Myasthenic Syndrome, Congenital, 18

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-18 (CMS18) is caused by heterozygous mutation in the SNAP25 gene (600322) on chromosome 20p11. One such patient has been reported.

Description

Congenital myasthenic syndrome-18 is an autosomal dominant presynaptic neuromuscular disorder characterized by early-onset muscle weakness and easy fatigability associated with delayed psychomotor development and ataxia (summary by Shen et al., 2014).

For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

Clinical Features

Shen et al. (2014) reported a girl who presented at birth with stiffness, respiratory insufficiency, and multiple joint contractures. Decreased fetal movements had been noted during pregnancy. She showed severely delayed psychomotor development, achieving head control at age 2 years and walking only with assistance in late childhood. She had ptosis, easy fatigability, and ataxic gait. Additional features included staring spells, EEG abnormalities, and poor speech with dysarthria. EMG showed a decremental response to repetitive stimulation, and pyridostigmine therapy was ineffective. Muscle biopsy showed no morphologic abnormalities, and acetylcholine receptor (AChR) density and acetylcholinesterase (AChE) levels were normal. Brain imaging was also normal. In vitro analysis of neuromuscular transmission showed a reduced frequency of miniature endplate potentials (MEPPs) and decreased probability of quantal release compared to controls.

Molecular Genetics

In a girl with CMS18, Shen et al. (2014) identified a de novo heterozygous missense mutation in the SNAP25 gene (I67N; 600322.0001). The mutation, which affected the SNAP25B isoform, was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro liposome fusion experiments showed that the I67N mutant interfered with calcium-induced fusion, and transfection of the mutation into chromaffin cells showed that it inhibited exocytosis of catecholamine-containing vesicles. The mutation exerted a dominant-negative effect.