Phenotypic heterogeneity in the presentation of d-2-hydroxyglutaric aciduria in monozygotic twins

d-2-Hydroxyglutaric aciduria (d-2-HGA) is a very rare autosomal recessive metabolic disorder that has recently been associated with mutations in the d-2-hydroxyglutarate dehydrogenase gene. The biochemical phenotype of d-2-HGA is defined by the accumulation of abnormal amounts of d-2-hydroxyglutarate in cerebrospinal fluid, blood, and urine while the clinical phenotype can vary from a severe epileptic encephalopathy to normal. The basis for this phenotypic variation is not well-defined. We report a set of 412-year-old monozygotic (MZ) female twins with d-2-hydroxyglutaric aciduria who are shown to be compound heterozygotes for c.326-327dupTC, p.Glu110ArgfsX19, and c.1123G→T, p.Asp375Tyr mutations in the d-2-hydroxyglutarate dehydrogenase gene, but who have remarkably different clinical phenotypes. One twin presented with multiple congenital anomalies, severe developmental delay, and abnormal neuroradiological findings, while the other had normal neurocognitive and neuroradiological phenotypes, without concomitant congenital abnormalities. Monozygosity of these twins implies that the differences in the clinical phenotype arise from postzygotic genetic changes, epigenetic differences, or environmental factors that influence the phenotypic response to biochemical perturbation rather than allelic or locus heterogeneity. Though the mechanistic role of these factors in d-2-HGA is far from apparent, the discordance in the phenotypes of these siblings establishes that these factors are at least as important as the nature of the mutant alleles in influencing the progression of the disorder.