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Biomedical subjects

E A Kvittingen

Publications and source records attributed to E A Kvittingen.

At least 19 recordsLinked to original sources
PubMed2006

Depletion of mitochondrial DNA copies/cell in peripheral blood mononuclear cells in HIV-1-infected treatment-naïve patients.

OBJECTIVES: Mitochondrial toxicity is believed to be the main reason for adverse effects related to nucleoside reverse transcriptase inhibitors (NRTIs). The aim of the present study was to compare mitochondrial toxicity in NRTI-treated HIV-positive patients, HIV-positive treatment-naïve patients and HIV-negative controls by comparing mitochondrial DNA (mtDNA) copies/cell in peripheral blood mononuclear cells (PBMCs) and lactate/pyruvate (L/P) ratios in the different groups. METHODS: We enrolled 60 participants in the study: 31 patients on combined antiretroviral therapy (CART), 14 HIV-positive treatment-naive patients and 15 HIV-negative controls. mtDNA (copies/cell) in peripheral blood was analysed using quantitative real-time polymerase chain reaction (PCR). Standard curves and serial dilutions of plasmid-cloned mitochondrion and retinoblastoma (RB1) PCR products with known concentrations were generated to estimate the mtDNA and nuclear DNA (nDNA) copy numbers in each sample. The L/P ratio was enzymatically and spectrophotometrically analysed in samples from individuals in a fasted, non-exercise state. Results The median mtDNA copy number was 63 copies/cell (interquartile range 33-94) in HIV-positive patients and 153 (132-283) in HIV-negative controls (P<0.001). No significant difference was seen between the HIV-positive NRTI-exposed patients and the HIV-positive treatment-naive patients. Current use of didanosine was negatively correlated with depletion of mtDNA (r=-0.36, P=0.046). HIV-positive patients also had a higher L/P ratio compared with HIV-negative controls (P=0.004). CONCLUSIONS: The number of mtDNA copies/cell in PBMCs was depleted in HIV-positive treatment-naive patients as well as in HIV-positive NRTI-exposed patients. HIV-positive patients also had a higher L/P ratio compared with HIV-negative controls, which supports this conclusion. The study suggests that neither mtDNA in PBMCs nor L/P ratio is a good marker of NRTI-associated mitochondrial toxicity.

Adult↗
PubMed2005

Tyrosinaemia type I--de novo mutation in liver tissue suppressing an inborn splicing defect.

Many patients with tyrosinaemia type 1 have a mosaic pattern of fumarylacetoacetase (FAH) immunopositive or immunonegative nodules in liver tissue. This phenomenon has been explained by a spontaneous reversion of the mutation in one allele to a normal genotype, but only a few nodules have been examined. We now report on a Norwegian patient, compound heterozygous for the mutations IVS12g(+5)-->a and G(1009-->)A, with liver mosaicism, but with an immunopositive nodule in which both primary mutations were intact. In the immunopositive hepatocytes of this nodule, genetic analyses showed a new mutation, C(1061-->)A, 6 bp upstream of the primary mutation IVS12g(+5)-->a in the FAH gene. The splicing defect caused by the primary mutation is most likely suppressed by the new mutation due to improvement of the splicing site. In the same liver we demonstrate another nodule of regenerating immunopositive tissue due to reversion of one of the primary mutations to a normal genotype. Together with the original cells this makes a triple mosaicism of hepatocytes with one, two or three point mutations in the FAH gene.

Alleles↗
PubMed2003

Acute respiratory distress syndrome in long-chain 3-hydroxyacyl-CoA dehydrogenase and mitochondrial trifunctional protein deficiencies.

Inborn errors of metabolism have not previously been recognized as a risk factor for acute respiratory distress syndrome (ARDS). We report this complication in four patients with defects of the mitochondrial trifunctional protein (MTP). This enzyme catalyses three steps in the beta-oxidation of long-chain fatty acids. Three of the patients were homozygous for the 'common' 1528G>C mutation in the alpha-subunit of the MTP, giving rise to long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. The fourth patient did not carry this mutation but had severely decreased activities of long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketoacyl-CoA thiolase. One patient died and histology in this patient showed severe interstitial pulmonary fibrosis. The other three patients recovered after being ventilated for up to 6 months. The high frequency of ARDS in patients with MTP defects suggests that this inborn error may be a risk factor for ARDS.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2000

Evidence that Alpers-Huttenlocher syndrome could be a mitochondrial disease.

We report an 11-year-old boy with a slight developmental delay and epilepsy. After he was placed on valproate, he developed hepatic failure and increasing neurologic symptoms, including epilepsia partialis continua, and died. Autopsy findings in liver and cerebrum were consistent with progressive neuronal degeneration of childhood with liver disease, also called Alpers-Huttenlocher syndrome. Ragged red fibers and cytochrome c oxidase negative fibers were present in muscle. These results suggest that Alpers-Huttenlocher syndrome, at least in some patients, is a mitochondrial disease.

Cerebral Cortex↗
PubMed2000

Association between apolipoprotein E genotypes and cancer risk in patients with acquired immunodeficiency syndrome.

The apolipoprotein E (apoE) genotype was determined in 197 deceased acquired immunodeficiency syndrome (AIDS) patients treated at Ullevaal Hospital in Oslo, Norway. A full autopsy had been performed on all. Cancer had developed in 71 individuals, mainly lymphomas (46) and Kaposi's sarcomas (18). The apoE genotype distribution was consistent with Hardy-Weinberg equilibrium, and allele frequencies were in the typical Scandinavian range (6.9% apoE2; 75.6% apoE3; and 17.5% apoE4). Cancer cases had a significantly higher frequency of apoE4 alleles than noncancer cases (24.6% and 13.5%, respectively) and a lower frequency of apoE2 alleles (3.5% versus 8.7%). Background factors, such as survival from AIDS diagnosis, could not explain these differences. Our study thus indicates that apoE genotype affects the development of cancers among AIDS patients.

Acquired Immunodeficiency Syndrome↗
PubMed1998

[Botulism in newborn infants].

Infant botulism, first described in 1976, is the most common form of botulism. The majority of cases are reported from the USA. The disease is rare in Europe, and this article describes the first patient reported in Norway. A three-month-old boy of Norwegian origin who had been fed Argentinian honey developed symptoms of botulism. Electromyography showed presynaptic neuromuscular dysfunction. The diagnosis was confirmed by the demonstration of Clostridium botulinum type A neurotoxin in the faeces. After supportive treatment, breast-milk feeding and lactobacillus supplementation he made a complete recovery. If spores of C. botulinum are ingested, they can bind to the epithelium, germinate and produce toxin which causes botulism. Because of the composition of their intestinal flora, children below one year of age are at risk. Ingestion of honey is a well known risk factor. Contamination of Norwegian honey has never been reported but we recommend that honey should not be given to children during their first year of life.

Botulinum Toxins, Type A↗
PubMed1997

Methionine synthase deficiency without megaloblastic anaemia.

UNLABELLED: We report findings on a child presenting with neonatal homocystinuria, hypomethioninaemia and severe neurological symptoms, including developmental delay and seizures. Methylmalonic aciduria was not present. The activity of methionine synthase in fibroblasts was severely deficient and formation of methylcobalamin from 57Co labelled cyanocobalamin was very low. The patients cells complemented with those of a cblE patient but not with those of two cblG patients. No biochemical or clinical response to injections of hydroxycobalamin was found. Both off treatment and on betaine and methionine supplementation the patient, at age 8 years, has not developed megaloblastic anaemia. In addition, the patient is homozygous for the C677T polymorphism in the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene and the concomitant existence of this mutation with the methionine synthase defect may prevent folate < > and thus anaemia. CONCLUSION: We report the lack of megaloblastic anaemia in a patient with severe methionine synthase deficiency who is also homozygous for C677T in MTHFR, hypothesize that the MTHFR polymorphism protects the patient against anaemia and speculate that homozygosity for MTHFR C677T could cause the dissociation between haematological and neurological disease seen in some patients with vitamin B12 deficiency.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1997

HIV dementia and apolipoprotein E.

The effect of apolipoprotein E genotypes on the occurrence of HIV dementia and HIV encephalitis was studied in a sample of 132 AIDS patients in whom clinical data on dementia was available and full autopsy had been performed. There was no statistically significant correlation between risk of HIV dementia or HIV encephalitis in relation to apolipoprotein E genotypes, even after correction for length of survival with AIDS and antiretroviral treatment.

AIDS Dementia Complex↗
PubMed1996

Fumarylacetoacetase mutations in tyrosinaemia type I.

Sixty-two hereditary tyrosinaemia type I (HT1) patients of various ethnic origins were classified clinically into acute, chronic, or intermediate phenotypes and screened for the 14 published causal mutations in the fumarylacetoacetase (FAH) gene. Restriction analysis of PCR amplified genomic DNA identified 74% of the mutated alleles. IVS12 + 5G --> A, predominant in the French Canadian HT1 patients, was the most common mutation found in 32 alleles in patients from Europe, Pakistan, Turkey, and the United States. IVS6-1G --> T, encountered in 14 alleles, was common in Central and Western Europe. There was an apparent "Scandinavian" 1009G --> A combined splice and missense mutation (12 alleles), a "Pakistani" 192G --> T splice mutation (11 alleles), a "Turkish" D233V mutation (6 alleles), and a "Finnish" or northern European W262X mutation (7 alleles). The remaining mutations were rare. Some of the mutations seem to predispose for acute and other for more chronic forms of HT1, but in our material no clearcut genotype phenotype correlation could be established.

Alleles↗
PubMed1996

Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship.

The complete fumarylacetoacetate hydrolase (FAH) genotype of probands of thirteen unrelated families with hereditary tyrosinemia type 1 (HT 1) was established. The screening was performed by analysis of exons 2-14 of the FAH gene by using the polymerase chain reaction (PCR) and of the mRNA by reverse transcription/PCR. Nine different mutations were identified, of which six are novel. Three mutations involve consensus sequences for correct splicing, viz. IVS 6-1 (g-t), IVS 7-1 (g-a) and IVS 12 + 5 (g-a). Two missense mutations (C193R and G369V) and three nonsense mutations (R237X, E357X and E364X) were found. One silent mutation N232N was associated with the skipping of exon 8 from the FAH mRNA. Analysis of the effect of the respective mutations on the FAH mRNA showed a strong reduction of FAH mRNA levels in association with the nonsense mutations, and normal levels with the missense mutations. The splice consensus mutations give deletions of complete or small parts of exon sequences from the FAH mRNA. Data suggest a founder effect for several of the mutations, with a frequency for both the IVS 6-1 (g-t) and IVS 12 + 5 (g-a) mutations of approximately 30% in the HT 1 probands. No strict correlation between genotype and phenotype, i.e. the acute, subacute or chronic form of HT 1, was evident.

Alleles↗
PubMed1995

Heterozygosity for an exon 12 splicing mutation and a W234G missense mutation in an American child with chronic tyrosinemia type 1.

Hereditary tyrosinemia type 1, an autosomal recessive disorder caused by deficiency of fumarylace-toacetate hydrolase (FAH), manifests in either an acute or a chronic form. We used reverse transcription and the polymerase chain reaction to amplify the FAH cDNA of a 12-year-old American boy with chronic tyrosinemia type 1. The patient is a compound heterozygote for mutations in the FAH gene. One allele contains a missense mutation in codon 234 changing a tryptophan to a glycine; this allele was of maternal origin. Mutagenesis and transfection into COS cells demonstrated that the W234G mutation abolishes FAH activity. The patient's paternally derived allele is a splicing mutation in the +5 position of intron 12, causing either insertion of a 105 bp fragment due to a cryptic splice site, or skipping of exon 12, or skipping of both exons 12 and 13. The chronic phenotype of tyrosinemia type 1 in this patient may be due to some residual, correct splicing by the allele with the splicing mutation.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

Tyrosinaemia--treatment and outcome.

Tyrosinaemia type I is, untreated, a fatal disease: in the acute form from liver failure, in the chronic form often from hepatocellular carcinoma. Acute neurological crisis is also a cause of death. Traditionally the treatment has been with diet, but for a decade liver transplantation has been the ultimate treatment. The continuous production of the pathological metabolites in the kidneys after transplantation appears to be without significance. Introduction of the enzyme inhibitor NTBC in the treatment of tyrosinaemia has reduced the need for liver transplants. Neonatal screening may be justified as efficient treatment has become available. The complex phenotype of lethal albino mice, with severe alterations in gene expression, has been shown to be caused by fumarylacetoacetase deficiency. Prolonged hypoglycaemia in otherwise adequately treated tyrosinaemia patients may result from depressed expression of genes coding for enzymes in gluconeogenesis, as seen in the mouse model. Self-induced genetic correction in liver tissue that occurs in many tyrosinaemia patients may reduce the risk of liver failure in some patients.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Two missense mutations causing tyrosinemia type 1 with presence and absence of immunoreactive fumarylacetoacetase.

Hereditary tyrosinemia type 1, due to a deficiency of fumarylacetoacetase (FAH), is characterized by progressive liver damage and renal tubular dysfunction and may occur in an acute or a chronic form. An Ala 134 to Asp (GCT to GAT) transition was found in one Turkish and two Norwegian patients with chronic tyrosinemia. SphI digestion of polymerase chain reaction (PCR) amplified genomic DNA identified the mutation and showed that the patients were heterozygous. All these patients had immunoreactive FAH protein in fibroblasts. Another Norwegian patient with chronic disease, without FAH immunoreactive material in fibroblasts, had a Pro 342 to Leu mutation (CCG to CTG). This mutation was identified by MspI digestion of PCR amplified genomic DNA, and the patient was heterozygous. Northern blotting showed FAH mRNA of normal size and amounts in all patients. Site directed mutagenesis and translation in a rabbit reticulocyte lysate demonstrated that both mutations abolished FAH activity.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Tyrosinemia type 1--complex splicing defects and a missense mutation in the fumarylacetoacetase gene.

Two mutations are reported in six tyrosinemia type 1 patients from northern Europe. In four patients, a G to A transition at nucleotide position 1009 (G1009-->A) of the fumarylacetoacetase (FAH) coding sequence caused aberrant splicing by introducing an acceptor splice site within exon 12, thereby deleting the first 50 nucleotides of this exon. The following exon-intron boundary was frequently missed, and a cryptic donor splice site within intron 12 caused a partial intron 12 retention of 105 bp. This point mutation alternatively gave a glycine 337 to serine substitution in instances of correct splicing. The mutation is rapidly detected by PvuII digestion of polymerase chain reaction (PCR)-amplified genomic DNA. Another mutation, g+5-->a in the intron 12 donor splice site consensus sequence (IVS12 g+5-->a), was found in five of the patients. This caused alternative splicing with retention of the first 105 nucleotides of intron 12, exon 12 skipping, and a combined deletion of exons 12 and 13. Rapid detection of this mutation is achieved by restriction digestion of PCR-amplified genomic DNA; a mismatch primer combined with the point mutation creates a Tru9I restriction site. One patient who was homozygous for the G1009-->A mutation had a chronic form of tyrosinemia. Three patients were combined heterozygotes for G1009-->A and IVS12 g+5-->a. Their clinical phenotypes varied from acute to chronic, indicating the impact of background genes and/or external factors on the presentation of tyrosinemia type 1.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Self-induced correction of the genetic defect in tyrosinemia type I.

A mosaic pattern of immunoreactive fumarylacetoacetase (FAH) protein was found in liver tissue in 15 of 18 tyrosinemia type I patients of various ethnic origins. One additional patient had variable levels of FAH enzyme activity in liver tissue. In four patients exhibiting mosaicism of FAH protein, analysis for the tyrosinemia-causing mutations was performed in immunonegative and immunopositive areas of liver tissue by restriction digestion analysis and direct DNA sequencing. In all four patients the immunonegative liver tissue contained the FAH mutations demonstrated in fibroblasts of the patients. In the immunopositive nodules of regenerating liver tissue one of the mutated alleles apparently had reverted to the normal genotype. This genetic correction was observed for three different tyrosinemia-causing mutations. In each case a mutant AT nucleotide pair was reverted to a normal GC pair.

Amino Acid Metabolism, Inborn Errors↗