Myasthenic Syndrome, Congenital, 25, Presynaptic

A number sign (#) is used with this entry because of evidence that presynaptic congenital myasthenic syndrome-25 (CMS25) is caused by homozygous mutation in the VAMP1 gene (185880) on chromosome 12p13.

Description

Congenital myasthenic syndrome-25 is an autosomal recessive neuromuscular disorder characterized by hypotonia and generalized muscle weakness apparent from birth. Affected individuals have feeding difficulties and delayed motor development, usually never achieving independent ambulation. Additional variable features include eye movement abnormalities, joint contractures, and rigid spine. Pyridostigmine treatment may be partially effective (summary by Shen et al., 2017).

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

Clinical Features

Shen et al. (2017) reported a girl, born of consanguineous Brazilian parents, with a lethal muscle disorder. At 6 months of age, the patient had severe hypotonia with lack of head control and inability to sit without support. By 2 years, she had severe muscle atrophy, slight limb movement, and areflexia. She was never able to walk and had slurred speech and limited extraocular movement, but was able to swallow. She died at age 14 years of respiratory failure associated with an infection. Electrophysiologic studies showed low-amplitude compound muscle action potentials (CMAPs) and a decremental response to 3-Hz stimulation. Rapid nerve stimulation resulted in marked potentiation of the action potentials, suggesting a presynaptic defect. Pyridostigmine treatment resulted in some improvement. Her parents were unaffected.

Salpietro et al. (2017) reported 4 patients from 2 unrelated consanguineous families from Kuwait and Israel with CMS25. The patients presented soon after birth with hypotonia, feeding difficulties, and delayed motor development. More variable features included ophthalmoplegia, strabismus, contractures, kyphoscoliosis, and joint laxity. None of the patients were able to walk without support. Electrophysiologic examinations showed a marked reduction in the CMAP and a significant increase in the amplitude with high stimulation, indicated a presynaptic defect at the neuromuscular junction. Pyridostigmine treatment resulted in some improvement.

Monies et al. (2017) identified reported 2 unrelated Saudi patients (16W-0091 and 16W-0082), born of consanguineous parents, with severe congenital hypotonia, rigid spine, myopathic facies, and delayed motor development who were found to have a homozygous mutations in the VAMP1 gene (see MOLECULAR GENETICS). One patient was noted to have normal serum creatine kinase, and the other had an atrial septal defect and contractures. Clinical details were limited, as the patients were part of a large cohort of over 1,000 Saudi families with various suspected Mendelian phenotypes who underwent next-generation sequencing. The parents were clinically unaffected.

Inheritance

The transmission pattern of CMS25 in the family reported by Shen et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a girl, born of consanguineous Brazilian parents, with CMS25, Shen et al. (2017) identified a homozygous frameshift mutation in the VAMP1 gene (185880.0002), resulting in elongation of the protein. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Expression of the mutation in HEK293 cells showed that it caused decreased levels of mutant A isoform (15% of normal) and the mutant D isoform (68% of normal). Transfection of the mutant VAMP1 isoforms into chromaffin cells resulted in significantly decreased depolarization-evoked exocytosis of catecholamine-containing vesicles (2 to 12%) compared to controls. These findings were consistent with a loss of function.

In 4 patients from 2 unrelated consanguineous families with CMS25, Salpietro et al. (2017) identified homozygous mutations in the VAMP1 gene (185880.0003 and 185880.0004). The mutations, which were found by whole-exome or whole-genome sequencing, segregated with the disorder in the families.

In 2 unrelated Saudi patients (16W-0091 and 16W-0082) with CMDS25, Monies et al. (2017) identified homozygous mutations in the VAMPS1 gene (185880.0005 and 185880.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families; the unaffected parents were heterozygous carriers of the mutations. Functional studies of the variants and studies of patient cells were not performed, but both were predicted to result in a loss of function. The patients were part of a large cohort of 1,000 Saudi families with suspected Mendelian disorders who underwent whole-exome sequencing.

Animal Model

The 'lethal-wasting' (lew) mouse is a spontaneous autosomal recessive mutant that manifests as a neurologic phenotype characterized by generalized lack of movement, wasting, and prewean death by age 15 days. By positional cloning, Nystuen et al. (2007) determined that the lew phenotype results from a 190G-T transversion in the coding region of the Vamp1 gene, predicted to result in truncation of nearly half of the protein. Western blot analysis showed no detectable Vamp1 protein in mutant mice. The authors noted that the phenotype was milder than that of Vamp2 (185881)-null mice, which die at birth. By immunostudies of normal mice, Nystuen et al. (2007) showed that Vamp1 is expressed primarily in certain neuronal tissues, including the retina and areas of the diencephalon and midbrain such as the zona incerta (subthalamus) and rostral periolivary region. The findings suggested that Vamp1 has a vital role in a subset of central nervous system tissues.

Salpietro et al. (2017) found that the neuromuscular synapses in Vamp1-null lew mice were markedly smaller than those in controls. Electrophysiologic studies showed that mutant mice had a severe reduction in endplate potentials and that low-frequency repetitive stimulation (10 Hz) caused synaptic facilitation, suggesting a presynaptic defect.