homoplasmy

**Definition:** Homoplasmy = every mitochondrial genome in a cell (or tissue) has the same sequence. A cell can be homoplasmic for wild-type mtDNA (normal) or homoplasmic for a pathogenic mutation (affected). Each cell contains hundreds to thousands of mtDNA copies, so the proportion of mutant vs. normal copies matters.

**Contrast with heteroplasmy:** Heteroplasmy is a mix of wild-type and mutant mtDNA in the same cell. Disease expression depends on the percentage of mutant mtDNA (the threshold effect) and on the tissue's energy demand. Heteroplasmy explains variable expressivity and variable severity within families.

**Inheritance (high-yield):** - mtDNA is maternally inherited, because sperm mitochondria are generally eliminated or diluted in the zygote. Affected fathers do not pass the mutation to offspring. - An affected mother who is homoplasmic for a mutation passes it to all of her children (male and female). Only daughters pass it on to the next generation. - Replicative segregation: during mitotic cell division, mitochondria are distributed randomly to daughter cells. This can shift a heteroplasmic cell toward homoplasmy (mutant or wild-type) over time. - The mitochondrial bottleneck in oogenesis (a small number of mtDNA copies populate the oocyte) causes large shifts in heteroplasmy between generations. This can produce homoplasmy in offspring even when the mother is heteroplasmic.

**Clinical significance:** - Homoplasmic mutations may be less severe in some cases because the mutation is often milder, or they may show incomplete penetrance. Classic example: Leber hereditary optic neuropathy (LHON), usually caused by homoplasmic point mutations in mtDNA genes encoding complex I subunits (e.g., m.11778G>A in MT-ND4). Penetrance is incomplete, and males are affected more often than females. Presentation is subacute, painless, bilateral central vision loss in young adults. Smoking and alcohol are triggers. - Severe pathogenic mutations are usually heteroplasmic because fully homoplasmic mutant mtDNA would often be incompatible with life or severely debilitating. Examples: MELAS (m.3243A>G, MT-TL1), MERRF (m.8344A>G, MT-TK), Kearns-Sayre syndrome and Pearson syndrome (large deletions), and Leigh syndrome/NARP (m.8993T>G/C, MT-ATP6). - Features common to mitochondrial disease: ragged red fibers on modified Gomori trichrome stain (muscle biopsy, subsarcolemmal mitochondrial accumulation), lactic acidosis, myopathy, encephalopathy, and high-energy-demand tissues (brain, muscle, eye, heart) most affected.

**Board pearls:** - Homoplasmy = uniform mtDNA population. Heteroplasmy = mixed population. - Mitochondrial inheritance: affected mother → all children affected (to variable degrees if heteroplasmic). Affected father → no children affected. - Do not confuse with "homozygous." Homoplasmy refers to organelle genomes (mtDNA), whereas homozygosity refers to the two alleles of a nuclear gene. - LHON is the classic homoplasmic mtDNA disease on exams.