mitochondrial inheritance

**Mechanism** - Mitochondria carry their own circular, double-stranded DNA (mtDNA; ~16.5 kb; 37 genes: 13 ETC/oxidative phosphorylation proteins, 22 tRNAs, 2 rRNAs). - The oocyte contributes essentially all cytoplasm and mitochondria to the zygote. Sperm mitochondria (in the midpiece/tail) are degraded after fertilization. Inheritance is therefore strictly maternal.

**Pedigree pattern (high-yield)** - Affected mother: ALL children (male and female) inherit the mutation and may be affected. - Affected father: NO children are affected. - No male-to-male or male-to-female transmission. Males and females are affected equally, but only females pass it on. - Can look like a "vertical" pattern in which every generation is affected via the mother.

**Key concepts** - **Heteroplasmy**: a cell contains a mixture of normal and mutant mtDNA. Replicative segregation during mitosis randomly distributes mitochondria to daughter cells. - **Threshold effect**: disease appears only when the proportion of mutant mtDNA exceeds a tissue-specific threshold. Tissues with high ATP demand (CNS, skeletal muscle, heart, eye, kidney, endocrine) have lower thresholds. - **Variable expression / incomplete penetrance**: affected family members can differ widely in severity because of different mutant loads (the bottleneck effect in oogenesis shifts heteroplasmy between generations). - **Homoplasmy**: all mtDNA is identical (all normal or all mutant). LHON is often homoplasmic. - mtDNA has a high mutation rate (no histones, limited repair, exposure to reactive oxygen species). Mutations can also arise sporadically (e.g., large single deletions in Kearns-Sayre and CPEO are usually sporadic, not inherited).

**Classic mitochondrial diseases** - **MELAS**: Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MT-TL1 tRNA-Leu mutation). - **MERRF**: Myoclonic epilepsy with ragged-red fibers (MT-TK tRNA-Lys mutation). - **LHON (Leber hereditary optic neuropathy)**: Subacute, painless bilateral central vision loss, typically in young adult males (complex I genes, e.g., ND4 11778). - **Kearns-Sayre syndrome**: Triad of onset before age 20, progressive external ophthalmoplegia, and pigmentary retinopathy, plus cardiac conduction block, ataxia, or elevated CSF protein (large mtDNA deletion, usually sporadic). - **Leigh syndrome**: Subacute necrotizing encephalopathy in infants. It can be caused by mtDNA or nuclear mutations (e.g., MT-ATP6, PDH, or complex I/IV defects). - **NARP**: Neuropathy, ataxia, retinitis pigmentosa (MT-ATP6). - Aminoglycoside-induced/maternally inherited sensorineural deafness (MT-RNR1 12S rRNA, A1555G).

**Clinical/lab clues** - Muscle biopsy: **ragged-red fibers** on modified Gomori trichrome (subsarcolemmal accumulation of abnormal mitochondria); also COX-negative fibers. - Elevated serum/CSF lactate and pyruvate, especially after exercise. - Multisystem involvement: myopathy, exercise intolerance, seizures, lactic acidosis, sensorineural hearing loss, diabetes, cardiomyopathy, optic atrophy, ophthalmoplegia, ptosis. - Diagnosis: mtDNA sequencing (blood, urine sediment, or muscle for heteroplasmy).

**Exam pearls** - Don't confuse with X-linked dominant inheritance: in X-linked dominant, an affected father passes the trait to all daughters and no sons. In mitochondrial inheritance, an affected father passes it to no one. - Many mitochondrial diseases are caused by nuclear DNA mutations (e.g., Friedreich ataxia, a frataxin GAA repeat; Wilson disease is NOT a mitochondrial disorder) and follow Mendelian patterns. Only mtDNA mutations follow maternal inheritance. - Management is supportive (e.g., CoQ10, riboflavin, L-carnitine; avoid valproate in POLG/mitochondrial disease). Mitochondrial replacement therapy (three-parent IVF) is an emerging way to prevent transmission.