RECENT DEVELOPMENTS IN THE MOLECULAR-GENETICS OF MITOCHONDRIAL DISORDERS

Rapid progress has been made in the identification of mitochondrial DN A mutations which are typically associated with diseases of the nervou s system and muscle. The well established mitochondrial disorders are maternally inherited and males and females are equally affected. An ex ception is Leber's hereditary optic atrophy (LHON) which is observed m uch more frequently in males than in females. There are three common p oint mutations in LHON wich can be homoplasmic or heteroplasmic. In mi tochondrial encephalomyopathy with lactic acidosis and stroke-like epi sodes (MELAS) most mutations are single base changes and lie within th e tRNA-Leu gene. Point mutations in myoclonic epilepsy with ragged red fibres (MERRF) usually occur within the tRNA-Lys gene but mutations o f the tRNA-Leu gene are also observed. MELAS and MERRF mutations are h eteroplasmic and there is considerable clinical overlap between these diseases. Point mutations within the ATPase6 gene result in either neu ropathy, ataxia and retinitis pigmentosa (NARP) or in Leigh's syndrome . The latter occurs if the mutation is present in the majority of mito chondria (extreme heteroplasmy). Finally, mitochondrial DNA deletions are the cause underlying Kearns-Sayre syndrome (KSS). Apart from the w ell-established mitochondrial diseases, there is increasing evidence t hat mitochondrial mutations may also play a role in the neurodegenerat ive disorders Parkinson, Alzheimer and Huntington disease. The complex I defect found in Parkinson disease is especially interesting in this respect. However, no causative mitochondrial mutation has as yet been established in any of these three common disorders. (C) 1998 Elsevier Science B.V.