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NDUFA1 is one of the 36 nuclear genes encoding subunits of the mitochondrial complex I involved in the respiratory chain. The human NDUFA1 has been cloned, completely sequenced and mapped to Xq24. In the present study, we searched for sequence variations in NDUFA1 as causative defects in complex I deficiency using genomic DNA of 152 patients with various clinical phenotypes. The patient sample consisted of 54 patients (46 male and 8 female) with Leber heriditary optic neuropathy (LHON) from 48 unrelated families from Germany and 98 patients (72 male and 26 female) with biochemically proven complex I deficiency including Leigh syndrome. Patient DNA was used to amplify all three exons, including the exon/intron boundaries and the promoter region of NDUFA1 for heteroduplex analysis and direct sequencing. In the 152 patients tested, no mutation was found that could be related to any of the disease phenotypes included. However, three single-nucleotide polymorphisms (SNPs) located in the promoter region (SNP G/C at nt -71 and SNP T/C at nt -189) and in intron 1 (SNP T/G nt 1454) were discovered. Allele frequencies of the SNPs were estimated in a German and Estonian control population and compared to complex I-deficient patients. There was no significant difference between the control population, the LHON patients, or the severely affected patients with complex I deficiency, excluding an association of the polymorphisms with the diseases. Our results suggest that mutations in NDUFA1 do not cause the gender difference observed in clinically severe and complex phenotypes with complex I deficiency.

An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA) responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic acid in plasma and urine. Multiple deficiency of oxidative phosphorylation was found in the patient's liver. We suggest that patients with B(12)-sensitive methylmalonic aciduria who have a milder clinical course should be carefully monitored for long-term complications.

Respiratory-chain deficiencies have long been regarded as neuromuscular diseases. In fact, oxidative phosphorylation, i.e. adenosine triphosphate (ATP) synthesis by the respiratory chain, does not occur only in the neuromuscular system. Indeed, a number of non-neuromuscular organs and tissues are dependent upon mitochondrial energy supply. For this reason, a respiratory chain deficiency can theoretically give rise to any symptom, in any organ or tissue, at any age and with any mode of inheritance, owing to the twofold genetic origin of respiratory enzymes (nuclear DNA and mitochondrial DNA, mtDNA). In recent years, it has become increasingly clear that genetic defects of oxidative phosphorylation account for a large variety of clinical symptoms in childhood. Among 100 patients with respiratory-chain deficiencies identified in our centre, 56% presented with a non-neuromuscular symptom and 44% were referred for a neuromuscular problem. It appears that the diagnosis of a respiratory-chain deficiency is difficult initially when only one symptom is present. In contrast, this diagnosis is easier to consider when two seemingly unrelated symptoms are observed.

Pearson syndrome (McKusick 260560) is a multisystem disorder of mitochondrial energy metabolism. Fatal outcome is widely reported and is usually related to liver failure (Rotig et al 1990). We describe the case of a 3-year-old boy with Pearson syndrome but with normal pancreatic, hepatic and renal function. Furthermore, he presents bilateral corneal opacity and hypoaldosteronism. In addition, altered Krebs' and urea-cycle metabolites were found

Hitherto, cardiomyopathy has never been reported as the presenting symptom of a mitochondrial disorder. Although it appears premature to conclude as to the prevalence of defects of oxidative phosphorylation in hypertrophic cardiomyopathies, this study demonstrates that such defects should be regarded as a potential cause of idiopathic hypertrophic cardiomyopathy in early infancy. While an abnormal redox status in plasma and widespread multitissue defects support the diagnosis of mitochondrial cardiomyopathy, normal results in such investigations do not preclude the possibility of heart-specific respiratory chain defect and should prompt one to carry outin vivo investigations on endomyocardial biopsies.

Mitochondrial disorders have long been regarded as neuromuscular diseases only. In fact, owing to the ubiquitous nature of the oxidative phosphorylation, a broad spectrum of clinical features should be expected in mitochondrial disorders. Here, we present eight puzzling observations which give support to the view that a disorder of oxidative phosphorylation can give rise to any symptom in any organ or tissue with any apparent mode of inheritance. Consequently, we suggest giving consideration to the diagnosis of a mitochondrial disorder when dealing with an unexplained association of symptoms, with an early onset and a rapidly progressive course involving seemingly unrelated organs. Determination of lactate/pyruvate and ketone body molar ratios in plasma can help to select patients at risk for this condition.

Pearson syndrome (PS) (McKusick 260560) is an often fatal disease of early childhood. We describe an 8-year-old boy with PS, who showed the typical haematological symptoms in early infancy. During his later course, increased CSF protein, ptosis and retinitis pigmentosa pointed to the Kearns-Sayre syndrome, another mtDNA deletion disorder. Analysis of leukocyte mtDNA revealed a 5.5-kb mtDNA deletion similar to that found in at least five other patients with PS (Rotig et al 1990)