A Novel AGRN Mutation Leads to Congenital Myasthenic Syndrome Only Affecting Limb-girdle Muscle

Abstract

Background: Congenital myasthenic syndromes (CMSs) are a group of clinically and genetically heterogeneous disorders caused by impaired neuromuscular transmission. The defect of AGRN was one of the causes of CMS through influencing the development and maintenance of neuromuscular transmission. However, CMS reports about this gene mutation were rare. Here, we report a novel homozygous missense mutation (c.5302G>C) of AGRN in a Chinese CMS pedigree.

Methods: We performed a detailed clinical assessment of a Chinese family with three affected members. We screened for pathogenic mutations using a disease-related gene panel containing 519 genes associated with genetic myopathy (including 17 CMS genes).

Results: In the family, the proband showed limb-girdle pattern of weakness with sparing of ocular, facial, bulbar, and respiratory muscles. Repetitive nerve stimulation showed a clear decrement of the compound muscle action potentials at 3 Hz only. Pathological analysis of the left tibialis anterior muscle showed predominance of type I fiber and the presence of scattered small angular fibers. The proband's two elder sisters shared a similar but more severe phenotype. By gene analysis, the same novel homozygous mutation (c.5302G>C, p. A1768P) of AGRN was identified in all three affected members, whereas the same heterozygous mutation was found in both parents, revealing an autosomal recessive transmission pattern. All patients showed beneficial responses to adrenergic agonists.

Conclusions: This study reports a Chinese pedigree in which all three children carried the same novel AGRN mutation have CMS only affecting limb-girdle muscle. These findings might expand the spectrum of mutation in AGRN and enrich the phenotype of CMS.

Figure 1

A Chinese congenital myasthenic syndrome pedigree with a novel AGRN mutation only affecting limb-girdle muscle. Arrow indicates the proband. The homozygous AGRN mutation (c.5302G>C) was inherited from parents.

Figure 2

Pathological results of left tibialis anterior muscle from the proband (original magnification, ×100). (a) Presence of scattered small angular fibers (H & E staining). (b) ATPase staining showed predominance of type I fiber (dark).

Figure 3

Sanger sequences of AGRN mutation (c.5302G>C) across the family. The red arrow indicated the mutation site.