Deletion of mitochondrial DNA in patients with combined features of kearns‐sayre and MELAS syndromes

A 9‐year‐old girl and an 11‐year‐old boy had ptosis, progressive external ophthalmoplegia, pigmentary retinopathy, and sensorineural hearing loss. The girl had diabetes mellitus and the boy had hypoparathyroidism. Both children also developed recurrent vomiting and cerebral infarcts with lactic acidosis. Muscle biopsy specimens showed ragged‐red fibers and Southern analysis demonstrated a distinct heteropolasmic deletion of muscle mitochondrial DNA in each patient but no evidence of the point mutation in the transfer RNALeu(UUR) generecently identified in mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes (MELAS). These 2 children had combined features of Kearns‐Sayre syndrome and MELAS, suggesting that mitochondrial DNA deletions occasionally can have pleomorphic clinical expression

Two cases of prenatal analysis for the pathogenic T to G substitution at nucleotide 8993 in mitochondrial DNA

We report the outcome of two prenatal analyses for the T to G mutation at nucleotide 8993 in the mitochondrial DNA. This mutation is associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) and the neurodegenerative condition, Leigh syndrome. One prospective mother was the sister of a severely affected individual, and had previously had an unaffected child and a stillborn child. The second prospective mother had two unaffected children and two affected children. The mutation was not detected in the chorionic villus sample from one fetus nor in the amniocytes from the other fetus. Both pregnancies were continued, and the resulting children were healthy at two years and five years of age. Prenatal diagnosis of this mitochondrial DNA mutation is an option likely to be acceptable to some families to prevent the birth of a child at high risk for neurological disease

Mitochondrial dysfunction in mut methylmalonic acidemia

Methylmalonic acidemia is an autosomal recessive inborn error of metabolism caused by defective activity of methylmalonyl-CoA mutase (MUT) that exhibits multiorgan system pathology. To examine whether mitochondrial dysfunction is a feature of this organic acidemia, a background-modified Mut-knockout mouse model was constructed and used to examine mitochondrial ultrastructure and respiratory chain function in the tissues that manifest pathology in humans. In parallel, the liver from a patient with mut methylmalonic acidemia was studied in a similar fashion. Megamitochondria formed early in life in the hepatocytes of the Mut−/− animals and progressively enlarged. Liver extracts prepared from the mutants at multiple time points displayed respiratory chain dysfunction, with diminished cytochrome c oxidase activity and reduced intracellular glutathione compared to control littermates. Over time, the exocrine pancreas and proximal tubules of the kidney also exhibited megamitochondria, and older mutant mice eventually developed tubulointerstitial renal disease. The patient liver displayed similar morphological and enzymatic findings as observed in the murine tissues. These murine and human studies establish that megamitochondria formation with respiratory chain dysfunction occur in a tissue-specific fashion in methylmalonic acidemia and suggest treatment approaches based on improving mitochondrial function and ameliorating the effects of oxidative stress.—Chandler, R. J., Zerfas, P. M., Shanske, S., Sloan, J., Hoffmann, V., DiMauro, S., Venditti, C. P. Mitochondrial dysfunction in mut methylmalonic acidemia

Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA

Large-scale deletions of mitochondrial DNA (mtDNA) have been described in patients with progressive external ophthalmoplegia (PEO) and ragged red fibers. We have determined the exact deletion breakpoint in 28 cases with PEO, including 12 patients already shown to harbor an identical deletion; the other patients had 16 different deletions. The deletions fell into two classes. In Class I (9 deletions; 71% of the patients), the deletion was flanked by perfect direct repeats, located (in normal mtDNA) at the edges of the deletion. In Class II (8 deletions; 29% of patients), the deletions were not flanked by any obviously unique repeat element, or they were flanked by repeat elements which were located imprecisely relative to the breakpoints. Computer analysis showed a correlation between the location of the deletion breakpoints and sequences in human mtDNA similar to the target sequence for Drosophila topoisomerase II. It is not known how these deletions originate, but both slipped mispairing and legitimate recombination could be mechanisms playing a major role in the generation of the large mtDNA deletions found in PEO