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December 2006

Pedaling From Genotype to Phenotype

Arch Neurol. 2006;63(12):1679-1680. doi:10.1001/archneur.63.12.1679

Because mitochondria are present in every tissue of the body (erythrocytes are apparently only an exception because they used to have mitochondria when they were young erythroblasts), mutations in mitochondrial DNA (mtDNA) can, and often do, cause multisystemic diseases. To complicate matters further, mtDNA mutations, unlike nuclear ones, do not come in pairs but in droves, sometimes affecting all the genomes (homoplasmy), but more often affecting some of them (heteroplasmy). As the proportion of mutant mtDNAs can vary from tissue to tissue, and different tissues are variably vulnerable to impairments of oxidative phosphorylation (threshold effect), it follows that mtDNA-related disorders are a headache for clinicians because phenotypic presentation and severity can differ widely in maternal relatives of the same family. In a single individual, symptoms can change with time if and when the mutation load surpasses the vulnerability threshold, and it is virtually impossible to offer a sound prenatal prognosis.1

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