Congenital myasthenic syndrome in China: genetic and myopathological characterization

Abstract

Objective: We aimed to summarize the clinical, genetic, and myopathological features of a cohort of Chinese patients with congenital myasthenic syndrome, and follow up on therapeutic outcomes.

Methods: The clinical spectrum, mutational frequency of genes, and pathological diagnostic clues of various subtypes of patients with congenital myasthenic syndrome were summarized. Therapeutic effects were followed up.

Results: Thirty-five patients from 29 families were recruited. Ten genes were identified: GFPT1 (27.6%), AGRN (17.2%), CHRNE (17.2%), COLQ (13.8%), GMPPB (6.9%), CHAT, CHRNA1, DOK7, COG7, and SLC25A1 (3.4% each, respectively). Sole limb-girdle weakness was found in patients with AGRN (1/8) and GFPT1 (7/8) mutations, whereas distal weakness was all observed in patients with AGRN (6/8) mutations. Tubular aggregates were only found in patients with GFPT1 mutations (5/6). The patients with GMPPB mutations (2/2) had decreased alpha-dystroglycan. Acetylcholinesterase inhibitor therapy resulted in no response or worsened symptoms in patients with COLQ mutations, a diverse response in patients with AGRN mutations, and a good response in patients with other subtypes. Albuterol therapy was effective or harmless in most subtypes. Therapy effects became attenuated with long-term use in patients with COLQ or AGRN mutations.

Interpretation: The genetic distribution of congenital myasthenic syndrome in China is distinct from that of other ethnic origins. The appearance of distal weakness, selective limb-girdle myasthenic syndrome, tubular aggregates, and decreased alpha-dystroglycan were indicative of the specific subtypes. Based on the follow-up findings, we suggest cautious evaluation of the long-term efficacy of therapeutic agents in congenital myasthenic syndrome.

Figure 1

Weakness distribution in this cohort of congenital myasthenic syndrome.

Figure 2

Muscle pathology in various subtypes of congenital myasthenic syndrome: (A) Tubular aggregates appeared within fibers. MGT staining. (B) Hypertrophic/atrophic fibers, rimmed vacuole, together with connective tissue replacement and infiltration. H&E staining. (C) Target like structure within an atrophic fiber. NADH staining. (D) Central nuclei, fiber necrosis, and hyalinized fibers. H&E staining. (E) Type 1 fiber predominance and fiber type disproportion with larger type 2 fibers than type 1. ATPase staining (pH 4.6). (F) Alpha‐DG decreased with the intact expression of dystrophin and sarcoglycans. (G) Grouped atrophic fibers. H&E staining. (H) Fiber type grouping. ATPase staining (pH 4.6).