Mutations in phenotypically mild-D-2-hydroxyglutaric aciduria

VU University Amsterdam, Amsterdamo, North Holland, Netherlands
Annals of Neurology (Impact Factor: 9.98). 10/2005; 58(4):626-30. DOI: 10.1002/ana.20559
Source: PubMed


D-2-hydroxyglutaric aciduria is a neurometabolic disorder with mild and severe phenotypes. Recently, we reported pathogenic mutations in the D-2-hydroxyglutarate dehydrogenase gene as the cause of the severe phenotype of D-2-hydroxyglutaric aciduria in two patients. Here, we report two novel pathogenic mutations in this gene in one patient with a mild presentation and two asymptomatic siblings with D-2-hydroxyglutaric aciduria from two unrelated consanguineous Palestinian families: a splice error (IVS4-2A-->G) and a missense mutation (c.1315A-->G;p.Asn439Asp). Overexpression of this mutant protein showed marked reduction of the enzyme activity.

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    • "D-2-HGA Remarks References Type I (n026) 1 patient affected with comorbid Sanfilippo syndrome type C Gibson et al 1993b; Craigen et al 1994; Van der Knaap et al 1999b; Misra et al 2005; Struys et al 2005a; b; Haliloglu et al 2009; Kranendijk et al 2010a; Pervaiz et al 2011 "
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    ABSTRACT: The organic acidurias D: -2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA) cause neurological impairment at young age. Accumulation of D-2-hydroxyglutarate (D-2-HG) and/or L-2-hydroxyglutarate (L-2-HG) in body fluids are the biochemical hallmarks of these disorders. The current review describes the knowledge gathered on 2-hydroxyglutaric acidurias (2-HGA), since the description of the first patients in 1980. We report on the clinical, genetic, enzymatic and metabolic characterization of D-2-HGA type I, D-2-HGA type II, L-2-HGA and D,L-2-HGA, whereas for D-2-HGA type I and type II novel clinical information is presented which was derived from questionnaires.
    Journal of Inherited Metabolic Disease 03/2012; 35(4):571-87. DOI:10.1007/s10545-012-9462-5 · 3.37 Impact Factor
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    • "Bayesian posterior probabilities expressed as percentage are indicated above the clades. D. pulex genes that appear to be untranslated are represented in bold b J Mol Evol (2009) 69:276–287 285 (Struys et al. 2005), and brain oxidative stress damage (Kuehnle et al. 2008), respectively. "
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    ABSTRACT: D-2-Hydroxyglutaric aciduria (D-2-HGA) is a neurometabolic inherited disorder first described in 1980. In the following years, it became clear that the clinical phenotype of the disease varies widely from severe neonatal to asymptomatic. However, the sparse biochemical knowledge made D-2-HGA a poorly understood disease. Much progress has been made in the last five years in various studies, revealing two human enzymes that play a role in the metabolism of D-2-hydroxyglutarate (D-2-HG): hydroxyacid-oxoacid transhydrogenase (HOT) and D-2-HG dehydrogenase. HOT is expected to be responsible for the formation of D-2-HG, while D-2-HG dehydrogenase converts D-2-HG into 2-ketoglutarate. We demonstrated pathogenic mutations in the D2HGD gene in patients with D-2-HGA, helping to unravel the primary defect causing D-2-HGA. However, in approximately 50% of the patients with D-2-HGA examined, no pathogenic mutations have yet been found.
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