MITOCHONDRIAL-DNA ALTERATIONS AND GENETIC-DISEASES - A REVIEW

We review the main features of human mitochondrial function and struct ure, and in particular mitochondrial transcription, translation, and r eplication cycles. Furthermore, some peculiarities such as mitochondri a's high polymorphism, the existence of mitochondrial pseudogenes, and the various considerations to take into account when studying mitocho ndrial diseases will also be mentioned. Mitochondrial syndromes mostly affecting the nervous system have, during the past few years, been as sociated with mitochondrial DNA (mt DNA) alterations such as deletions , duplications, mutations and depletions. We suggest a possible classi fication of mitochondrial diseases according to the kind of mt DNA mut ations: structural mitochondrial gene mutation as in LHON (Leber's Her editary Optic Neuropathy) and NARP (Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa) as well as some cases of Leigh's syndrome; transfer RNA and ribosomal RNA mitochondrial gene mutation as in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Strokelike Epis odes) or MERRF (Myoclonic Epilepsy with Ragged Red Fibers) or deafness with aminoglycoside; structural with transfer RNA mitochondrial gene mutations as observed in large-scale deletions or duplications in Kear ns-Sayre syndrome, Pearson's syndrome, diabetes mellitus with deafness , and CPEO (Chronic Progressive External Ophtalmoplegia). Depletions o f the mt DNA may also be classified in this category. Even though muta tions are generally maternally inherited, most of the deletions are sp oradic. However, multiple deletions or depletions may be transmitted i n a mendelan trail which suggests that nuclear gene products play a pr imary role in these processes. The relationship between a mutation and a particular phenotype is far from being fully understood. Gene dosag e and energic threshold, which are tissue-specific, appear to be the b est indicators. However, the recessive or dominant behavior of both th e wild type or the mutated genome appears to play a significant role, which can be verified with in vitro studies.