Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders (original) (raw)

Prevalence of nuclear and mtDNA mutations related to adult mitochondrial disease

Annals of neurology, 2015

Objective: The prevalence of mitochondrial disease has proven difficult to establish, predominantly as a result of clinical and genetic heterogeneity. The phenotypic spectrum of mitochondrial disease has expanded significantly since the original reports that associated classic clinical syndromes with mitochondrial (mt) DNA rearrangements and point mutations. The revolution in genetic technologies has allowed interrogation of the nuclear genome in a manner that has dramatically improved the diagnosis of mitochondrial disorders. We comprehensively assessed the prevalence of all forms of adult mitochondrial disease to include pathogenic mutations in both nuclear and mtDNA. Methods: Adults with suspected mitochondrial disease in the North East of England were referred to a single neurology center from 1990 to 2014. For the mid-year period of 2011, we evaluated the minimum prevalence of symptomatic nuclear DNA mutations and symptomatic and asymptomatic mtDNA mutations causing mitochondri...

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

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1995

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 RNA Leu(UtJ~) 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 MELAS 3243 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.

Mitochondrial diseases caused by mtDNA mutations: a mini-review

Therapeutics and Clinical Risk Management

There are several types of mitochondrial cytopathies, which cause a set of disorders, arise as a result of mitochondria's failure. Mitochondria's functional disruption leads to development of physical, growing and cognitive disabilities and includes multiple organ pathologies, essentially disturbing the nervous and muscular systems. The origins of mitochondrial cytopathies are mutations in genes of nuclear DNA encoding mitochondrial proteins or in mitochondrial DNA. Nowadays, numerous mtDNA mutations significant to the appearance and progress of pathologies in humans are detected. In this mini-review, we accent on the mitochondrial cytopathies related to mutations of mtDNA. As well known, there are definite set of symptoms of mitochondrial cytopathies distinguishing or similar for different syndromes. The present article contains data about mutations linked with cytopathies that facilitate diagnosis of different syndromes by using genetic analysis methods. In addition, for every individual, more effective therapeutic approach could be developed after wide-range mutant background analysis of mitochondrial genome.

Mitochondrial disease in childhood: mtDNA encoded

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2013

Since the first description of a mitochondrial DNA (mtDNA)-associated disease in the late 1980s, there have been more than 275 mutations within the mtDNA genome described causing human disease. The phenotypic expression of these disorders is vast, as disturbances of the unique physiology of mitochondria can create a wide range of clinical heterogeneity. Features of heteroplasmy, threshold effect, genetic bottleneck, mtDNA depletion, mitotic segregation, and maternal inheritance have been identified and described as a result of novel biochemical and genetic controls of mitochondrial function. We hope that as we unfold this fascinating part of clinical medicine, the reader will see how alterations in the tapestry of mitochondrial biochemistry and genetics can give rise to human illness.

Mitochondrial DNA mutations in human disease

Biochimica Et Biophysica Acta-bioenergetics, 2001

The small, maternally inherited mitochondrial DNA (mtDNA) has turned out to be a Pandora's box of pathogenic mutations: 13 years into the era of “molecular mitochondrial medicine,” more than 100 pathogenic point mutations and innumerable rearrangements have been associated with a striking variety of multisystemic as well as tissue-specific human diseases. After reviewing the principles of mitochondrial genetics, we consider disorders due to mutations in genes affecting mitochondrial protein synthesis and disorders due to mutations in protein-coding genes. In contrast to the remarkable progress in our understanding of etiology, pathogenesis is only partially explained by the rules of mitochondrial genetics and remains largely unclear. We review recent progress in prenatal diagnosis, epidemiology, and in the development of animal models harboring mtDNA mutations. © 2001 Wiley-Liss, Inc.

Identification of a new mtDNA mutation (14724G>A) associated with mitochondrial leukoencephalopathy

Biochemical and Biophysical Research Communications, 2007

We report a novel 14724G>A mutation in the mitochondrial tRNA glutamic acid gene in a 4-year-old boy with myopathy and leukoencephalopathy. A muscle biopsy showed cytochrome c oxidase-negative ragged-red fibers and biochemical analysis of the respiratory chain enzymes in muscle homogenate revealed partial complex I and complex IV deficiencies. The mutation, which affects the dihydrouridine arm at a conserved site, was nearly homoplasmic in muscle and heteroplasmic in blood DNA of the proband, but it was absent in peripheral leukocytes from the asymptomatic mother, sister, and two maternal aunts, suggesting that it arose de novo. This report proposes to look for variants in the mitochondrial genome when dealing with otherwise undetermined leukodystrophies of childhood.

Neurologic Disorders Due to Mitochondrial DNA Mutations

Seminars in Pediatric Neurology, 2012

The mitochondrial DNA (mtDNA) is a compact genome inherited through the maternal lineage. Mutations in mtDNA lead to many of the earliest identified syndromic mitochondrial diseases and display a diverse range of age of onset, symptoms, and outcomes-from isolated childhood onset vision or hearing loss to a multisystemic neurodegenerative disorder with strokes, neuropathy, ophthalmoparesis, and epilepsy beginning at any age. As a heterogeneous group, mitochondrial diseases represent one of the most common metabolic disorders in children and adults, frequently seen by both pediatric and adult specialists. Although the myriad of diseases can make diagnosis seems daunting, the need for extensive supportive care and treatment (the latter for at least a select few mitochondrial disorders) and a rapid and accurate recognition of these disorders is necessary. Here, we provide a review of the most common mitochondrial disease syndromes due to mtDNA mutations.