Myasthenic Syndrome, Congenital, 21, Presynaptic

A number sign (#) is used with this entry because of evidence that presynaptic congenital myasthenic syndrome-21 (CMS21) is caused by homozygous or compound heterozygous mutation in the SLC18A3 gene (600336) on chromosome 10q11.

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

Clinical Features

O'Grady et al. (2016) reported 2 unrelated patients with congenital myasthenic syndrome apparent since infancy. The patients presented with hypotonia, apneas, and feeding difficulties in the first months of life. One patient, born of nonconsanguineous Filipino parents, was less severely affected: he had normal early development and fatigue during the preschool years. At age 14 years, he had ptosis, ophthalmoplegia, mild muscle weakness, and mildly decreased cardiac left ventricular function. Creatine kinase levels were normal, and repetitive nerve stimulation showed only a decrement after isometric contraction, suggesting a presynaptic origin. This patient also had mild learning difficulties. The second patient, a girl born of consanguineous Turkish parents, required nasogastric feeding in infancy. She had nystagmus, ophthalmoplegia, ptosis, fluctuating hypotonia, and contractures of the knees. Her edrophonium test was positive, and repetitive nerve stimulation showed an extreme electrodecrement response. She had normal cognition and no evidence of cardiac involvement. Both patients showed a partial response to treatment with pyridostigmine.

Inheritance

The transmission pattern of CMS in the family reported by O'Grady et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated patients with CMS21, O'Grady et al. (2016) identified biallelic mutations in the SLC18A3 gene: 1 patient was compound heterozygous for a missense mutation (G186A; 600336.0001) and a large deletion encompassing several genes, and the other had a homozygous missense mutation (D398H; 600336.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed.

Animal Model

Lara et al. (2010) noted that Vacht -/- mice are unable to release acetylcholine (ACh) in response to depolarization and die shortly after birth due to respiratory failure. Lara et al. (2010) studied a line of mutant mice termed 'Vacht knockdown homozygous' (Vacht KD(HOM)) that show reduced Vacht expression and altered ACh release. Young Vacht KD(HOM) mice had normal cardiac function, but by 3 months of age they exhibited reduced cardiac contractility and left ventricle fractional shortening. These changes were alleviated by pharmacologic restoration of ACh at synapses. Isolated Vacht KD(HOM) heart preparations had reduced systolic tension with elevated expression of markers of cardiomyocyte stress, and these changes were also alleviated by restoration of ACh. Vacht KD(HOM) and Vacht -/- mice exhibited altered autonomic control of heart rate, overexpression of the M2 muscarinic receptor (CHRM2; 118493), and decreased expression of beta-1 adrenergic receptors (ADRB1; 109630). Expression of the G-protein kinase Grk2 (ADRBK1; 109635) was also elevated in Vacht KD(HOM) hearts compared with wildtype.