Mitochondrial disorders

DiMauro, Salvatore; Tanji, Kurenai

doi:10.1007/bf02767024

Cited by 6 publications

(6 citation statements)

References 41 publications

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“…Although case 7, which showed mtDNA depletion by Southern blot analysis as well as by immunohistochemistry, could be considered a long surviving case of primary mtDNA depletion syndrome, this is highly unlikely. MtDNA depletion syndrome is a devastating autosomal recessive disorder seen in childhood (17–19). To our knowledge, only one adult patient with this disorder has been reported: a now 32‐year‐old woman with ptosis, ophthalmoplegia and myopathy, but without liver involvement (20).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA dysfunction in oncocytic hepatocytes

Tanji

Bhagat²,

et al. 2003

Liver International

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Hepatic oncocytes with abundant granular, eosinophilic cytoplasm due to mitochondrial hyperplasia are seen in various chronic liver diseases, particularly chronic hepatitis and cirrhosis. Increased mitochondria in oncocytes are thought to be a compensatory mechanism for deficiencies in the hepatocellular respiratory chain, although the pathogenesis of these deficiencies has been uncertain. We selected seven cases of cirrhosis (six with oncocytes, one without) for the following analysis: histoenzymatic and immunohistochemical staining of several mitochondrial DNA (mtDNA)- and nuclear DNA (nDNA)-encoded respiratory chain enzymes; immunostaining using antibodies against double-strand-DNA (anti-DNA) and against Ki-67 (a cell proliferation marker); and Southern blot analysis for mtDNA and nDNA. Eighty percent of oncocytes showed histoenzymatic and immunohistochemical deficiencies of cytochrome c oxidase and the mtDNA-encoded subunit I of complex IV, with preserved expression of nDNA-encoded succinate dehydrogenase and the iron-sulfur subunit of complex III (FeS). Cytoplasmic (but not nuclear) anti-DNA staining was partially or completely absent in approximately 50% of oncocytes. Three cases with oncocytes studied by Southern blot showed mtDNA reductions of 66%, 71%, and 85%. In conclusion, hepatic oncocytes demonstrate significant deficiencies of mtDNA and mtDNA-encoded respiratory chain enzymes. We propose that mtDNA depletion plays an important role in hepatocellular oncocytic transformation.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA dysfunction in oncocytic hepatocytes

Tanji

Bhagat²,

et al. 2003

Liver International

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“…These disruptions may be transient, as in hypoglycemia and ischemia, or constant, as caused by mutations that disrupt mitochondrial function (DiMauro et al 2002;Nordli and De Vivo 2002;Vigevano and Bartuli 2002). Mutations affecting the two enzymes upstream of citrate synthase in the Krebs cycle, pyruvate carboxylase and pyruvate dehydrogenase, as well as less common mutations perturbing various steps in the TCA cycle, have been linked with human seizure disorders (De Vivo 1993;De Meirleir 2002).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Disruption in Drosophila Bang-Sensitive Seizure Mutants

2006

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We examined a number of Drosophila mutants with increased susceptibility to seizures following mechanical or electrical stimulation to better understand the underlying factors that predispose neurons to aberrant activity. Several mutations in this class have been molecularly identified and suggest metabolic disruption as a possible source for increased seizure susceptibility. We mapped the bang-sensitive seizure mutation knockdown (kdn) to cytological position 5F3 and identified citrate synthase as the affected gene. These results further support a role for mitochondrial metabolism in controlling neuronal activity and seizure susceptibility. Biochemical analysis in bang-sensitive mutants revealed reductions in ATP levels consistent with disruption of mitochondrial energy production in these mutants. Electrophysiological analysis of mutants affecting mitochondrial proteins revealed an increased likelihood for a specific pattern of seizure activity. Our data implicate cellular metabolism in regulating seizure susceptibility and suggest that differential sensitivity of neuronal subtypes to metabolic changes underlies distinct types of seizure activity.

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“…However, given that mitochondrial disorders can be linked to mitochondrial (mt) or nuclear DNA defects, a mendelian pattern of inheritance does not exclude a mitochondrial disorder [13]. Furthermore, it is not unusual that the disease clinically appears as sporadic, especially in small families.…”

Section: Mitochondrial Diseases Are Suspected In Male or Female Patiementioning

confidence: 99%

“…A series of consolidated notions helps in assessing the potential pathologic role of any known or novel mutation: heteroplasmia, absence from controls, conservation of the wilde type nucleotide along evolution, all contribute to the likelihood that the mutation plays a role in the disease [3,13,27]. Once the defect has been identified, the only clinical implication is for genetic counseling; treatment strategies for mitochondrial cardiomyopathies are not substantially modified.…”

Section: Mitochondrial Diseases Are Suspected In Male or Female Patiementioning

confidence: 99%

Genetics of Idiopathic Dilated Cardiomyopathy

Arbustini

Morbini

Pilotto

et al. 2000

Herz

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Familial dilated cardiomyopathy (DCM) should be an "evidence-based" diagnosis derived from clinical and echocardiographic screening of informed and consenting relatives of index patients, and on the examination of clinical reports for deceased relatives. Most familial dilated cardiomyopathy pedigrees show an autosomal pattern of inheritance. Very few of them are X-linked and matrilinear. Autosomal recessive inheritance is difficult to be assessed in an evidence-based setting. By linkage analysis, several loci, but no disease gene, have been identified. At present, few cases of familial dilated cardiomyopathy can benefit of a molecular diagnosis. The diagnosis of dystrophin defect-related dilated cardiomyopathy is important for patients and families, especially for carrier detection. These patients present X-linked inheritance, dominant cardiac involvement and raised levels of serum creatine phosphokinase. Defects of the glycoprotein complex associated to dystrophin (DAG) are rare skeletal muscle diseases with possible cardiac involvement. Mitochondrial diseases, both pure cardiomyopathies and multiorgan syndromes involving the heart, are associated to defects of mitochondrial DNA genes or of nuclear genes coding for mitochondrial proteins. Barth's syndrome develops in male children with granulocytopenia, dilated cardiomyopathy, and methylglutaconic aciduria. Cardiomyopathies with atrioventricular block are observed in hemochromatosis, Emery-Dreifuss syndrome, desmin storage disease, and in isolated familial dilated cardiomyopathy. Actin defects were recently identified in 2 unrelated patients with familial dilated cardiomyopathy. Desmin defects were also recently identified in 1 familial dilated cardiomyopathy. The overall knowledge, although in progression, is still limited. Clinical family screening identifies familial forms, preclinical cases, and inheritance pattern. By candidate gene screening, the molecular diagnosis can be provided for dystrophin, DAG, mitochondrial DNA, actin and desmin gene defects.

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Mitochondrial disorders

Cited by 6 publications

References 41 publications

Mitochondrial DNA dysfunction in oncocytic hepatocytes

Mitochondrial DNA dysfunction in oncocytic hepatocytes

Metabolic Disruption in Drosophila Bang-Sensitive Seizure Mutants

Genetics of Idiopathic Dilated Cardiomyopathy

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