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

Abstract

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.

Genetics and molecular pathogenesis of mitochondrial respiratory chain diseases

“…(A comprehensive list of pathogenic mtDNA mutations and associated phenotypes is provided in reference [7].) Respiratory chain dysfunction has been documented in most of these disorders, although there is often no clear correlation between the site of the biochemical defect and the clinical phenotype [52,53]. It had been hoped that the advent of specific mtDNA defects might allow clear genotype-phenotype correlations to be made.…”

Mitochondrial Cardiomyopathy: Molecular and Biochemical Analysis

“…Defects in mitochondrial based diseases of MELAS and MERFF have shown defects most often in Complex I and Complex IV activities [13,40,59,62]. Deficiencies in either Complex V (ATP synthase), Complex IV (cytochrome c oxidase), or in pyruvate dehydrogenase activities have been described in Leigh syndrome [12,34,46,67].…”

Mitochondrial Pathology in Parkinson's Disease

“…Primary mutations of mtDNA only rarely manifest with parkinsonism. 9,10 Inherited mtDNA-mediated defects of complex I usually manifest with encephalomyopathic features rather than parkinsonism. 11,12 Other inherited primary specific respiratory chain defects (eg, affecting complex IV) produce a broader phenotype.…”