Abnormal decrement on high-frequency repetitive nerve stimulation in congenital myasthenic syndrome with GFPT1 mutations and review of literature

Abstract

Objectives: Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders characterized by neuromuscular junction defects. Mutations in GFPT1 have been shown to underlie CMS. An increasing number of patients with CMS due to mutations in GFPT1 have been reported. However, a comprehensive review of clinical and genetic analyses of GFPT-related CMS worldwide is lacking, especially, given that the common or hotspot mutations in GFPT1 have not been reported. Here, we described the clinical and genetic findings of three patients with GFPT1 mutations from southwestern China and reviewed the clinical and genetic features of patients with GFPT1-related CMS worldwide.

Methods: Clinical, laboratory, electrophysiological, myopathological, and genetic analyses of three patients with GFPT1-related CMS from southwestern China were conducted, and a review of previously published or reported cases about congenital myasthenic syndrome with GFPT1 mutations in the PubMed database was made.

Results: The clinical, laboratory, electrophysiological, and myopathological features by muscle biopsy of three patients with GFPT1-related CMS were consistent with those of previously reported patients with GFPT1 mutations. Additionally, an abnormal decrement in high-frequency RNS was found. Two different homozygous missense mutations (c.331C>T, p.R111C; c.44C>T, p.T15M) were detected by whole-exome sequencing (WES) or targeted neuromuscular disorder gene panels.

Conclusion: A distinct decremental response to high-frequency RNS was found in three patients with GFPT1-related CMS from southwestern China, which has never been reported thus far. In addition, the location and degree of tubular aggregates (TAs) seemed to be associated with the severity of clinical symptoms and serum creatine kinase levels, further expanding the phenotypic spectrum of GFPT1-related CMS. Lastly, some potential hotspot mutations in GFPT1 have been found in GFPT1-CMS worldwide.

Keywords: GFPT1; RNS; congenital myasthenic syndrome; high-frequency; repetitive nerve stimulation; tubular aggregates.

Figure 1

The results of low-frequency and high-frequency repetitive nerve stimulation (RNS) for three patients with GFPT1-related CMS from southwestern China. The amplitude of compound muscle action potential (CMAP) on RNS at both low-frequency (3, 5 HZ) and high-frequency (10, 20, and 50 Hz), which decreased by more than 15 and 30%, respectively, are considered abnormal. A dramatic decrement in the right abductor hallucis (top row) on RNS at 5, 20, and 50 Hz and in the right trapezius (bottom row) at 3, 5, 10, and 20 Hz stimulation was observed in patient 1 (A). Additionally, decremental responses in the right trapezius at 3, 5, and 10 Hz (top row) and the left trapezius (bottom row) at 3, 5, 10, and 20 Hz were detected in patient 2 (B). In patient 3 (C), RNS in the right trapezius (top row) at 3, 5, and 10 Hz and in the left trapezius (bottom row) at 3, 5, 10, and 20 Hz showed a decremental response. Repetitive nerve stimulation at low-frequency (3–5 Hz) and high-frequency (10–50 Hz), producing decremental responses >15 and 30%, respectively, were considered abnormal.

Figure 2

Myopathological findings of the patients with three GFPT1-related CMS from southwestern China. (A–D) Remarkable large and small tubular aggregates (TAs) (arrow head) located in both the subsarcolommal and inner cytoplasmic regions in patient 1. (A) H&E; (B), Modified Gomori trichrome stain; (C) NADH-TR stain; (D) ATPase stain at pH 4.7 revealing the negatively stained TAs predominantly located in type 2 fibers. (E,F) Many small TAs located in both the subsarcolemmal and inner cytoplasmic regions in patient 2. (E) NADH-TR stain; (F) AMP stain. (G,H) A few TAs located in the subsarcolemmal region and focal fiber necrosis in patient 3. (G) H&E; (H) acid phosphatase stain. (I,J) Electron microscopy images of TAs in patient 1 and patient 2. (I) TAs located both beneath the sarcolemma and in the inner cytoplasmic region. (J) TAs in both transverse and longitudinal sections.