Congenital Myasthenic Syndrome 2A is a muscular disorder characterized by hypotonia, motor developmental delay, limb muscle weakness and muscle atrophy, as well as musculoskeletal abnormalities including joint contractures, and eye abnormalities including ptosis and ophthalmoplegia. Additional characteristics include dysmorphic facial features (e.g. thin long face). This disorder may be onset at birth and is diagnosed through family history, appearance of clinical features, muscle fiber electromyography tests, and response to therapy.
This disorder is caused by prolonged activity of acetylcholine receptors which function on the postsynaptic side of the neuromuscular junction; the resulting damage to the connection between nerve and muscle cells produces the abnormal motor and muscular clinical features. Management therapy currently involves the use of open-channel blockers such as quinine, quinidine, and fluoxetine.
Congenital Myasthenic Syndrome 2A is a rare autosomal dominant disorder caused by heterozygous missense mutations in the CHRNB1 gene. While the exact incidence of this disease subtype is unknown, the incidence of Congenital Myasthenic Syndromes in general is reported to be between 1 and 9 in 1000000 births.
CHRNB1 encodes the beta subunit of the acetylcholine (nicotinic cholinergic) receptor. Missense variants in this gene cause prolonged activity of the receptor, increasing current duration and eventual cationic overload at the postsynaptic side of the neuromuscular junction; this results in endplate myopathy, postsynaptic membrane remodeling, and neuromuscular junction fold degeneration all of which give rise to the clinical symptoms.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism and other genetic disorders. 1 patient harboring a likely pathogenic denovo mutation in CHRNB1 was diagnosed with congenital myasthenic syndrome 2A (CMS2A). The patient had presented with motor developmental delay, hypotonia, seizures, pulmonary hypertension, and signs of autism; tests on nerve conductance in the patient yielded unremarkable results. Family history of disorders revealed paranoid schizophrenia exhibited by the patient’s father.
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