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Treatment of manifestations: Most individuals with CMS benefit from acetylcholinesterase (AChE) inhibitors and/or the potassium channel blocker 3,4-diaminopyridine (3,4-DAP); however, caution must be used in giving 3,4-DAP to young children and individuals with fast-channel CMS (FCCMS). Individuals with COLQ and DOK7 mutations usually do not respond to long-term treatment with AChE inhibitors. Some individuals with slow-channel CMS (SCCMS) are treated with quinidine, which has some major side effects and may be detrimental in individuals with acetylcholine receptor (AChR) deficiency. Fluoxetine is reported to be beneficial for SCCMS. Ephedrine and albuterol have been beneficial in a few individuals, especially as a therapeutic option for those with DOK7 or COLQ mutations.

Prevention of primary manifestations: Prophylactic anticholinesterase therapy to prevent sudden respiratory insufficiency or apneic attacks provoked by fever or infections in those with mutations in CHAT or RAPSN. Parents of infants are advised to use apnea monitors and be trained in CPR.

Agents/circumstances to avoid: Drugs known to affect neuromuscular transmission and exacerbate symptoms of myasthenia gravis (e.g., ciprofloxacin, chloro- quine, procaine, lithium, phenytoin, beta-blockers, procainamide, quinidine).

Evaluation of relatives at risk: If the disease-causing mutations in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk asymptomatic family members, especially newborns or young children, who could benefit from early treatment to prevent sudden respiratory failure.

Genetic Counseling

Congenital myasthenic syndromes are inherited in an autosomal recessive or, less frequently, autosomal dominant manner.

In autosomal recessive CMS (AR-CMS), the parents of an affected child are obligate heterozygotes and therefore carry one mutant allele. Heterozygotes (carriers) are asymptomatic. At conception, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

In autosomal dominant CMS (AD-CMS), some individuals have an affected parent, while others have a de novo mutation. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with AD-CMS has a 50% chance of inheriting the mutation.

Prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.

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