-Related Disorders

CLINICAL CHARACTERISTICS

-related disorders comprise a continuum of overlapping phenotypes that were clinically defined before the molecular basis was known. -related disorders can therefore be considered an overlapping spectrum of disease presenting from early childhood to late adulthood. The age of onset broadly correlates with the clinical phenotype. Liver involvement, feeding difficulties, seizures, hypotonia, and muscle weakness are the most common clinical features. This group has the worst prognosis. Disease is typically characterized by peripheral neuropathy, ataxia, seizures, stroke-like episodes, and, in individuals with longer survival, progressive external ophthalmoplegia (PEO). This group generally has a better prognosis than the early-onset group. Characterized by ptosis and PEO, with additional features such as peripheral neuropathy, ataxia, and muscle weakness. This group overall has the best prognosis.

DIAGNOSIS/TESTING: Establishing the diagnosis of a -related disorder relies on clinical findings and the identification of biallelic pathogenic variants on molecular genetic testing for all phenotypes except autosomal dominant progressive external ophthalmoplegia (adPEO), for which identification of a heterozygous pathogenic variant on molecular genetic testing is diagnostic.

MANAGEMENT

Clinical management is largely supportive and involves standard approaches for associated complications including occupational, physical, and speech therapy; nutritional support; respiratory support; and standard treatment of liver failure, epilepsy, movement abnormalities, sleep disorders, vision, and hearing issues. Evaluations by a multidisciplinary team of health care providers based on clinical findings; routine evaluation of growth, nutrition, oral intake, and respiratory status; monitoring of liver enzymes every three months or as clinically indicated; monitoring of epilepsy with repeat liver function tests after introduction of any new anti-seizure medication. Valproic acid (Depakene) and sodium divalproate (divalproex) (Depakote) because of the risk of precipitating and/or accelerating liver disease.

GENETIC COUNSELING

Early-onset and juvenile/adult-onset -related disorders are typically caused by biallelic pathogenic variants and inherited in an autosomal recessive manner. Late-onset PEO may be caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygous sibs of a proband with an autosomal recessive -related disorder are typically asymptomatic. Once the pathogenic variants have been identified in an affected family member, testing for at-risk family members is possible. Most individuals with PEO caused by a heterozygous pathogenic variant (i.e., adPEO) have an affected parent, although age of onset and severity of presentation can vary greatly from generation to generation. Each child of an individual with -related adPEO has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for -related disorders is possible.