Clinical characteristics: Myotonia congenita is characterized by muscle stiffness present from childhood; all striated muscle groups including the extrinsic eye muscles, facial muscles, and tongue may be involved. Stiffness is relieved by repeated contractions of the muscle (the "warm-up" phenomenon). Muscles are usually hypertrophic. Whereas autosomal recessive (AR) myotonia congenita is often associated with more severe manifestations (such as progressive minor distal weakness and attacks of transient weakness brought on by movement after rest), autosomal dominant (AD) myotonia congenita is not. The age of onset varies: in AD myotonia congenita onset is usually in infancy or early childhood; in AR myotonia congenita the average age of onset is slightly older. In both AR and AD myotonia congenita onset may be as late as the third or fourth decade of life.
Diagnosis/testing: The molecular diagnosis of myotonia congenita is established in a proband with suggestive findings of myotonia and sometimes muscle hypertrophy, and either a heterozygous CLCN1 pathogenic variant or biallelic CLCN1 pathogenic variants identified on molecular genetic testing.
Management: Treatment of manifestations: Muscle stiffness may respond to sodium channel blockers such as mexiletine (currently the medication with best documented effect), lamotrigine carbamazepine, or phenytoin. Beneficial effects have also been reported with quinine, dantrolene, and acetazolamide.
Agents/circumstances to avoid: Depolarizing muscle relaxants (e.g., suxamethonium), adrenaline, beta-adrenergic agonists, and propranolol may aggravate myotonia.
Evaluation of relatives at risk: Because individuals with myotonia congenita may be at increased risk for adverse anesthesia-related events, molecular genetic testing of at-risk family members (for the CLCN1 pathogenic variant[s] identified in the proband) during childhood is appropriate.
Genetic counseling: Myotonia congenita is inherited in either an autosomal recessive (Becker disease) or an autosomal dominant (Thomsen disease) manner; the same pathogenic variant may be associated with both autosomal dominant and autosomal recessive inheritance. Establishing the mode of inheritance in a simplex case (i.e., a single occurrence in a family) may not be possible unless molecular genetic testing reveals two CLCN1 pathogenic variants in trans in a proband with unaffected parents, in which case inheritance can be assumed to be autosomal recessive.
Autosomal recessive inheritance: If both parents are known to be heterozygous for a CLCN1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
Autosomal dominant inheritance: The majority of individuals diagnosed with autosomal dominant myotonia congenita have an affected parent. The proportion of individuals with myotonia congenita caused by a de novo pathogenic variant is unknown but is presumably very low. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
Once the CLCN1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
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