heteroplasmy

**Definition:** Heteroplasmy = a mixture of mutated and wild-type mtDNA in the same cell/tissue/individual. Contrast with *homoplasmy*, in which all mtDNA copies are identical (all normal or all mutant).

**Pathophysiology:** - Each cell contains hundreds to thousands of mitochondria, each with multiple copies of circular mtDNA (37 genes: 13 ETC proteins, 22 tRNAs, 2 rRNAs). - Oocytes contain ~100,000+ mtDNA copies. During oogenesis, the **mitochondrial bottleneck** (a marked reduction in mtDNA copy number in primordial germ cells/early oocytes) followed by random segregation (replicative segregation) leads to widely variable mutant loads among offspring of the same mother. - During mitosis, mitochondria are distributed randomly to daughter cells (mitotic segregation), so mutant load can drift over time and differ among tissues. - **Threshold effect:** Symptoms appear only when the mutant mtDNA proportion exceeds a tissue-specific threshold (often ~60-90%). Tissues with high oxidative demand (brain, skeletal and cardiac muscle, retina, kidney, endocrine organs) are most vulnerable and have lower thresholds.

**Inheritance and clinical significance:** - **Maternal (matrilineal) inheritance:** Sperm mitochondria are generally degraded after fertilization. Affected mothers can transmit to all children (males and females), but only affected females pass it on. An affected father does not transmit it. - Results in **variable expression, variable severity, and incomplete penetrance** within families, even among siblings. - Mutant load can change with age (often rising in post-mitotic tissues such as muscle and neurons), so disease may be progressive and late-onset.

**Classic mitochondrial diseases (high-yield):** - **MELAS:** Mitochondrial myopathy, Encephalopathy, Lactic acidosis, Stroke-like episodes (commonly m.3243A>G in MT-TL1, a tRNA-Leu gene). - **MERRF:** Myoclonic Epilepsy with Ragged-Red Fibers (MT-TK, tRNA-Lys). - **Leigh syndrome:** Subacute necrotizing encephalopathy in infants (can be mtDNA or nuclear DNA). - **Kearns-Sayre syndrome:** Ophthalmoplegia, pigmentary retinopathy, cardiac conduction block, onset before age 20 (usually a sporadic large mtDNA deletion). - **LHON (Leber hereditary optic neuropathy):** Painless, subacute bilateral central vision loss in young men; often homoplasmic, with incomplete penetrance and male predominance. - **NARP:** Neuropathy, Ataxia, Retinitis Pigmentosa (MT-ATP6). Higher mutant load (>90%) causes Leigh syndrome, which is a classic example of how load determines phenotype.

**Diagnostic clues:** - **Muscle biopsy:** Ragged-red fibers on modified Gomori trichrome stain (subsarcolemmal accumulation of abnormal mitochondria); also COX-negative fibers. - Elevated serum lactate and pyruvate, especially after exercise. - Genetic testing: mtDNA sequencing, best done on affected tissue (muscle) because blood mutant load can be low or decline with age.

**Board pearls:** - Heteroplasmy explains why a mitochondrial (maternally inherited) pedigree shows variable severity among affected family members. - A "maternal inheritance pattern with variable expression" is the stem clue. - Do not confuse with **mosaicism** (nuclear DNA differences between cell lines) or **genomic imprinting** (parent-of-origin gene expression, as in Prader-Willi/Angelman). - Management is largely supportive (CoQ10, L-carnitine, riboflavin, and other cofactors; avoid mitochondrial toxins such as valproate in suspected POLG disease). Mitochondrial replacement therapy (e.g., pronuclear transfer) is an emerging strategy to prevent transmission.