The diagnosis of primary lactic acidaemia due to defects in the metabolism of pyruvate and of the mitochondrial respiratory chain complexes is difficult (Robinson 1989). In most instances, other than elevated blood lactate levels there are no metabolic markers to direct investigations towards the site of the deficiency. Frequently the only way a diagnosis can be established is by the sequential analysis of all enzymes in fresh biopsied tissue or in cultured skin fibroblasts, a process that is both expensive and time-consuming. It would be of great advantage if metabolic markers could be identified to direct investigations to the defective site. Complex 1 (NADH:coenzyme Q oxidoreductase) is one such enzyme. There are no metabolic markers for the defect (McKusick 312450) and investigation is further complicated by the clinical heterogeneity of the disorder (Robinson 1989). The first complex of the mitochondrial respiratory chain is composed of 25 polypeptide subunits, 7 of which are encoded by mitochondrial DNA. Complex 1 functions to oxidize NADH to NAD+ and in doing so transfers electrons and reduces coenzyme Q. The NAD+ so produced is then available as a cofactor for numerous dehydrogenation reactions. Theoretically, complex 1 deficiency, through raising the intracellular ratio of NADH:NAD+ should result in relative deficiency of NAD+ and thus inhibit metabolic pathways dependent upon NAD+ as a cofactor. This should result in the accumulation of the enzyme substrates and their excretion in urine.
