Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy

We investigated the etiology of Leigh syndrome in 67 Australian cases from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups, ie, 80% in the tightly defined group and 41% in the "Leigh-like" group. Eleven patients had mitochondrial DNA point mutations (nucleotide [nt] 8993 T to G, nt 8993 T to C, or nt 8344 A to G) and 1 Leigh-like patient had a heteroplasmic deletion. Twenty-nine patients had enzyme defects, ie, 13 respiratory chain complex I, 9 complex IV, and 7 pyruvate dehydrogenase complex (PDHC). Complex I deficiency is more common than recognized previously. Six PDHC-deficient patients had mutations in the X-chromosomal gene encoding the E1alpha subunit of PDHC. Parental consanguinity suggested autosomal recessive inheritance in two complex IV-deficient sibships. We found no strong correlation between the clinical features and basic defects. An assumption of autosomal recessive inheritance (frequently made in the past) would have been wrong in nearly one-half (11 of 28 tightly defined and 18 of 41 total patients) of those in whom a cause was found. A specific defect must be identified if reliable genetic counseling is to be provided.

Leigh syndrome: Clinical features and biochemical and DNA abnormalities

Mitochondrial DNA mutations and human disease

The mitochondrial encephalomyopathies are a diverse group of disorders that result from the structural, biochemical, or genetic derangement of mitochondria.1 Since mitochondrial dysfunction can affect virtually all organ systems (Figure 1), physicians in many specialties see patients with mitochondrial diseases. Despite a bewildering array of clinical manifestations (Table 1 and Table 2) and variations in the mode of onset, course, and progression of disease, many mitochondrial disorders share prominent systemic effects (Table 2) that contribute to their morbidity. Our understanding of the role of mitochondrial DNA in certain diseases has evolved rapidly since 1988, when the first mutations in mitochondrial DNA were . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199509073331007

Seminars in medicine of the Beth Israel Hospital, Boston. Mitochondrial DNA and disease.

Approximately three years ago, this journal published a review on the clinical and molecular analysis of mitochondrial encephalomyopathies, with emphasis on defects in mitochondrial DNA (mtDNA). At that time, approximately 30 point mutations associated with a variety of maternally-inherited (or rarely, sporadic) disorders had been described. Since that time, almost twenty new pathogenic mtDNA point mutations have been described, and the pace of discovery of such mutations shows no signs of abating. This accumulating body of data has begun to reveal some patterns that may be relevant to pathogenesis.

Mitochondrial DNA mutations and pathogenesis.

We looked for the A-->G transition at position 8344 of mtDNA in 150 patients, most of them with diagnosed or suspected mitochondrial disease, to assess the specificity of this mutation for the MERRF phenotype, to define the clinical spectrum associated with the mutation, and to study the relationship between percentage of mutation in muscle and clinical severity. Our results confirm the high correlation between the A-->G transition at position 8344 and the MERRF syndrome, but they also show that this mutation can be associated with other phenotypes, including Leigh's syndrome, myoclonus or myopathy with truncal lipomas, and proximal myopathy. The absence of the mutation in four typical MERRF patients suggests that other mutations in the tRNA(Lys) gene, or elsewhere in the mitochondrial DNA, can produce the same phenotype.

M. Sumi

Papers

Clinical features associated with the A-->G transition at nucleotide 8344 of mtDNA ("MERRF mutation").