Morgan-Hughes Ja

A mitochondrial myopathy with a deficiency of respiratory chain NADH-CoQ reductase activity ☆

This paper presents data on two sisters with a mitochondrial myopathy characterised by weakness, marked exercise intolerance and a fluctuating lactic acidaemia. Both patients also experienced episodes of increased weakness which could be brought on by unaccustomed activity, going without food or by taking small quantities of alcohol. Metabolic studies during exercise showed a marked and sudden rise in blood lactate and pyruvate levels. Biochemical studies in one case showed that mitochondrial respiratory rates were markedly decreased with all NAD-linked substrates tested but were normal with succinate and with TMPD + ascorbate. The mitochondrial cytochrome components were normal as determined by low temperature spectroscopy and the addition of uncoupler did not enhance state 3 respiratory rates utilising NAD-linked substrates. It was concluded, therefore, that the mitochondrial lesion was located at the level of the NADH-CoQ reductase complex.

Mitochondrial DNA (mtDNA) diseases: correlation of genotype to phenotype

This study examines the relationship of genotype to phenotype in 14 unselected patients who were found to harbour the A3243G transition in the mitochondrial transfer RNALeu(UUR) gene commonly associated with the syndrome of mitochondrial encephalopathy, lactic acidosis and strokes (MELAS). Only 6 of the 14 cases (43%) had seizures and recurrent strokes, the core clinical features of the MELAS phenotype. Of the remaining cases, four had an encephalomyopathy with deafness, ataxia and dementia, two had syndromes with progressive external ophthalmoplegia and two had limb weakness alone. Even within the MELAS subgroup, the majority of patients had one or more clinical manifestations considered to be atypical of the MELAS syndrome. They included developmental delay, ophthalmoparesis, pigmentary retinopathy and intestinal pseudo-obstruction. The proportion of mutant mitochondrial DNA (mtDNA) in muscle was generally higher in patients with recurrent strokes than in those without strokes, the highest levels being observed in MELAS cases with early onset disease. Studies of isolated muscle mitochondria identified a range of respiratory chain abnormalities mostly involving Complex I; immunoblots of Complex I in 3 of 10 cases showed selective loss of specific subunits encoded by nuclear genes. In the group as a whole, however, no clear correlations were observed between the severity or extent of the respiratory chain abnormality and clinical phenotype or the proportion of mutant mtDNA in biopsied skeletal muscle. These discrepancies suggest that, in patients harbouring the common MELAS3243 mutation, differences in heteroplasmy and the proportions of mutant mtDNA may not be the sole determinants of disease expression and that additional genetic mechanisms are involved in defining the range of clinical and biochemical phenotypes associated with this aberrant mitochondrial genome.

MOLECULAR DEFECTS OF NADH-UBIQUINONE OXIDOREDUCTASE (COMPLEX-I) IN MITOCHONDRIAL DISEASES

Defects in Complex I of the mitochondrial respiratory chain have been identified in 38 patients. The clinical and laboratory features are reviewed and the results of recently devised strategies aimed at characterizing the primary molecular and genetic abnormalities are presented. Although not exhaustive, these studies have provided a molecular basis for the contention that defects in Complex I may have their origin in nuclear or in mitochondrial genes.

Mitochondrial myopathy: Biochemical studies revealing a deficiency of NADH-cytochrome b reductase activity

This paper presents biochemical data upon a young male with a mitochondrial myopathy characterised by weakness, severe exercise intolerance, muscle wasting and exercise-induced lactic acidaemia. Two similar cases have been previously documented (Morgan-Hughes et al. 1979). This report more precisely locates the mitochondrial defect. In vitro mitochondrial studies show markedly decreased respiratory rates with all NAD-linked substrates whilst that with flavin-linked succinate is normal. Oxidative phosphorylation is normally coupled. Mitochondrial cytochrome components as determined by low temperature spectroscopy are normal. NADH-ferricyanide reductase and primary dehydrogenase activities are present at levels far in excess of that required to support normal NAD-linked substrate oxidation rates. Intramitochondrial NAD levels are similar to those found in other mammalian muscle. It is proposed therefore that the mitochondrial defect is situated between NADH dehydrogenase and the CoQ--Cytochrome b complex; possibly being a derangement of a non-haem iron sulphur centre.

Mitochondrial Myopathy with a Defect of Mitochondrial-Protein Transport

The clinical and biochemical heterogeneity of the mitochondrial myopathies is now well established.1 , 2 Recent work has focused on identifying the molecular basis of these disorders and has demons...

Salbutamol treatment in a patient with hyperkalaemic periodic paralysis due to a mutation in the skeletal muscle sodium channel gene (SCN4A)

A 35 year old woman with clinical features of hyperkalaemic periodic paralysis confirmed on provocative exercise testing was investigated. DNA sequence analysis of the gene for the α-subunit of the skeletal muscle voltage gated sodium channel (SCN4A) on chromosome 17q23 identified a point mutation at nucleotide position 2188. This results in a threonine to methionine substitution at amino acid position 704. The patient was intolerant of diuretic medication but showed a striking clinical and electrophysiological improvement with salbutamol therapy. Treatment with β-adrenergic agents should be considered in patients with hyperkalaemic periodic paralysis who are intolerant of, or resistant to, diuretic medications.

Mitochondrial DNA mutation underlying Leigh's syndrome: Clinical, pathological, biochemical, and genetic studies of a patient presenting with progressive myoclonic epilepsy

An 18-year-old male patient presented with clinical and radiological evidence of Leighs syndrome (LS), having developed progressive myoclonic epilepsy and ataxia 11 years previously. Muscle biopsy showed cytochrome oxidase deficiency but no ragged red fibres. Autopsy confirmed the diagnosis of LS; there was additional degenerative change in the cerebellum and dentate and olivary nuclei, and an axonal peripheral neuropathy. Biochemical studies showed reduced activity of complexes I and IV of the respiratory chain in mitochondria from heart, liver and kidney. The mutation of mitochondrial DNA (mtDNA) at position 8344, commonly associated with the syndrome of myoclonic epilepsy and ragged red fibres, was detected in the patients blood and was present in muscle, brain, liver, heart, and kidney in uniformly high amounts. It is clear that LS is genetically heterogeneous and represents one of the most severe phenotypes of a number of different mtDNA defects.

Kearns-Sayre syndrome associated with mitochondrial DNA deletion or duplication: a molecular genetic and pathological study

The neuropathological findings in 2 patients with Kearns-Sayre syndrome and mitochondrial DNA (mtDNA) rearrangements, one a predominant deletion and the other a predominant duplication, were remarkably similar, showing diffuse vacuolation of white matter. There were some of the pathological features of Leighs syndrome in the spinal cord of the patient with a duplication. In the patient with a predominant deletion, rearranged mtDNA was undetectable in blood, spleen, and testis, and present in highest amounts in muscle and the brain, but relatively low in cerebellum, reflecting the ratio seen, albeit in much smaller amounts, in normal aged brains. MtDNA rearrangements in this patient were largely deletions or deletion dimers; duplicated mtDNA was present in only trace amounts in some tissues and there was none in skeletal muscle. The patient with a predominant duplication of mtDNA had higher amounts of rearranged mtDNA in blood (mainly duplicated) than muscle (mainly deleted). Correlation of these data with tissue dysfunction is probably complicated by the replicative behaviour of deleted, duplicated and normal mtDNA.

Impaired mitochondrial translation in human myoblasts harbouring the mitochondrial DNA tRNA lysine 8344 A → G (MERRF) mutation: relationship to proportion of mutant mitochondrial DNA

The mitochondrial DNA transfer RNA lysine A8344G mutation is commonly associated with the MERRF (myoclonus epilepsy with ragged red fibre) phenotype. The molecular pathogenesis of disease associated with this mutation is unclear. Theoretically, a mitochondrial tRNA mutation might affect transcription or translation, or both. We therefore studied these processes in cloned primary human myoblast cultures containing different proportions of mutant mtDNA. No abnormality of transcription was observed. However, there was a progressive decrease in mitochondrially encoded protein synthesis as the proportion of mutant mtDNA increased. Furthermore, there was evidence that subunits were differentially affected, based on selective reduction of cytochrome c oxidase subunits with relatively low proportions of mutant mtDNA.

Evidence for intramitochondrial complementation between deleted and normal mitochondrial DNA in some patients with mitochondrial myopathy

Twenty-three patients with mitochondrial myopathies and mitochondrial DNA deletions in muscle were studied by means of deletion mapping and sequencing, histochemistry and polarography. Histochemistry showed significantly less focal cytochrome oxidase deficiency relative to number of ragged red fibres when the deletion did not involve reading frames for cytochrome oxidase subunits. Polarography in such patients showed defects exclusively involving complex I, in contrast to the others with larger deletions who generally had more diffuse respiratory chain defects. Analysis of other published histochemical data showed similar findings to our own. It is concluded that translation of a proportion of deleted mitochondrial DNAs occurs in at least some patients with mitochondrial DNA deletions, implying that deleted and normal mitochondrial genomes share transfer RNAs within mitochondria in such cases.