A 28-year-old woman presents with recurrent stroke-like episodes, progressive encephalopathy, and elevated serum and CSF lactate levels. Genetic testing confirms a mitochondrial DNA mutation. Her two children (one son, one daughter) are both asymptomatic on examination. Her brother, who carries the same mutation, has two children who are unaffected. The inheritance pattern shown in the diagram at **A** (Maternal Mitochondrial Inheritance) explains why the proband's children are at risk, but her brother's children are not. Which of the following best explains the pedigree pattern observed in this family?

Explanation

## Why option 1 is correct The fundamental principle of mitochondrial inheritance is **maternal transmission**. The egg cytoplasm contains thousands of mitochondria, while sperm contribute essentially no functional mitochondria to the zygote—the few paternal mitochondria that enter are actively degraded or diluted out during early embryonic development. Therefore, all mitochondria in the offspring are inherited exclusively from the mother. In this case, the affected mother will transmit her mutant mitochondria to all her children (both sons and daughters), placing them at risk for disease. The affected uncle, despite carrying the mutation, will NOT transmit it to his children because his sperm contributes no mitochondria. This explains why the proband's children are at genetic risk while her brother's children are completely unaffected—a classic maternal-only inheritance pattern that is pathognomonic for mitochondrial disease. ## Why each distractor is wrong - **Option 2**: While it is true that paternal mitochondria are excluded from the zygote, the mechanism is not "active exclusion after fertilization" but rather the absence of mitochondria in sperm in the first place. Sperm are streamlined for motility and contain few mitochondria in the midpiece; these do not survive in the zygote. The phrasing is mechanistically imprecise and misleading. - **Option 3**: Mitochondrial DNA is not sex-linked. The mutation is inherited from the mother to both sons and daughters equally. There is no sex-specific pattern in transmission from mother to offspring. The statement that "affected fathers pass to sons only" is completely incorrect—affected fathers pass to no children. - **Option 4**: Both parents do NOT contribute equally to mitochondrial inheritance. Although the oocyte does have a higher copy number of mitochondria than sperm, the critical point is that sperm mitochondria are essentially absent or non-functional in the zygote. The inheritance is exclusively maternal, not a matter of preferential retention based on copy number. **High-Yield:** Maternal-only inheritance + affected father → unaffected children = mitochondrial disease. Affected mother → all children at risk (variable severity due to heteroplasmy). [cite: Harper 32e Ch 46; Robbins 10e Ch 6]