Clinical characteristics: GJB1 disorders are typically characterized by peripheral motor and sensory neuropathy with or without fixed CNS abnormalities and/or acute, self-limited episodes of transient neurologic dysfunction (especially weakness and dysarthria). Peripheral neuropathy typically manifests in affected males between ages five and 25 years. Although both men and women are affected, manifestations tend to be less severe in women, some of whom may remain asymptomatic.

Less commonly, initial manifestations in some affected individuals are stroke-like episodes (acute fulminant episodes of reversible CNS dysfunction).

Diagnosis/testing: The diagnosis of CMT1X is established in a male by identification of a hemizygous GJB1 pathogenic variant on molecular genetic testing and in a female by identification of a heterozygous GJB1 pathogenic variant.

Management: Treatment of manifestations: Treatment by a multidisciplinary team includes special shoes and/or ankle/foot orthoses to correct foot drop and to aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility; daily heel cord stretching to prevent Achilles' tendon shortening; exercise as tolerated. Treatment of stroke-like episodes is supportive, as these are self-limited.

Surveillance: Yearly examinations by: a neurologist of motor function and pain; a physical therapist of gross motor skills and activities of daily living (ADL), an occupational therapist of fine motor skills and ADL; a foot care specialist for pressure sores and/or poorly fitting footwear. More frequent self-foot examination by the affected individual.

Agents/circumstances to avoid: Obesity (makes ambulation more difficult); medications that are toxic or potentially toxic to persons with CMT.

Genetic counseling: CMT1X is inherited in an X-linked manner. Affected males transmit the GJB1 pathogenic variant to all of their daughters and none of their sons. Women with a GJB1 pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may have mild-to-no manifestations or, more often, mild-to-moderate manifestations that may progress. Once the GJB1 pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk female relatives to determine their genetic status, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.