Myasthenic Syndrome, Congenital, 12

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-12 (CMS12) is caused by homozygous or compound heterozygous mutation in the GFPT1 gene (138292) on chromosome 2p13.

Description

Congenital myasthenic syndrome-12 is an autosomal recessive neuromuscular disorder characterized by onset of proximal muscle weakness in the first decade. EMG classically shows a decremental response to repeated nerve stimulation. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors (summary by Senderek et al., 2011).

For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

Clinical Features

Johns et al. (1966) reported 4 sibs, 2 male and 2 female, who developed a proximal myopathy involving the pectoral and pelvic girdles. Onset was in adolescence; 10 years later, they showed a prominent myasthenic reaction and good response to cholinesterase inhibitors. Electromyographic findings were typical of myasthenia gravis. Dobkin and Verity (1978) described 3 sisters with asymptomatic cardiomyopathy and nonprogressive proximal muscle weakness and lordosis that began in childhood. Small type 1 fibers and tubular aggregates in both fiber types were found on muscle biopsy. In addition, myasthenic features were characterized by fatigability with moderate exercise, decremental response to repetitive nerve stimulation, and improved function with anticholinesterase drug therapy.

McQuillen (1966) described limb-girdle myasthenia in a father and his 3 children. Two of the children also had dystrophic changes in the weak muscles. The atrophy was not marked, however, and no oculobulbar involvement was present. EMG studies suggested myasthenia, and there was a favorable response to anticholinesterase therapy.

Sieb et al. (1996) reported a Libyan family in which 5 of 7 sibs had a slowly progressive limb-girdle weakness accentuated by exercise since childhood. Neither ptosis nor ophthalmoplegia was observed. Electrophysiologic studies showed a decremental motor response to repetitive stimulation in affected muscles. Muscle biopsy of 1 patient showed basophilic subsarcolemmal tubular aggregates in type 2 fibers. Ultrastructural examination showed that the tubules were about 6 angstroms in diameter arranged in a hexagonal array. The authors noted that the tubular aggregates may reflect a response to increased calcium.

Furui et al. (1997) reported affected Japanese sisters. Repetitive nerve stimulation resulted in decremental responses, and single-fiber EMG showed increased jitter and blocking. AChR autoantibodies were not present, and neither sister had ocular or bulbar involvement. The neuromuscular junctions appeared morphologically normal.

Rodolico et al. (2002) reported 5 patients with familial limb-girdle myasthenia. All patients had consanguineous parents, indicating autosomal recessive inheritance. Disease onset ranged from 7 to 12 years, and was characterized by proximal muscle weakness and wasting with normal or slightly increased serum creatine kinase. One patient reported muscle cramps and another had easy fatigability. EMG showed a myopathic pattern with low-amplitude and short-duration motor unit potentials. Repetitive nerve stimulation showed a decremental compound motor action potential (CMAP) response. Single fiber EMG showed impaired neuromuscular transmission with increased jitter. Muscle biopsy showed 60- to 80-nm parallel tubular aggregates located predominantly in type 2 muscle fibers. AChE inhibitors resulted in symptom improvement. No patients had ocular or bulbar involvement.

Beeson et al. (2006) differentiated limb-girdle myasthenia with tubular aggregates from a form without tubular aggregates (254300) caused by mutations in the DOK7 gene (610285). Moreover, by contrast with patients harboring DOK7 mutations, patients with tubular aggregates tend to respond well to anticholinesterase medication, suggesting that this phenotype constitutes a separate disorder. One of the patients reported by Slater et al. (2006) had limb-girdle myasthenia with tubular aggregates, while the other 6 without tubular aggregates harbored mutations in DOK7.

Helman et al. (2019) reported 4 patients from 2 unrelated families with congenital myasthenic syndrome-12. The patients presented with proximal muscle weakness and difficulty walking. In one family, both children had neonatal respiratory distress, while in the other family, the children had episodic deteriorations. Muscle biopsies showed ragged-red fibers, and MRIs were consistent with a mitochondrial leukoencephalopathy, with extensive deep cerebral white matter T2 hyperintense signal and selective involvement of the middle blade of the corpus callosum. Nerve conduction studies showed a decremental response to repetitive nerve stimulation, which confirmed the diagnosis of myasthenia.

Clinical Management

Helman et al. (2019) reported that 2 children (family 1) with CMS12 who were treated with pyridostigmine showed significant improvement, with better exercise tolerance and improved ability to run and climb stairs.

Inheritance

Congenital myasthenic syndrome-12 is an autosomal recessive disorder (Senderek et al., 2011).

Mapping

By homozygosity mapping in the consanguineous Libyan family with limb-girdle myasthenia reported by Sieb et al. (1996), Senderek et al. (2011) found linkage to chromosome 2p15-p12 (maximum lod score of 3.24). Analysis of other affected families allowed refinement of the locus to a 5.92-Mb region.

Molecular Genetics

In 13 unrelated families with autosomal recessive CMS12, Senderek et al. (2011) identified 18 different mutations in the GFPT1 gene (see, e.g., 138292.0001-138292.0006). All mutations were in the homozygous or compound heterozygous state in affected individuals. Two of the families had previously been reported by Sieb et al. (1996) and Rodolico et al. (2002), respectively. In vitro expression studies in HEK293 cells indicated that the missense mutations did not always result in significantly decreased enzyme activity, but studies of patient muscle biopsies and cultured myoblasts showed reduced amounts of the GFPT1 protein, suggesting increased turnover or defective translation. In addition, study of 1 patient's muscle sample showed a strongly reduced number of acetylcholine receptors (AChR), and muscle samples from several patients showed decreased protein glycosylation. Senderek et al. (2011) noted that many key proteins at the neuromuscular junction are glycosylated, including subunits of the AChR, and that glycosylation is involved in intracellular signaling, factors that may play a role in the pathogenesis of myasthenia due to GFPT1 mutations.

By genome sequencing in 4 patients from 2 unrelated families segregating CMS12, Helman et al. (2019) identified homozygous missense mutations in the GFPT1 gene (138292.0007-138292.0008).

Animal Model

Senderek et al. (2011) found that Gfpt1 knockdown in zebrafish embryos induced a neuromuscular phenotype and resulted in altered muscle histology and delayed neuromuscular junction maturation. Mutant zebrafish showed curly and shortened tails, as well as defects in motility. Histologic studies showed morphologic abnormalities ranging from wavy fibers to severely damaged fibers that were detached from the vertical myoseptum.