Myasthenic Syndrome, Congenital, 24, Presynaptic

A number sign (#) is used with this entry because presynaptic congenital myasthenic syndrome-24 (CMS24) is caused by homozygous or compound heterozygous mutation in the MYO9A gene (604875) on chromosome 15q23.

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

Clinical Features

Bayram et al. (2016) reported a boy (patient BAB6499), born of unrelated parents (family HOU2431), who presented with distal arthrogryposis of the hands and feet, knee contractures, camptodactyly, and talipes equinovarus. Additional clinical details were limited, but Bayram et al. (2016) noted that arthrogryposis is often a secondary effect resulting from abnormalities in the neuromuscular system. O'Connor et al. (2016) noted that arthrogryposis may result from reduced fetal movements due to neuromuscular transmission defects in utero.

O'Connor et al. (2016) reported 3 patients from 2 unrelated families with CMS24. Patient 1 was a 4-year-old German girl, born of unrelated parents, who showed swallowing difficulties, proximal and distal muscle weakness, episodic apnea, respiratory failure, and ptosis in the neonatal period. Electrophysiologic studies showed abnormal jitter of the orbicularis oculi, suggesting a diagnosis of CMS. She may have had mild cognitive dysfunction and was tube-fed; brain imaging was normal. She responded positively to a combination of pyridostigmine and 3,4-DAP, showing marked improvements in motor and respiratory function. The second family was a consanguineous Kurdish family with 2 affected sibs. Decreased fetal movements were observed during the pregnancies, and both patients showed ptosis, swallowing difficulties, and hypotonia in the first months of life. They had delayed motor development with walking at 3 to 5 years of age, and ocular abnormalities, including nystagmus, ophthalmoplegia, and oculomotor apraxia. Respiratory crises occurred with infections. One patient was noted to have learning disabilities and did not speak at age 5 years. EMG showed abnormal jitter and there was a decremental response on repetitive nerve stimulation, consistent with a diagnosis of CMS. The patients responded well to pyridostigmine treatment. Family history revealed that the patients had 4 sibs who died in the first year of life with respiratory failure and hypotonia. Muscle and nerve biopsies were not performed.

Clinical Management

The patients with CMS24 reported by O'Connor et al. (2016) showed a favorable, if varied, response to treatment with either 3.4-DAP or pyridostigmine.

Inheritance

The transmission pattern of CMS24 in the families reported by O'Connor et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a boy with CMS24, Bayram et al. (2016) identified compound heterozygous missense mutations in the MYO9A gene (604875.0001-604875.0002). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing: 1 was inherited from the unaffected mother and the other occurred de novo. The patient was part of a cohort of 52 patients with a clinical presentation of arthrogryposis who underwent genetic studies. Functional studies of the variants and studies of patient cells were not performed, but Bayram et al. (2016) noted that Myo9a is expressed in murine skeletal muscle and nervous system, suggesting a primary neuromuscular cause of the arthrogryposis.

In 3 patients from 2 unrelated families with CMS24, O'Connor et al. (2016) identified homozygous or compound heterozygous missense mutations in the MYO9A gene (604875.0003-604875.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. All mutations occurred in the tail end of the protein, adjacent to functional domains. Functional studies of the variants were not performed, but knockdown of the myo9a gene in murine motor neurons and zebrafish (see ANIMAL MODEL) resulted in aberrant axonal branching and abnormalities of the neuromuscular junction. O'Connor et al. (2016) concluded that MYO9A deficiency may adversely affect the presynaptic motor axon, resulting in CMS.

Animal Model

O'Connor et al. (2016) found that morpholino knockdown of myo9a orthologs in zebrafish embryos resulted in curly tails, abnormal swimming, decreased movement, and cardiac edema. Mutant zebrafish showed aberrant axonal branching and motor neuron guidance, which would likely result in abnormal formation and development of the neuromuscular junction.