Clinical characteristics: CHCHD10-related disorders are characterized by a spectrum of adult-onset neurologic phenotypes that can include:
Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance
Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons and lower motor neurons
Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs
Late-onset spinal motor neuronopathy (SMA, Jokela type): weakness, cramps, and/or fasciculations; areflexia
Axonal Charcot-Marie-Tooth neuropathy: slowly progressive lower-leg muscle weakness and atrophy, small hand muscle weakness, loss of tendon reflexes, sensory abnormalities
Cerebellar ataxia: gait ataxia, kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements), dysarthria/dysphagia, nystagmus, cerebellar oculomotor disorder
Because of the recent discovery of CHCHD10-related disorders and the limited number of affected individuals reported to date, the natural history of these disorders (except for SMAJ caused by the p.Gly66Val pathogenic variant) is largely unknown.
Diagnosis/testing: The diagnosis is established when a heterozygous CHCHD10 pathogenic variant is detected in an individual with one or more characteristic clinical findings.
Management: Treatment of manifestations: Adequate nutrition and weight maintenance are essential. Appropriate bracing and stretching can minimize joint contractures, which are often painful and can interfere with caregiving. Those with weakness benefit from assistance with ambulation and posture. Management of ALS, FTD, SMA, and cerebellar ataxia is the same as for other causes of these disorders.
Surveillance: Regular evaluations to detect manifestations that can occur with time including neurologic deficits, psychiatric abnormalities, impaired respiratory function, and sensorineural hearing loss.
Agents/circumstances to avoid: Baclofen (used to treat spasticity) can sometimes worsen muscle weakness; some drugs used to treat the behavioral manifestations of FTD may worsen dysarthria, dysphagia, and/or respiratory weakness.
Genetic counseling: CHCHD10-related disorders are inherited in an autosomal dominant manner. Many individuals diagnosed with a CHCHD10-related disorder have an affected parent. The proportion of probands with a CHCHD10-related disorder caused by a de novo pathogenic variant is unknown. Each child of an individual with a CHCHD10-related disorder has a 50% chance of inheriting the CHCHD10 pathogenic variant. Because significant clinical heterogeneity is observed within families, it is impossible to accurately predict the age at onset and manifestations that will develop in individuals who inherit a CHCHD10 pathogenic variant. Once the CHCHD10 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for a CHCHD10-related disorder and preimplantation genetic testing are possible.
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