Abstract
Isovaleric acidemia (IVA) is one of the most common organic acidemias found in South Africa. Since 1983, a significant number of IVA cases have been identified in approximately 20,000 Caucasian patients screened for metabolic defects. IVA is caused by an autosomal recessive deficiency of isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of isovaleryl-CoA and its metabolites. In total, 10 IVA patients and three carriers were available for phenotypic and genotypic investigation in this study. All patients were found to be homozygous for a single c.367 G > A (p.G123R) mutation. The amino acid substitution of a glycine to arginine resulted in a markedly reduced steady-state level of the IVD protein, which explains the nearly complete lack of IVD enzyme activity as assessed in fibroblast homogenates. Despite the genetic homogeneity of this South African IVA group, the clinical presentation varied widely, ranging from severe mental handicap and multiple episodes of metabolic derangement to an asymptomatic state. The variation may be due to poor dietary intervention, delayed diagnosis or even epigenetic and polygenetic factors of unknown origin.
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Acknowledgements
We are very grateful to the patients and their families for participation in this study. The study was financially supported as a Carolina MacGillavry PhD Fellowship awarded by “Koninklijke Nederlandse Akademie van Wetenschappen”. We thank the staff of the enzyme and DNA sections of the Laboratory Genetic Metabolic diseases at the Academic Medical Centre, University of Amsterdam, for their expert advice and assistance. The study was also made possible with the logistic and scientific contribution of the staff of the Laboratory for Inherited Metabolic Defects in Potchefstroom. We thank Regina Ensenauer (University of Munich) and PJ. Pretorius (University of the North West) for their valuable discussions.
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Communicated by: Matthias Baumgartner
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Dercksen, M., Duran, M., IJlst, L. et al. Clinical variability of isovaleric acidemia in a genetically homogeneous population. J Inherit Metab Dis 35, 1021–1029 (2012). https://doi.org/10.1007/s10545-012-9457-2
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DOI: https://doi.org/10.1007/s10545-012-9457-2