Guanosine diphosphate-mannose pyrophosphorylase-B gene mutations causing limb-girdle muscular dystrophy overlapping with congenital myasthenic syndrome

Abstract

Objective To report four patients with secondary α-dystroglycanopathy caused by guanosine diphosphate-mannose pyrophosphorylase-B (GMPPB) gene mutations and review the literature aiming to analyze the clinical manifestations, muscle image, molecular pathology and genetic characteristics of the disease. Methods The medical history, physical examination, electromyography and other clinical data of four patients with secondary α-dystroglycanopathy from two families were collected and retrospectively reviewed from 2009 to 2017. Case 1 (proband of pedigree 1) and case 2 ( proband of pedigree 2) were then further analyzed with muscle imaging, muscle pathology and targeted next generation gene sequencing (NGS). Results Four patients came from two families (three from the same pedigree), two males and two females, with an onset age of 17-18 years. All four cases presented as limb-girdle muscular dystrophy (LGMD) overlapping with congenital myasthenic syndrome (CMS) characterized by evident proximal limb weakness in early adulthood and fluctuating muscle weakness. They all had delayed motor milestone and did not perform well in physical education since childhood. Serum creatine kinase was elevated markedly (1 877-5 275 U/L). Myogenic changes on electromyography and marked attenuation on three Hz repetitive nerve stimulation were observed in all patients. Muscle MRI showed prominent involvement of bilateral hamstrings in case 1 and case 2. Muscular dystrophic patterns were demonstrated on muscle biopsies. Targeted NGS revealed two compound heterozygous missense mutations in GMPPB for each case. Case 1 carried c. 860G>T (p.R287L)/c851T>C (p.V284L). Case 2 and his two affected sisters (case 3 and case 4) carried c. 1097A>G (p.N366S)/c.589G>T(p.V197F). All of these mutations were novel variants and pedigree analysis suggested that the two mutations were from parents. Compared with normal controls, immunohistochemistry and Western blotting showed significantly decreased expression of α-dystroglycan in the muscle tissue from case 1 and case 2. The myasthenic symptoms of all four patients were improved to varying degrees after treatment with pyridostigmine bromide. Conclusions Mutations in GMPPB can lead to dysfunction both in muscle and in neuromuscular transmission causing overlapping between LGMD and CMS phenotypes. Cholinesterase inhibitors can partly improve the symptoms of myasthenia in such patients. Key words: GDP-mannose pyrophosphorylase; Muscular dystrophy; Myasthenic syndrome; Dystroglycan; Glycosylation