G.P.141

• Published in: Neuromuscular disorders : NMD Vol. 24; no. 9; p. 843
• Main Authors: Öncel, İ, Töpf, A, Evangelista, T, Konuşkan, B, Talim, B, Abicht, A, Lochmüller, H, Topaloglu, H
• Format: Journal Article
• Language: English
• Published: 01.10.2014
• Subjects: Neurology
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2014.06.171

Congenital myasthenic syndromes (CMSs) are heterogeneous genetic disorders that result from impaired signal transmission at the neuromuscular junction (NMJ). Congenital disorders of glycosylation (CDG) are a challenging group of diseases affecting different organs in particular the central nervous system and the skeletal muscle. Only recently CDG have been implicated in some forms of post-synaptic autosomal recessive CMS. The protein encoded by the DPAGT1 gene is an enzyme that catalyzes the first step in the dolichol-linked oligosaccharide pathway for glycoprotein biosynthesis. Mutations in DPAGT1 were described in patients with CMS and tubular aggregates on muscle biopsy. We report a 16 year old young man, first child of a consanguineous family, who presented with walking difficultywith onset by the age of 3 year. The motor milestones were slightly delayed. There was speech difficulty which fluctuated during the day. On examination, he had generalized muscle weakness with proximal groups being more affected, excessive lordosis, waddling gait, and contractures of the Achilles tendons. There was no bulbar or extra-ocular muscle involvement. He had a mild intellectual disability with an IQ score of 50–55. Tensilon test was positive. Electromyography revealed decrementing response to repetitive nerve stimulation. He responded well to pyridostigmine, 3,4-diaminopyridine and salbutamol treatment. We carried out whole exome sequencing and identified a novel homozygous DPAGT1 mutation (c.509A>T). The non-synonymous change (p.Tyr170Phe) is predicted to be deleterious by in silico analysis and affects an aminoacid residue that is highly conserved across species. In conclusion we report a novel mutation on the DPAGT1 gene responsible for a form of “limb-girdle CMS”. Comparing with the previously reported cases this family has mental retardation as an unusual feature and a good response to a combined treatment with pyridostigmine and 3,4-diaminopyridine.