Myasthenic Syndrome, Congenital, 23, Presynaptic

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-23 (CMS23) is caused by homozygous mutation in the SLC25A1 gene (190315) on chromosome 22q11. One such family has been reported.

Biallelic mutation in the SLC25A1 gene can also cause combined D-2- and L-2-hydroxyglutaric aciduria (D2L2AD; 615182), a more severe disorder with earlier onset and prominent central nervous system abnormalities.

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

Clinical Features

Chaouch et al. (2014) reported 2 adult Caucasian sibs, born of consanguineous English parents, with CMS. The patients had fatigable muscle weakness mainly affecting the limbs since infancy or early childhood. They also showed delayed motor development with some impaired intellectual development and speech delay, more marked in the younger sister. The 33-year-old brother had intermittent exercise-induced leg weakness that improved with rest, mild ptosis, dysarthria, decreased reflexes, pes cavus, and calf hypertrophy. The 19-year-old sister had recurrent falls in early infancy, facial weakness, neck muscle weakness, and limb weakness. She complained of intermittent double vision, but had no bulbar or respiratory difficulties. The brother had mild learning difficulties but was able to attend mainstream schooling; he also developed obsessive-compulsive tendencies in adulthood. His sister attended a school for special needs. Neurophysiologic studies showed no evidence of neuropathy or myopathy and there was no decremental response on repetitive nerve stimulation, but there was marked jitter in several muscles, indicating impaired transmission at the neuromuscular junction (NMJ). Muscle biopsy was normal, although electron microscopy of an earlier biopsy suggested enlarged and numerous mitochondria. The disease course remained fairly static in both individuals. Neither patient had abnormal urinary organic acid levels. The brother was initially treated with pyridostigmine with no clear benefit, and later started on 3,4-DAP with a favorable response. His sister received pyridostigmine since early childhood, but the benefit of this treatment was unclear. Chaouch et al. (2014) found that another unrelated 2-year-old patient with D2L2AD (Edvardson et al., 2013) had markedly increased jitter and blocking on EMG, consistent with myasthenic syndrome. Her symptoms did not fluctuate and did not improve with 3,4-DAP and ephedrine. Chaouch et al. (2014) noted that patients with D2L2AD may have features consistent with CMS, but it is likely undetected in patients with the more disabling, often fatal, phenotype of D2L2AD.

Clinical Management

The patients with CMS23 reported by Chaouch et al. (2014) showed a favorable, if varied, response to treatment with either 3.4-DAP or pyridostigmine.

Inheritance

The transmission pattern of CMS23 in the family reported by Chaouch et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous parents, with CMS23, Chaouch et al. (2014) identified a homozygous missense mutation in the SLC25A1 gene (R247Q; 190315.0007). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Mutations in other genes causing CMS were excluded. In vitro functional expression studies in yeast showed that the mutation resulted in decreased transport activity compared to controls, although there was residual activity. Patient fibroblasts showed normal mitochondrial content and morphology. All of these features were consistent with the milder overall phenotype and normal levels of urinary hydroxyglutaric acid. Screening of 58 additional patients with CMS and 100 patients with undefined neuromuscular disorders did not reveal mutations in the SLC25A1 gene, suggesting that it is a rare cause of the disorder.

Animal Model

Chaouch et al. (2014) found that morpholino knockdown of slc25a1 orthologs in zebrafish embryos resulted in altered tail morphology, impaired swimming, edema, and abnormal heart development. Histologic studies showed normal muscle morphology, but the neuromuscular junction was abnormal with short motor axon terminals and incomplete synapse formation, consistent with a presynaptic defect.