Novel compound heterozygous GFPT1 mutations in a family with limb-girdle myasthenia with tubular aggregates.

Limb-girdle myasthenia with tubular aggregates, a subtype of congenital myasthenic syndrome, is an extremely rare autosomal recessive genetic disease characterized by prominent limb-girdle weakness and good response to acetylcholinesterase inhibitor therapy. Herein, we reported two novel mutations of GFPT1 gene in a Chinese pedigree. Two siblings presented with fatigue, weakness of limb-girdle and decrement of the muscle action potential with repetitive nerve stimulation. Thus, myasthenia gravis was initially suspected, but anti-AChR antibodies were negative. Two novel missense mutations (p.Lys154Asn and p.Asn363Ser) in GFPT1 were identified through genetic testing conducted on 167 well-established genes associated with muscular diseases by targeted high throughput sequencing. Both mutations have not been recorded in the dsSNP database, Exome Aggregation Consortium database and 1000 Genomes Project database. The mutation sites were co-segregated with the phenotype and conserved between the different species. The mutations were not found in the 200 unrelated normal controls. Muscle biopsies revealed tubular aggregates, in accordance with previous reports with GFPT1 mutations. Subsequently, dramatic improvement in strength occurred following anti-cholinesterase therapy. Our study will be helpful for the diagnosis and treatment for Limb-girdle myasthenia with tubular aggregates.