It is over 40 years since the first human mitochondrial disease was described in a patient with non-thyroidal hypermetabolism (Luft disease).1 Although this disorder is exceptionally rare (only two cases have been described), the clinical description and biochemical studies paved the way for three decades of clinical and pathological research on patients with suspected mitochondrial disease. Patients were classified into groups based upon the pattern of clinical involvement, histological and ultrastructural abnormalities of mitochondria, and biochemical assays of mitochondrial function. It was clear that there were clinical similarities among some patients, allowing the definition of syndromes such as the Kearns–Sayre syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO), but it was recognised that there was considerable phenotypic diversity and that many patients did not fit neatly into a specific diagnostic group.
The inheritance pattern also varied. Some patients appeared to be sporadic cases, whereas others were clearly familial. It was known for some time that mitochondrial DNA (mtDNA) was maternally inherited, and while some families displayed a clear maternal inheritance pattern, others did not. There were attempts to classify based upon the number and size of mitochondria in skeletal muscle, leading to terms such as pleoconial or megaconial myopathies,2 and also on the pattern of respiratory chain involvement. There were those who wanted to subdivide suspected mitochondrial disease into discrete categories (the "splitters"3) and those who thought of all mitochondrial disease as a single, if wide, spectrum of disorders (the "lumpers"4). At this early stage it was apparent that mitochondrial disorders were a heterogeneous group—clinically, histologically, biochemically, and probably genetically.
Following the discovery in the early 1960s that mitochondria contain their own DNA (mtDNA),5 there were two major advances, both in the 1980s: the human mtDNA sequence was published in 1981,6 and in 1988 the first pathogenic mtDNA mutations were identified.7,8 The floodgates were opened, and the 1990s became the decade of the mitochondrial genome. Over 150 different pathogenic point mutations and a larger number of different rearrangements (that is, partial deletions and duplications) of mtDNA were associated with disease,9 and there were major advances in our understanding of the molecular pathophysiology.10,11 There has been a change of emphasis in the first few years of the new millennium, away from the "magic circle" of mtDNA and back to the nuclear genome.12 Various nuclear genes have been identified that are fundamentally important for mitochondrial homeostasis, and when these genes are disrupted, they cause autosomally inherited mitochondrial disease.13 Moreover, mitochondrial dysfunction plays an important role in the pathophysiology of several well established nuclear genetic disorders, such as dominant optic atrophy (mutations in OPA1),14 Friedreich’s ataxia (FRDA),15 hereditary spastic paraplegia (SPG7),16 and Wilson’s disease (ATP7B).17 The next major challenge is to define the more subtle interactions between nuclear and mitochondrial genes in health and disease. It is likely that these mechanisms will have broader relevance for our understanding of many inherited and sporadic neurological disorders.
In this article we will review the basic scientific principles that underpin our understanding of mitochondrial pathology. Rather than giving a comprehensive description of mitochondrial biology, we will focus on the bare essential facts that will help the practising general neurologist to understand, identify, investigate, and manage patients with primary mitochondrial disease (by which we mean disorders that result directly from mutations either in mtDNA or in nuclear genes affecting the respiratory chain or mtDNA homeostasis). Mitochondrial abnormalities have been identified in more common sporadic neurological disorders, including Alzheimer’s disease and Parkinson’s disease, and they also occur as part of normal aging.18 The role of these secondary mitochondrial abnormalities is uncertain, and they will be discussed in other articles in this series.
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