Mitochondrial encephalomyopathies: what next?

DiMauro, Salvatore

doi:10.1007/bf01799110

Cited by 49 publications

(42 citation statements)

References 64 publications

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“…We are following up unaffected mutated relatives. If the cardiomyopathy phenotype indeed is related to the amount of mutated mtDNA in the affected organ as in encephalomyopathies, 13 clinical follow-up of mutated but healthy relatives should allow early detection of disease. A recent study done in 58 unrelated patients with DCM showed that mtDNA point mutations are significantly more frequent in patients than in controls.…”

Section: Discussionmentioning

confidence: 99%

“…Activity of complex II is not affected as it is entirely encoded by nuclear DNA, whereas cytochrome C oxidase (Cox) activity (or complex IV), which is partially encoded by mtDNA genes and constitutes the electron transport chain along with complex I, 12 is frequently reduced in patients with mtDNA tRNA mutations. Pathological tRNA mutations are characteristically heteroplasmic and absent from controls and affect highly conserved regions; 12,13 tRNA mutations have been reported in patients with hypertrophic cardiomyopathy, particularly in those who develop late congestive heart failure 14 or with not otherwise defined cardiomyopathies and congestive heart failure. 5,6,9 Rarely, missense mutations in polypeptide-coding genes have been linked to multisystem syndromes.…”

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confidence: 99%

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Mitochondrial DNA Mutations and Mitochondrial Abnormalities in Dilated Cardiomyopathy

Arbustini

Diegoli

Fasani

et al. 1998

The American Journal of Pathology

219

140

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Mitochondrial (mt)DNA defects , both deletions and tRNA point mutations , have been associated with cardiomyopathies. The aim of the study was to determine the prevalence of pathological mtDNA mutations and to assess associated defects of mitochondrial enzyme activity in dilated cardiomyopathy (DCM) patients with ultrastructural abnormalities of cardiac mitochondria. In a large cohort of 601 DCM patients we performed conventional light and electron microscopy on endomyocardial biopsy samples. Cases with giant organelles , angulated , tubular , and concentric cristae , and crystalloid or osmiophilic inclusion bodies were selected for mtDNA analysis. Mutation screening techniques , automated DNA sequencing, restriction enzyme digestion , and densitometric assays were performed to identify mtDNA mutations, assess heteroplasmy , and quantify the amount of mutant in myocardial and blood DNA. Of 601 patients (16 to 63 years; mean , 43.5 ؎ 12.7 years) , 85 had ultrastructural evidence of giant organelles , with abnormal cristae and inclusion bodies; 19 of 85 (22.35%) had heteroplasmic mtDNA mutations (9 tRNA, 5 rRNA , and 4 missense , one in two patients) that were not found in 111 normal controls and in 32 DCM patients without the above ultrastructural mitochondrial abnormalities. In all cases , the amount of mutant was higher in heart than in blood. In hearts of patients that later underwent transplantation , cytochrome c oxidase (Cox) activity was significantly lower in cases with mutations than in those without or controls (P ‫؍‬ 0.0008). NADH dehydrogenase activity was only slightly reduced in cases with mutations (P ‫؍‬ 0.0388) , whereas succinic dehydrogenase activity did not significantly differ between DCM patients with mtDNA mutations and those without or controls. The present study represents the first attempt to detect a morphological, easily identifiable marker to guide mtDNA mutation screening. Pathological mtDNA mutations are associated with ultrastructurally abnormal mitochondria, and reduced Cox activity in a small subgroup of non-otherwise-defined, idiopathic DCMs, in which mtDNA defects may constitute the basis for, or contribute to, the development of congestive heart failure. (Am J Pathol 1998, 153:1501-1510)

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Mitochondrial DNA Mutations and Mitochondrial Abnormalities in Dilated Cardiomyopathy

Arbustini

Diegoli

Fasani

et al. 1998

The American Journal of Pathology

219

140

View full text Add to dashboard Cite

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“…We believe that much of the clinical and biochemical heterogeneity can be explained by the rules of mitochondrial genetics and attributed to various factors (DiMauro, 1996).…”

Section: Defects Of Mitochondrial Genesmentioning

confidence: 93%

Mitochondrial disorders

DiMauro

Tanji

1997

Jap J Human Genet

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SummaryIn this minireview, we attempt to survey the three main group of mitochondrial disorders, defects of nuclear DNA, defects of mitochondrial DNA, and defects of intergenomic signaling, with emphasis on recent contributions and pathogenetic mechanisms. In so doing, we have tried to point out some of the numerous unsolved problems in genotype/phenotype correlation and to indicate future directions of research. Key Words mitochondria, mitochondrial DNA, intergenomic signaling, respiratory chain, mitochondrial encephalomyopathiesThe fascinating and still unfolding story of mitochondrial disorders is not only a "tale of two genomes," but also a tale of their sometimes less than harmonious interaction. Thus, we have to review succinctly three types of human diseases: 1) Defects of nuclear genes, inherited as mendelian traits; 2) Defects of mitochondrial genes, which can be sporadic conditions or maternally-inherited disorders; and 3) Defects of intergenomic communication, in which the still unknown culprits are nuclear genes and inheritance is mendelian. Though in our review we will consider these three groups in sequence, a unified biomolecular classification of the mitochondrial disorders, including acquired conditions, is offered in Table I. Because of the concise nature of these minireviews, we will limit references to the most recent contributions. Other references are provided in recent comprehensive reviews, including three chapters in a row in the 2nd edition of The

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“…Since then, the field of mitochondrial disorders has become a focus not only within neurology but also of various other disciplines (Moraes, 1996;Ozawa, 1997). In few areas of medicine has progress been more spectacular (DiMauro, 1996). Primary defects in mitochondrial function are now implicated in over 100 diseases, and the list continues to grow (Luft, 1994).…”

Section: Introductionmentioning

confidence: 97%

Neurodegeneration and aging: Role of the second genome

et al. 1998

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The latest Health Report of the World Health Organization predicts a significant increase in the age of human populations over the next two decades. In the developed world, at least 20% of the population will be older than 65 years. This development together with the as yet unknown etiology of many neurodegenerative disorders has caused an increased interest in the biology and pathophysiology of mitochondria. Dysfunction of mitochondria has been linked to both normal aging and neurodegenerative disorders, with the latter occurring much more frequently at higher age. Specifically, genetic defects in mitochondria have been shown to accumulate during life, and certain mutations of mitochondrial genes have been implicated in the etiology of Parkinson's and Alzheimer's diseases. In addition, a large number of new mitochondrial diseases have been identified following the first description of mitochondrial mutations 10 years ago. While there can be little doubt that DNA defects of mitochondria play a role in aging, specific mutations of mitochondrial genes underlying Parkinson's or Alzheimer's diseases remain to be identified. There is evidence, however, that mutations of the mitochondrial genome may increase the susceptibility to neurodegeneration.

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Mitochondrial encephalomyopathies: what next?

Cited by 49 publications

References 64 publications

Mitochondrial DNA Mutations and Mitochondrial Abnormalities in Dilated Cardiomyopathy

Mitochondrial DNA Mutations and Mitochondrial Abnormalities in Dilated Cardiomyopathy

Mitochondrial disorders

Neurodegeneration and aging: Role of the second genome

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