ABSTRACT
INTRODUCTION The first human mitochondrial disease was described in a patient with non-thyroidal hypermetabolism (Luft disease) nearly 50 years ago.139 Although this disorder is exceptionally rare, the clinical description and biochemical studies paved the way for three decades of clinical and pathological research on cases of 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 for the definition of syndromes such as the Kearns-Sayre syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO), but it was recognized 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 whereas some families displayed a clear maternal inheritance pattern, others were sporadic cases and some families showed autosomal dominant and recessive transmission of the same trait. Attempts to classify the mitochondrial diseases were based upon the number and size of mitochondria in skeletal muscle, leading to terms such as pleoconial or megaconial myopathies,221 and also on the pattern of respiratory chain involvement. Different groups attempted to subdivide suspected mitochondrial disease into discrete categories (the ‘splitters’)199 and those who thought of all mitochondrial disease as a single, if wide, spectrum of disorders (the ‘lumpers’).191 At this early stage it was apparent that mitochondrial disorders were a heterogeneous group: clinically, histologically, biochemically and, probably, genetically.
