Myasthenic Syndrome, Congenital, 15

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-15 (CMS15) is caused by compound heterozygous mutation in the ALG14 gene (612866) on chromosome 1p21. One such family has been reported.

Description

Congenital myasthenic syndrome-15 is one of a heterogeneous group of disorders that arise from impaired signal transmission at the neuromuscular synapse and are characterized by fatigable muscle weakness (summary by Cossins et al., 2013).

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

Clinical Features

Cossins et al. (2013) reported 2 sisters of European descent with onset of progressive fatigable proximal muscle weakness in childhood. The patients were 62 and 51 years of age, respectively, at the time of the report. Symptoms included difficulty walking, running, and climbing stairs. At age 18 years, the older sister was diagnosed with autoimmune myasthenia gravis based on a positive tensilon test and a decrement of compound muscle action potentials (CMAP) in response to repetitive nerve stimulation on electromyography; however, autoantibodies to the acetylcholine receptor (AChR) were not found. As an adult, she had generalized limb and trunk weakness and contractures in multiple joints; she remained ambulatory and had no ptosis or defects in extraocular movements. Muscle biopsy was largely unremarkable and did not demonstrate the presence of tubular aggregates. The younger sister had a similar disease course and similar laboratory findings, although no muscle biopsy was performed. Both patients showed long-term benefit from anticholinesterase medication and had no response to immunosuppressive therapy.

Inheritance

The transmission pattern of congenital myasthenic syndrome-15 in the family reported by Cossins et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sisters of European descent with congenital myasthenic syndrome-15, Cossins et al. (2013) identified compound heterozygous mutations in the ALG14 gene (P65L, 612866.0001 and R104X, 612866.0002). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. Muscle biopsy was not available to analyze endplate AChR density in the patients, but cell culture models showed that knockdown of ALG14 expression resulted in reduced expression of AChR at the cell surface, consistent with the myasthenic features. Although ALG14 is involved in glycosylation, transferrin (190000) glycosylation was not abnormal in the patients, suggesting that the mutations resulted in only a modest impairment of N-linked glycosylation.