Congenital Myasthenia and ChAT

Abstract & Commentary

Source: Schmidt C, et al. Congenital myasthenia syndrome due to a novel missense mutation in the gene encoding choline acetyltransferase. Neuromuscul Disord. 2003; 13:245-251.

Congenital myasthenic syndromes (CMS) are present at birth. Some patients, however, may not seek medical attention until later in childhood or adulthood. Classified as presynaptic, synaptic, or postsynaptic defects, multiple gene mutations have been described. Involvement of the a, b, d, or e subunit of the acetylcholine receptor (AchR) encompasses slow channel syndrome, fast channel syndrome, and AchR deficiency, all postsynaptic defects, as are end plate rapsyn deficiency and end plate acetylcholinesterase deficiency. These latter 2 reside on chromosomes 11p and 3p, respectively. Only recently has a presynaptic mutation been elucidated for CMS.

Three patients from 2 separate kinships were studied, both from Turkey, and both reported consanguinity in the parents. Presentation was neonatally or after age 1 year. In 1, feeding and swallowing difficulties were noted at birth, followed by fatigability in the second year of life. In 2 other children, exercise-induced muscle weakness or ptosis were noted after 1 year. All 3 patients experienced multiple episodes of sudden apnea. Mutation analysis of the choline acetyltransferase (ChAT) gene revealed a single, novel, and identical point mutation in all patients, resulting in the exchange of isoleucine for threonine at codon 336. Unaffected family members either did not carry the mutation or demonstrated only a single allele with the mutation. This was consistent with recessive inheritance. CMS with episodic apnea is the first presynaptic CMS to be genetically elucidated and confirmed.


CMS should be considered in any patient with a suspected neuromuscular junctionopathy in whom AchR and calcium channel antibodies are negative. Infantile or childhood symptoms and a family history of possible CMS will often be uncovered by a meticulous history. Electrodiagnostic studies and therapeutic response to acetylcholinesterase (AchE) inhibitors will then permit accurate diagnosis in most instances. Repetitive nerve stimulation in CMS reveals a decemental pattern at low rates (2-5 Hz) of stimulation, similar to that seen in autoimmune myasthenia gravis (MG). Higher rates (10-50 Hz) may also produce a decrement, allowing differentiation of CMS from MG. When rapid repetitive nerve stimulation results in an incremental response, consider congenital Eaton Lambert myasthenic syndrome, which, like episodic apnea, is a presynaptic CMS. Exercise and AchE inhibitors partially or fully reverse the decrement in most CMS, as does 3,4-diamonopyridine. Exceptions to this rule include AchE deficiency and slow channel syndrome. Morphological studies are only rarely required for precise diagnosis. These include electron microscopic examination of the end plate to estimate AchR number and AchE amount and microelectrode studies to assess end plate potentials and quantal release of Ach. Peripheral blood DNA analysis for molecular genetic testing is available for diagnostic confirmation when indicated. — Michael Rubin

Dr. Rubin is Professor of Clinical Neurology, New York Presbyterian Hospital - Cornell Campus.