Depletion of mitochondrial deoxyribonucleic acid in a family with fatal neonatal liver disease

Bakker, Henk D.; Scholte, H.R.; Dingemans, K. P.; Spelbrink, Johannes N.; Wijburg, Frits A.; Coby, Van den Bogert

doi:10.1016/s0022-3476(96)80135-1

Cited by 86 publications

(47 citation statements)

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“…3 Patients with the hepatic form of MDS present during the first 6 months of life with rapidly progressive liver failure and frequent neurological involvement. [3][4][5][6][7][8][9] Metabolic investigations reveal hypoglycemia and elevated lactate levels in body fluids. Abnormal liver histology including steatosis and fibrosis progressing to cirrhosis and increased number of pleomorphic mitochondria with abnormal cristae has been reported.…”

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“…Abnormal liver histology including steatosis and fibrosis progressing to cirrhosis and increased number of pleomorphic mitochondria with abnormal cristae has been reported. [3][4][5][6][7][8][9] Biochemical studies of liver biopsies disclose reduced cytochrome c oxidase (COX) histochemistry. The activity of complex I, III, IV, and V, which consists of both nuclear and mitochondrial encoded subunits, is decreased, whereas the activity of complex II (succinate: ubiquinone reductase), which does not contain any mtDNA encoded subunit, is normal.…”

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“…[3][4][5][6][7][8][9] The molecular defects underlying MDS are not yet known. The involvement of siblings of both sexes, the lack of affected parents, and the presence of consanguinity in a few previously reported couples, 6,7,10 provide evidence for autosomal recessive inheritance. [10][11][12] Although the differential tissue involvement in MDS could suggest mtDNA heteroplasmy, sequence analysis of mtDNA in previously reported patients did not reveal any abnormality that could account for the low copy number.…”

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confidence: 99%

“…[10][11][12] Although the differential tissue involvement in MDS could suggest mtDNA heteroplasmy, sequence analysis of mtDNA in previously reported patients did not reveal any abnormality that could account for the low copy number. 3,5,6 Introduction of patient-derived mitochondria into mtDNA-less cells, resulting in restoration of normal mtDNA levels provided further evidence that mtDNA depletion is caused by mutations in nuclear genes controlling mtDNA replication. 10,11 We present a detailed description of hepatic ultrastructural changes in 10 infants with hepatic MDS.…”

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The hepatic mitochondrial DNA depletion syndrome: Ultrastructural changes in liver biopsies

et al. 2001

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Mitochondrial respiratory chain disorders are an established cause of liver failure in early childhood. In some patients, the levels of mitochondrial DNA are markedly reduced, a condition referred to as mtDNA depletion syndrome (MDS). We report here on the ultrastructural changes in the livers of 10 infants with the hepatic form of this syndrome. All patients displayed progressive liver failure, neurological abnormalities, hypoglycemia, and lactic acidosis that warranted investigation of respiratory chain disorder in liver tissue, specifically expressing the disease. Decreased activity of respiratory chain complexes containing mtDNA-encoded subunits (complexes I, III, IV) was shown in 5 patients. Mitochondrial DNA depletion was confirmed by Southern blot analysis in the livers of 6 patients. We found hepatocytes filled with mitochondria having aspects of "oncocytic transformation," associated with numerous changes in shape, size, cristae, and matrix. The changes were virtually identical in all specimens. In many hepatocytes, microvesicular steatosis was the salient feature. Additional findings included cholestasis and focal cytoplasmic biliary necrosis (CBN), as well as cytosiderosis in hepatocytes and sinusoidal cells. In some hepatocytes the damage appeared extreme, but fibrosis was identified only in the few patients who died beyond 6 months of age. Although individual ultrastructural findings are not specific, when taken together, they show a diagnostic pattern highly suggestive of a respiratory chain disorder. In the appropriate clinical context, these findings can direct the clinician towards the diagnosis of hepatic MDS. (HEPATOLOGY 2001;34:776-784.)The mitochondrial respiratory chain is a highly organized system involved in the ATP-generating, oxidative phosphorylation (OXPHOS) process. It is composed of 5 enzymatic complexes, which include more than 100 proteins. Thirteen of the polypeptides are encoded by mitochondrial DNA (mtDNA) whereas the remaining subunits by the nuclear genome.

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The hepatic mitochondrial DNA depletion syndrome: Ultrastructural changes in liver biopsies

et al. 2001

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“…Clonal deletions or partial duplications of mtDNA typically manifest sporadically, whereas point mutations are usually maternally inherited. Two other kinds of mtDNA lesion appear to depend upon nuclear rather than mitochondrial genotype: mtDNA depletion [3][4][5] and multiple mtDNA deletions with autosomal dominant or recessive inheritance. [6][7][8][9] Autosomal dominant progressive external ophthalmoplegia (ad-PEO) associated with multiple deletions of mtDNA is genetically heterogeneous, with mapped loci on chromosomes 3p14.1-21.2 and 10q24, and other affected families unlinked to either of these.…”

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Analysis of the trinucleotide CAG repeat from the human mitochondrial DNA polymerase gene in healthy and diseased individuals

et al. 1999

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The human nuclear gene (POLG) for the catalytic subunit of mitochondrial DNA polymerase (DNA polymerase γ) contains a trinucleotide CAG microsatellite repeat within the coding sequence. We have investigated the frequency of different repeat-length alleles in populations of diseased and healthy individuals. The predominant allele of 10 CAG repeats was found at a very similar frequency (approximately 88%) in both Finnish and ethnically mixed population samples, with homozygosity close to the equilibrium prediction. Other alleles of between 5 and 13 repeat units were detected, but no larger, expanded alleles were found. A series of 51 British myotonic dystrophy patients showed no significant variation from controls, indicating an absence of generalised CAG repeat instability. Patients with a variety of molecular lesions in mtDNA, including sporadic, clonal deletions, maternally inherited point mutations, autosomally transmitted mtDNA depletion and autosomal dominant multiple deletions showed no differences in POLG trinucleotide repeat-length distribution from controls. These findings rule out POLG repeat expansion as a common pathogenic mechanism in disorders characterised by mitochondrial genome instability.

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Mitochondrial DNA polymerase ? deficiency and mtDNA depletion in a child with Alpers' syndrome

Naviaux¹,

Nyhan²,

Barshop³

et al. 1999

Ann Neurol.

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Deficiency of mitochondrial DNA polymerase γ activity was found in a patient with mtDNA depletion and Alpers' syndrome. Metabolic evaluation revealed fasting hypoglycemia, dicarboxylic aciduria, and reduced activity of the electron transport chain in skeletal muscle. The patient died in early childhood of fulminant hepatic failure, refractory epilepsy, lactic acidemia, and coma. mtDNA content was 30% of normal in skeletal muscle and 25% in the liver. The activity of mtDNA polymerase γ was undetectable. Ann Neurol 1999;45:54–58

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Depletion of mitochondrial deoxyribonucleic acid in a family with fatal neonatal liver disease

Cited by 86 publications

References 16 publications

The hepatic mitochondrial DNA depletion syndrome: Ultrastructural changes in liver biopsies

The hepatic mitochondrial DNA depletion syndrome: Ultrastructural changes in liver biopsies

Analysis of the trinucleotide CAG repeat from the human mitochondrial DNA polymerase gene in healthy and diseased individuals

Mitochondrial DNA polymerase ? deficiency and mtDNA depletion in a child with Alpers' syndrome

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