Clinical features in a large Iranian family with a limb-girdle congenital myasthenic syndrome due to a mutation in DPAGT1

Keivan Basiri,Maryam Sedghi,Susan Maxwell,Wei Wei Liu,Katsiaryna Belaya,David Beeson

doi:10.1016/j.nmd.2013.03.003

Abstract

Mutations in DPAGT1 are a newly recognised cause of congenital myasthenic syndrome. DPAGT1 encodes an early component of the N-linked glycosylation pathway. Initially mutations in DPAGT1 have been associated with the onset of the severe multisystem disorder – congenital disorder of glycosylation type 1J. However, recently it was established that certain mutations in this gene can cause symptoms restricted to muscle weakness resulting from defective neuromuscular transmission. We report four cases from a large Iranian pedigree with prominent limb-girdle weakness and minimal craniobulbar symptoms who harbour a novel mutation in DPAGT1, c.652C>T, p.Arg218Trp. This myasthenic syndrome may mimic myopathic disorders and is likely under-diagnosed.

Highlights

The congenital myasthenic syndromes (CMS) constitute a group of rare genetic disorders that result in impaired synaptic transmission at the neuromuscular junction
We present a large consanguineous Iranian family in which a limb-girdle myasthenia co-segregates with mutations in the newly identified CMS-associated gene, DPAGT1
The affected family members expand the phenotypic features associated with mutations in DPAGT1 and highlight clinical characteristics that differ from the more common forms of CMS

Summary

Introduction

The congenital myasthenic syndromes (CMS) constitute a group of rare genetic disorders that result in impaired synaptic transmission at the neuromuscular junction. The number of genes shown to harbour mutations that underlie CMS continues to grow with at least 16 described [1,2]. Whereas many of the CMS involve mutations in proteins with well-defined functions at the neuromuscular junction, the two most recently identified causes of CMS are mutations in GFPT1 [3] and DPAGT1 [4] both of which encode ubiquitously expressed proteins. A number of beneficial treatments are available for CMS, but appropriate treatment often depends upon recognition of a myasthenic disorder, knowledge of which gene is mutated, and an understanding of the underlying molecular mechanism [6]. We provide case reports for a large Iranian family harbouring a previously unreported mutation in DPAGT1, which both expands the described phenotype and may help recognition of this disorder

Mutation analysis

Findings

Discussion