From the Archives

Hitherto, morphological changes seen in mitochondria obtained from samples of skeletal muscle in a variety of neuromuscular disorders have not been correlated with functional abnormalities and so have not been considered significant for the pathogenesis of these conditions. But more recently, investigators from Cornell University have linked these same ultrastructural features to a primary biochemical abnormality of mitochondrial function. The evidence hints at a disturbance of cellular respiration in the presence of various substrates. In Luft’s disease, hypermetabolism (not of thyroid origin) is observed but, for the rest, insights into the disease mechanisms are lacking. Now that situation changes. ‘The present paper reports the findings in a man whose weakness and striking muscular fatigability appeared to be due to a primary disturbance of mitochondrial function. Biochemical studies of isolated mitochondrial fractions have shown a specific deficiency of reducible cytochrome b’. N.T., now aged 38 years, has had weakness and muscle fatigue since early childhood and has not been able to run or play games from his mid-teens. Nor was he able to continue his apprenticeship as a tailor through inability to work the foot-operated treadle of a sewing machine. Later, some bulbar symptoms emerged. Cold and alcohol seem to make him worse. On examination, he is short in stature with normal appearing if somewhat wasted muscles but showing weakness of the face (sparing the eyelids and eye movements), neck, and shoulder and pelvic girdles. The tendon reflexes are absent in the legs. ‘The most striking abnormality was a marked and progressive increase in muscle weakness during sustained activity . . . or repetitive manoeuvres . . . after a few minutes of complete rest, muscle strength returned to its pre-exercise level’. Screening investigations show only an excess of urinary lactate and pyruvate. Routine electromyography is equally unremarkable although his ability to exert maximal voluntary force at the elbow is reduced to 5.5 kg; and motor and sensory nerve conduction studies are also normal. Against this background, neurophysiological tests are carried out of electrical and mechanical responses to repetitive stimulation of the abductor digiti minimus and anterior tibial group, each constrained in a suitable jig for studying isometric responses to varying degrees of resistance, at rates that do not lead to fusion of the twitch responses, and before and after sustained voluntary muscle activity. Control observations on oxygen consumption and electrophysiology are made in ‘a healthy male subject’ (P.D.). We might now ask how fair was this physiological comparison? Dr Paul Darveniza had arrived from Australia to work with John Morgan-Hughes bringing a record of sporting achievement that included international caps for Rugby Union although his career was curtailed by the courageous boycott taken by Paul and six other Wallabies in protest at handling of the 1971 tour from South Africa to Australia during the height of the apartheid influence on sport. Next, John Morgan-Hughes and colleagues proceed to muscle biopsy from both the arm (for histochemistry and electron microscopy) and the leg (for in vitro mitochondrial studies and electron microscopy). Mitochondria are isolated for oxygen uptake studies and estimations made of pyruvate dehydrogenase and citrate synthase activity. The cytochromes are studied from low temperature spectra. On a separate occasion, N.T. undergoes exercise testing on a bicycle ergometer without added load for 5–15 min at a rate of around 10 km/h during which venous blood is sampled at regular intervals over 90 min and measurements made of serum lactate, pyruvate and ketones; and during a second test, N.T. is assessed for pulmonary respiratory function with measurement of exhaled oxygen and carbon dioxide. So what has been learnt? First, over 75% of the type 1 and 2A muscle fibres are ‘ragged-red’ giving an intense reaction for succinic dehydrogenase, nicotinomide adenine dinucleotide (NADH)tetrazolium reductase and lactate dehydrogenase, and with increased amounts of neutral lipid and periodic acid–Schiff (PAS)-positive material (Fig. 1). Perhaps, the affected fibres are slightly smaller than those that are histologically normal. Under electron microscopy both the arm and the leg muscles show separation of the myofibrils by tightly packed glycogen granules. But the striking feature is packing of the many mitochondria with an unusual network of branching cristae enclosing an amorphous matrix material and occasional dense crystalline inclusions orientated in the long axis of the organelle and with structures that produce a latticed arrangement of broad bars and cross striations (Fig. 2). Mitochondrial respiration rates for N.T. are markedly reduced in the presence of doi:10.1093/brain/awn286 Brain (2008), 131, 2805^2808