Congenital Myasthenic Syndrome via the GFPT1 Gene

Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from defects in presynaptic, synaptic, or postsynaptic proteins. Clinically, a limb-girdle pattern of muscle involvement makes DOK7, AGRN, and GFPT1-related CMS unique from other CMS. Senderek et al. (Am J Hum Genet 88:162-172, 2011) found variants in the GFPT1 gene (OMIM 138292) in 13 families with autosomal recessive limb-girdle myasthenic syndrome with tubular aggregates (OMIM 610542). In vitro studies showed evidence for increased turnover or defective translation as an underlying pathological mechanism. Reduced numbers of acetylcholine receptors and decreased protein glycosylation were also noted (Senderek et al. 2011). Clinical symptoms, with onset during adolescence, include limb-girdle weakness and wasting with normal or slightly elevated serum CK levels (Rodolico et al. Neuromusc Disord 12:964-969, 2002). Muscle cramps and moderate exercise-induced fatigability are also documented (Sieb et al. Neuromusc Disord 6:115-119, 1996). Neither ptosis nor ophthalmoplegia are findings in GFPT1-related CMS. Electrophysiologic studies show decremental compound motor action potential responses in affected muscles, and single fiber EMG show impaired neuromuscular transmission with increased jitter (Rodolico et al. 2002). Muscle biopsies demonstrate 60-80 nm parallel subsarcolemmal tubular aggregates located predominantly in type 2 muscle fibers (Sieb et al. 1996). In contrast to DOK7-related CMS, tubular aggregates may be a universal finding in GFPT1-related CMS (Slater et al. Brain 129:2061-2076, 2006). Patients with limb-girdle myasthenic syndrome with tubular aggregates respond well to treatment with acetylcholinesterase inhibitors (Rodolico et al. 2002; Beeson et al. Science 313: 1975-1978, 2006).

Abnormalities of proteins involved with neuromuscular transmission underlie familial limb-girdle myasthenic syndrome, congenital myasthenic syndromes, fetal akinesia deformation sequence, and multiple pterygium syndromes. These disorders, which may represent a phenotypic continuum of a single entity, are most often inherited in an autosomal recessive manner. Familial limb-girdle myasthenic syndrome with tubular aggregates due to GFPT1 variants is inherited as an autosomal recessive disorder (Senderek et al. 2011).

DOK7, AGRN, and GFPT1 variants are the only known cause of familial limb-girdle myasthenic syndrome. Clinical sensitivity should be high for patients meeting rigorous clinical, histopathological, and electrophysiological criteria.

This test provides full coverage of all coding exons of the GFPT1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.