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Why can mitochondrial genetic diseases vary greatly in severity?
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human genetic disease
Photomicrograph of the BRCA2 tumor suppressor gene on chromosome 13 of the human genome. Inactivation of this growth-regulating gene is associated with a higher risk of developing breast cancer.
Mitochondrial genetic diseases exhibit a wide spectrum of severity due to several complex biological factors. When mutations occur in the mitochondrial DNA (mtDNA), the resulting clinical presentation is heavily influenced by the concept of heteroplasmy—the presence of a mixed population of both normal and mutant mtDNA within a single cell.123
Because mitochondria are randomly distributed to daughter cells during cell division, the proportion of abnormal mitochondria can vary significantly between different cells and tissues. If a cell contains a high percentage of mutant mitochondria, its function—and consequently the function of the tissue it belongs to—becomes impaired. The severity of the disease is further determined by:1
- Energy Requirements: Tissues with high metabolic demands, such as the nervous and muscular systems, are typically more severely affected by mitochondrial dysfunction.4
- Extent of Tissue Involvement: The disease may range from mild, single-organ involvement to debilitating, multi-organ failure depending on how widespread the mitochondrial dysfunction is throughout the body.15
- Confounding Factors: Other genetic or environmental influences can also modify the expression and penetrance of these disorders.23