Myasthenic Syndrome, Congenital, 20, Presynaptic

A number sign (#) is used with this entry because of evidence that presynaptic congenital myasthenic syndrome-20 (CMS20) is caused by homozygous or compound heterozygous mutation in the SLC5A7 gene (608761) on chromosome 2q12.

Description

Congenital myasthenic syndrome-20 is an autosomal recessive neuromuscular disorder characterized by severe hypotonia associated with episodic apnea soon after birth. Patients have muscle weakness resulting in delayed walking, ptosis, poor sucking and swallowing, and generalized limb fatigability and weakness. EMG studies usually show a decremental response to repetitive nerve stimulation, and some patients may show a good response to AChE inhibitors (summary by Bauche et al., 2016).

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

Clinical Features

Bauche et al. (2016) reported 7 patients, including 2 brothers, with CMS20. The patients presented at birth with hypotonia and frequent episodic apneas often requiring ventilatory assistance. The 2 brothers had a more severe phenotype with antenatal hydramnios and arthrogryposis; these infants died at day 10 and day 15 of life. The 5 remaining patients, who ranged in age from 3 years and 9 months to 16 years, had delayed walking, proximal weakness of the lower limbs, axial weakness, fatigability, ptosis, ophthalmoparesis, chronic hypoventilation, and bulbar signs, such as poor sucking and swallowing, dysphonia, dysphagia, and stridor. There was daily or several-day fluctuations of the disease course. Four patients showed a decremental response on repetitive nerve stimulation, all of whom had a favorable response to treatment with AChE inhibitors. Three patients were noted to have cognitive deficits, whereas the other 2 had normal cognition. Muscle biopsies from the 16-year-old male and 1 of the deceased brothers with the antenatal form of the disorder showed abnormalities at the neuromuscular junction (NMJ). The older surviving boy had evidence of a denervation-renervation process with small nerve terminals and empty synaptic gutters, although the postsynaptic element looked normal. The deceased infant had immature NMJs with thin and unbranched terminal axons. Both biopsies showed abnormally strong immunostaining for butyrylcholinesterase (BChE), possibly suggesting synaptic remodeling or impaired maintenance.

Inheritance

The transmission pattern of CMS20 in the families reported by Bauche et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 7 patients, including 2 sibs, with CMS20, Bauche et al. (2016) identified biallelic mutations in the SLC5A7 gene (see, e.g., 608761.0002-608761.0006). The mutations in the first 2 families were found by whole-exome sequencing; mutations in the 4 subsequent families were found by Sanger sequencing of exons in the SLC5A7 gene in 95 individuals with a similar disorder. In vitro functional expression studies in HEK293 cells of 5 missense mutations showed that all were expressed at normal levels, but had significantly decreased choline uptake compared to controls, consistent with a recessive loss of function.