Myasthenic Syndrome, Congenital, 7, Presynaptic

A number sign (#) is used with this entry because of evidence that presynaptic congenital myasthenic syndrome-7 (CMS7) is caused by heterozygous mutation in the SYT2 gene (600104) on chromosome 1q32.

Description

Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. CMS7 is an autosomal dominant CMS resulting from a presynaptic defect; patients have onset of symptoms in early childhood (summary by Engel et al., 2015).

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

Clinical Features

Herrmann et al. (2014) reported 2 unrelated multigenerational families with congenital myasthenic syndrome. The first family was from the United States and contained 4 patients who presented in early childhood with foot deformities, including pes cavus and hammertoes. They had variable proximal and distal limb weakness, muscle fatigue that improved with rest, mild gait difficulties, and reduced deep tendon reflexes that could be elicited after brief exercise. Two of 4 individuals also had hearing loss, which was associated with vertigo in 1. Electrophysiologic studies showed reduced compound muscle action potential (CMAP) amplitudes, consistent with presynaptic dysfunction of the NMJ, and marked CMAP facilitation following brief exercise. The second family was from the United Kingdom and contained 6 affected individuals. The patients presented in early childhood with foot deformities as well as congenital hip dislocation. There was distal weakness and atrophy of the lower extremities and absent deep tendon reflexes. Electromyography showed a slight reinnervation of distal muscles, consistent with a motor neuropathy. Sensory nerve conduction studies were normal in all individuals from both families.

Whittaker et al. (2015) reported the electrophysiologic findings of affected members of the 2 families with CMS9 reported by Herrmann et al. (2014). Repetitive nerve stimulation resulted in large decrements of the motor amplitude, consistent with myasthenic syndrome, and maximum voluntary contraction resulted in posttetanic potentiation lasting up to 60 minutes. These findings were consistent with a presynaptic defect at the neuromuscular junction. Two patients in 1 family showed no therapeutic response to pyridostigmine, but showed slight improvement in exercise tolerance with 3,4-diaminopyridine. The improvement with 3,4-diaminopyridine was confirmed by single-fiber EMG studies on 1 of the patients.

Inheritance

The transmission pattern of presynaptic congenital myasthenic syndrome in the families reported by Herrmann et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 2 unrelated Caucasian families with CMS7, Herrmann et al. (2014) identified 2 different heterozygous missense mutations in the SYT2 gene (D307A, 600104.0001 and P308L, 600104.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in both families. Transfection of D362A (the Drosophila mutation corresponding to human D307A) in the Drosophila ortholog Dsyt1 was unable to rescue neurotransmitter release defects in Dsyt1-null flies. Flies transfected with the mutation lacked synchronous neurotransmitter release at the NMJ, showed enhanced asynchronous release, and exhibited increased spontaneous fusion rates with a strong dominant-negative effect. The findings indicated that the D362A mutation abolished the ability of the protein to support calcium-triggered neurotransmitter release in peripheral motor nerve terminals.