3-Hydroxyisobutyric aciduria, also called HIBA, is an extremely rare inherited inborn error of metabolism (IEM) of valine metabolism. Only 12-13 patients have been identified with this condition. It is an autosomal recessive disorder that may be caused, in some cases, by a defective aldehyde dehydrogenase 6 family member A1 (ALDH6A1) gene which codes for methylmalonate semialdehyde dehydrogenase (MMSDH). MMSDH is a mitochondrial methylmalonate semialdehyde dehydrogenase that plays a role in the valine and pyrimidine catabolism. This protein catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA. Another possible cause of the disorder is a mutation in 3-hydroxyisobutyrate dehydrogenase, a mitochondrial enzyme which catalyzes the conversion of 3-hydroxyisobutyrate into methylmalonic semialdehyde, or in the conversion of the semialdehyde to propionyl-CoA. Individuals with this disorder have very high levels of 3-hydroxyisobutyric acid secreted in their urine. Other indications of organic acidemia are also present. Signs and symptoms of 3-hydroxyisobutyric aciduria include developmental delay, dysmorphic facial features, and brain abnormalities. The excretion of 3-hydroxyisobutyric acid in the urine can range from 170 to 390 mmol/mol of creatinine. Concentrations of free carnitine are also low, and esterified carnitine can be elevated in patients. Protein-restricted diets and carnitine supplementation have been tried with varying degrees of success.
References
3-Hydroxyisobutyric Aciduria References
Ko FJ, Nyhan WL, Wolff J, Barshop B, Sweetman L: 3-Hydroxyisobutyric aciduria: an inborn error of valine metabolism. Pediatr Res. 1991 Oct;30(4):322-6. doi: 10.1203/00006450-199110000-00006.
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Wanders RJ, Duran M, Loupatty FJ: Enzymology of the branched-chain amino acid oxidation disorders: the valine pathway. J Inherit Metab Dis. 2012 Jan;35(1):5-12. doi: 10.1007/s10545-010-9236-x. Epub 2010 Nov 23.
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