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Clinical variability of isovaleric acidemia in a genetically homogeneous population
Author(s) -
Dercksen M.,
Duran M.,
IJlst L.,
Mienie L. J.,
Reinecke C. J.,
Ruiter J. P. N.,
Waterham H. R.,
Wanders R. J. A.
Publication year - 2012
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-012-9457-2
Subject(s) - medicine , asymptomatic , genetic heterogeneity , population , genotype , glycine , amino acid , propionic acidemia , phenotype , genetics , endocrinology , gastroenterology , biology , gene , environmental health
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.