Purpose: Mitochondrial abnormalities are major causes of human disease. Pearson syndrome illustrates many features of abnormal mitochondrial function and genetics.
Design: Mitochondria from adenosine triphosphate (ATP) via five multienzyme complexes of the electron transport chain and oxidative phosphorylation, composed from a blend of nuclear and mitochondrial gene products. Mitochondrial DNA (mtDNA) is small (16.6 kb), encoding some subunits of these complexes as well as transfer RNA (tRNA) and ribosomal RNA, but is replicated and transcribed by nuclear encoded polymerases. Multiple copies of mtDNA are passed on to progeny cells via the cytoplasm, accounting for maternal inheritance. Normal and mutant mtDNA can coexist within the same cell (heteroplasmy); when the proportion of mutant mtDNA exceeds a threshold, cellular function is impaired, resulting in disease.
Results and conclusions: MtDNA abnormalities include point mutations, deletions, and depletion. Point mutations in an enzyme subunit cause a specific disorder, whereas point mutations in the tRNAs result in general impairment of protein synthesis and are associated with a variety of disorders. Large mtDNA deletions, initially described in Kearns-Sayre syndrome (KSS), were found soon thereafter in Pearson syndrome. Survivors of Pearson syndrome have gone on to develop KSS. A whole spectrum of disease forms, ranging from isolated sideroblastic anemia to combined Pearson and KSS, are associated with deletions of mtDNA. Diagnosis of mitochondrial disorders depends on clinical suspicion, enhanced by evidence of abnormal mitochondrial structure, number, and/or function. Effective treatment for mitochondrial disorders is very limited, including correction of the metabolic milieu, activation of enzyme activity by drugs or cofactors, and removal of reactive oxygen species.