PubMed Health⌕ Search

Biomedical subjects

Willy Lehnert

Publications and source records attributed to Willy Lehnert.

6 recordsLinked to original sources
PubMed2005

Glutaconyl-CoA is the main toxic agent in glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I).

Despite early diagnosis and treatment, 35% of the patients with glutaric aciduria type I (GA I) develop severe neurologic damage. Glutaric acid and 3-hydroxyglutaric acid have been suspected to cause neurodegeneration. Lately, this has been questioned, however. We postulate that glutaconyl Coenzyme A (glutaconyl-CoA) is responsible for brain damage. Chemically, glutaconyl-CoA is an analogue of acrylyl-CoA, the parent substance of the extremely reactive class of acrylates. It is expected to react spontaneously with sulfhydryl groups, thus modifying membranes, disturbing enzyme functions and trapping glutathione. Enhanced production of glutaconyl-CoA together with lack of glutathione precipitates brain damage. Such a mechanism is supported by three findings. (1) The addition product of glutaconyl-CoA to cysteine is present in small amounts in normal human urine. (2) Reaction of methacrylyl-CoA with free sulfhydryl groups has been reported previously in a patient with 3-hydroxyisobutyryl CoA deacylase deficiency. (3) Glutathione has been found to be decreased in homozygous glutaryl-CoA dehydrogenase-deficient knock-out mice.

Acyl Coenzyme A↗
PubMed2003

2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene.

2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency is a novel inborn error of isoleucine degradation. In this article, we report the elucidation of the molecular basis of MHBD deficiency. To this end, we purified the enzyme from bovine liver. MALDI-TOF mass spectrometry analysis revealed that the purified protein was identical to bovine 3-hydroxyacyl-CoA dehydrogenase type II. The human homolog of this bovine enzyme is a short-chain 3-hydroxyacyl-CoA dehydrogenase, also known as the "endoplasmic reticulum-associated amyloid-beta binding protein" (ERAB). This led to the identification of the X-chromosomal gene involved, which previously had been denoted "HADH2." Sequence analysis of the HADH2 gene from patients with MHBD deficiency revealed the presence of two missense mutations (R130C and L122V). Heterologous expression of the mutant cDNAs in Escherichia coli showed that both mutations almost completely abolish enzyme activity. This confirms that MHBD deficiency is caused by mutations in the HADH2 gene.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2003

Complete deficiency of mitochondrial trifunctional protein due to a novel mutation within the beta-subunit of the mitochondrial trifunctional protein gene leads to failure of long-chain fatty acid beta-oxidation with fatal outcome.

UNLABELLED: The mitochondrial trifunctional protein (MTP) is a multienzyme complex which catalyses three of the four chain-shortening reactions in the beta-oxidation of long-chain fatty acids. Clinically, failure of long-chain fatty acid beta-oxidation leads to hypoketotic hypoglycaemia associated with coma, hepatopathy, skeletal myopathy and cardiomyopathy. We report on consanguineous parents with six children, four of whom had unexpectedly died in Egypt during the neonatal period due to cardiomyopathy of unknown aetiology and respiratory failure. After moving to Germany, two further children died at the age of 4 months and 12 h, respectively, with signs of respiratory and cardiac failure, hydrops fetalis and acidosis. Analysis of acylcarnitine profiles in dried blood spots of the last two children by electrospray tandem mass spectrometry was indicative of a long-chain fatty acid beta-oxidation disorder. Both infants were homozygous for a novel missense mutation (976G-->C) within a highly conserved region of the MTP beta-subunit gene. Immunoblot analysis in chorionic villi obtained during the subsequent pregnancy demonstrated absence of MTP. In fibroblasts and liver, activities of all three catalytic units of MTP were markedly decreased, further confirming the diagnosis of MTP deficiency. CONCLUSION: the detected mutation (976G-->C) within the beta-subunit of the mitochondrial trifunctional protein gene destabilises the protein, leading to complete deficiency and a poor prognosis. Immunoblot analysis of mitochondrial trifunctional protein in chorionic villi may be a valuable tool for the prenatal diagnosis of the disorder when the molecular genetic defect is unknown.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2002

3-Methylglutaconic aciduria type I is caused by mutations in AUH.

3-Methylglutaconic aciduria type I is an autosomal recessive disorder clinically characterized by various symptoms ranging from delayed speech development to severe neurological handicap. This disorder is caused by a deficiency of 3-methylglutaconyl-CoA hydratase, one of the key enzymes of leucine degradation. This results in elevated urinary levels of 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid. By heterologous expression in Escherichia coli, we show that 3-methylglutaconyl-CoA hydratase is encoded by the AUH gene, whose product had been reported elsewhere as an AU-specific RNA-binding protein. Mutation analysis of AUH in two patients revealed a nonsense mutation (R197X) and a splice-site mutation (IVS8-1G-->A), demonstrating that mutations in AUH cause 3-methylglutaconic aciduria type I.

Acyl Coenzyme A↗
PubMed2002

Clinical variability in 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency.

We report the identification of two new 7-year-old patients with 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency, a recently described inborn error of isoleucine metabolism. The defect is localized one step above 3-ketothiolase, resulting in a urinary metabolite pattern similar to that seen for deficiency of the latter. One patient has progressive neurodegenerative symptoms, whereas the clinical phenotype of the other patient is characterized by psychomotor retardation without loss of developmental milestones. A short-term biochemical response to an isoleucine-restricted diet was observed in both children.

3-Hydroxyacyl CoA Dehydrogenases↗