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Screening in clinical trials
(2002)
2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene
(2003)
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.
Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle defect. The clinical presentation in female manifesting carriers varies both in onset and severity. We report on a female with insulin dependent diabetes mellitus and recurrent episodes of hyperammonemia. Since OTC activity measured in a liver biopsy sample was within normal limits, OTC deficiency was initially excluded from the differential diagnoses of hyperammonemia. Due to moderately elevated homocitrulline excretion, hyperornithinemia-hyperammonemia-homocitrullinuria-syndrome was suggested, but further assays in fibroblasts showed normal ornithine utilization. Later, when mutation analysis of the OTC gene became available, a known pathogenic missense mutation (c.533C>T) in exon 5 leading to an exchange of threonine-178 by methionine (p.Thr178Met) was detected. Skewed X-inactivation was demonstrated in leukocyte DNA. In the further clinical course the girl developed marked obesity. By initiating physical activities twice a week, therapeutic control of both diabetes and OTC deficiency improved, but obesity persisted. In conclusion, our case confirms that normal hepatic OTC enzyme activity measured in a single liver biopsy sample does not exclude a clinical relevant mosaic of OTC deficiency because of skewed X-inactivation. Mutation analysis of the OTC gene in whole blood may be a simple way to establish the diagnosis of OTC deficiency. The joint occurrence of OTC deficiency and diabetes in a patient has not been reported before.
