Mitochondrial DNA (mtDNA) deletion syndromes predominantly comprise three overlapping phenotypes that are usually simplex (i.e., a single occurrence in a family), but rarely may be observed in different members of the same family or may evolve in a given individual over time. The three phenotypes are Kearns-Sayre syndrome (KSS), Pearson syndrome, and progressive external ophthalmoplegia (PEO). Rarely Leigh syndrome can be a manifestation of a mtDNA deletion. KSS is a multisystem disorder defined by the triad of onset before age 20 years, pigmentary retinopathy, and PEO. In addition, affected individuals have at least one of the following: cardiac conduction block, cerebrospinal fluid protein concentration greater than 100 mg/dL, or cerebellar ataxia. Onset is usually in childhood. Pearson syndrome is characterized by sideroblastic anemia and exocrine pancreas dysfunction and is usually fatal in infancy. PEO, characterized by ptosis, paralysis of the extraocular muscles (ophthalmoplegia), oropharyngeal weakness, and variably severe proximal limb weakness, is relatively benign.
Diagnosis of mtDNA deletion syndromes relies on presence of characteristic clinical findings and, in KSS, changes on muscle biopsy (ragged-red fibers [RRF] with the modified Gomori trichrome stain, hyperactive fibers with the succinate dehydrogenase [SDH] stain, failure of both RRF and some non-RRF to stain with the histochemical reaction for cytochrome c oxidase [COX]) and decreased activity of respiratory chain complexes containing mtDNA-encoded subunits in muscle extracts. In Pearson syndrome, bone marrow examination reveals ringed sideroblasts, normoblasts with excessive deposits of iron in mitochondria detected by iron stains. Mitochondrial DNA deletion syndromes are caused by mtDNA deletions ranging in size from two to ten kilobases. Approximately 90% of individuals with KSS have a large-scale (i.e., 1.1- to 10-kb) mtDNA deletion that is usually present in all tissues; however, mutant mtDNA is often undetectable in blood cells, necessitating examination of muscle. In Pearson syndrome, mtDNA deletions are usually more abundant in blood than in other tissues. In PEO, mtDNA deletions are confined to skeletal muscle.
Mitochondrial DNA deletion syndromes are caused by deletion of mtDNA and, when inherited, are transmitted by maternal inheritance. The father of a proband is not at risk of having the disease-causing mtDNA mutation. The mother of a proband with a mtDNA deletion syndrome is usually unaffected and does not have mtDNA deletions in her tissues; therefore, the risk to the sibs of a proband is usually extremely low. Offspring of a female proband are usually not at risk of inheriting the mutation; however, exceptions occur. Offspring of males with a mtDNA mutation are not at risk. Although prenatal testing for pregnancies at increased risk is theoretically possible, interpretation of test results is difficult. No laboratories offering molecular genetic testing for prenatal diagnosis of mitochondrial DNA deletion syndromes are listed in the GeneTeststrade mark Laboratory Directory; however, prenatal testing may be possible through a laboratory offering custom prenatal testing for families in which the mitochondrial deletions are known.