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Key Points

  • Disease summary:

    • Dysfunction of the electron transport chain (ETC) causes a group of multisystem disorders which can present in any age group. Mitochondrial disorders should be suspected in patients with diffuse involvement of several organ systems that does not conform to an established pattern of conventional disease, particularly in the presence of myopathy or neurologic symptoms.

    • The major clinical features of mitochondrial diseases include stroke or stroke-like events, dementia, seizures, myopathy, external ophthalmoplegia, pigmentary retinopathy, optic atrophy, hearing loss, cardiomyopathy, cardiac conduction abnormalities, hepatopathy, severe gastrointestinal (GI) dysmotility, autonomic dysfunction, and endocrinopathies.

    • Clinical features most specific to mitochondrial disorders include strokes that do not follow vascular territory, external ophthalmoplegia, unexplained lactic acidosis, and maternal inheritance pattern. The most common symptoms reported by patients include migraine, fatigue or exercise intolerance, heat intolerance, dyspnea, and GI dysmotility.

    • While many patients develop clusters of symptoms that fall into discrete clinical syndromes (Table 166-1), most affected individuals do not fit neatly into any particular syndromic category.

  • Hereditary basis:

    • Mitochondrial disease can result from mutations of both nuclear and mitochondrial genes.

    • Nuclear mutations can be inherited in autosomal dominant, autosomal recessive, or X-linked patterns.

    • Mutations of the mitochondrial DNA (mtDNA) are inherited through the maternal lineage. Each cell carries multiple copies of the mitochondrial genome and deleterious mutations usually affect some but not all copies of the mitochondrial genome (heteroplasmy). The expression of mitochondrial disease due to mtDNA mutations depends on the relative proportions of normal and abnormal mtDNA.

Table 166-1Syndromic Presentations

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