Mitochondrial diseases.

Abstract

Mitochondrial diseases are heterogeneous and characterized by a primary defect of the mitochondrial energy output. Genetic defects of mitochondrial energy enzymes may be due to either nuclear DNA gene mutations or mitochondrial DNA (mtDNA) mutations. Among hereditary defects of nuclear-encoded mitochondrial enzymes, carnitine palmitoyltransferase II (CPT-II) deficiency and pyruvate dehydrogenase complex (PDHC) deficiency are of major interest to the neurologist. Several mutations in the CPT-II gene as well as in the X-linked E1 alpha subunit gene of PDHC have been reported and associated with different clinical phenotypes. mtDNA-related syndromes include mitochondrial encephalomyopathies (e.g. MELAS, MERRF, NARP, MIMyCa, etc.), 'pure' encephalopathies (e.g. LHON) and a few syndromes involving only non-neurological systems (e.g. Pearson's pancreas-bone marrow syndrome or diabetes mellitus). Three kinds of molecular lesions have been identified in mtDNA-related disorders: point mutations of protein-encoding mtDNA genes (mit- mutations), point mutations of mtDNA-tRNA genes (syn- mutations) and large-scale rearrangements of mtDNA (rho- mutations). Point mutations (mit- and syn+) are usually maternally inherited, while single large-scale mtDNA rearrangements are usually sporadic. Furthermore, mendelian traits leading to either qualitative or quantitative abnormalities of mtDNA (i.e. multiple mtDNA deletions and tissue-specific mtDNA depletion, respectively) are the first examples of genetic dysfunction of nuclear-mitochondrial communication. In most cases, the molecular detection of the known defects of mtDNA can be carried out by non-invasive techniques, thus making it an easy and relatively inexpensive procedure in the differential diagnosis of the mitochondrial disorders, a rapidly expanding area of clinical neurology.