girdle congenital myasthenic syndrome with tubular aggregates, Belaya et al. (2012) identified 7 different mutations in the DPAGT1 gene (see, e.g., 191350.0002-191350.0006). All mutations were in the compound heterozygous state. The first 4 mutations were identified by exome sequencing of 2 unrelated patients and were confirmed by Sanger sequencing. The mutations segregated with the disorder in those families with available material. In vitro studies showed that DPAGT1 is required for efficient glycosylation of AChR subunits and for efficient export of AChR receptors to the cell surface. The findings demonstrated the importance of N-linked protein glycosylation for proper functioning of the neuromuscular junction, and suggested that the primary pathogenic mechanism of DPAGT1 mutations is reduced levels of AChR at the endplate region. Laboratory studies of 2 patients showed abnormal glycosylation of transferrin, consistent with a functional defect of DPAGT1. Belaya et al. (2012) postulated that the defect in glycosylation of certain proteins may lead to misfolding and aggregation in the sarcoplasmic reticulum, resulting in formation of tubular aggregates within muscle tissue.