A case of D-2 hydroxyglutaric aciduria

In 2010, Kranendijk et al. defined D-2-hydroxyglutaric aciduria (D-2-HGA) type II in patients who accumulated D-2 hydroxyglutarate (D-2-HG) in body fluids, without any mutation in the already known D-2- HGDH (D-2-hydroxyglutarate dehydrogenase) gene. While D-2-HGA type I, an autosomal recessive disorder, is associated with mutations in the D-2-HGDH gene and leads to impaired enzyme activity, the type II disorder is correlated to “gain-of-function” mutations in the IDH2 (isocitrate dehydrogenase) gene. The IDH2 gene defect has not been detected in DNA of the parents, suggesting the de novo occurrence with an autosomal dominant pattern of inheritance. However, isolated cases of somatic mosaicism in the mother have been described. Here we report the case of a 11-year old girl who was evaluated at the age of 23 months for a psychomotor delay. She is the first child of healthy and non consanguineous parents and was born at term. An intrauterine growth failure associated with smoking marked the pregnancy. The child presented with severe language impairment and behavioural disturbance with a restless attitude. Later, cognitive skills and learning disabilities required educational support. Clinical examination showed dysmorphic features (thin upper lip and low-set ears) and strabismus. She suffered from chronic diarrhea during the first year of life. Neurological evaluation involving cerebral MRI at 2 years revealed developmental abnormalities involving hypoplasia of the cerebellar tentorium and a T2 hyperintense signal in the frontal withe matter. The electroencephalogram was normal and cardiac ultrasounds didn’t reveal any cardiac abnormalities. Karyotyping was unremarkable. Metabolic screening performed in duplicate showed elevated concentration of D-2-hydroxyglutarate (D-2 HG) in urine, plasma and CSF. Amino acid analysis was normal whereas the acylcarnitine profile showed a mild increase of C6DC. When the child was 9, DNA investigation of the isocitrate dehydrogenase 2 (IDH2) gene was performed and a de novo heterozygous c.419G>A mutation was detected. Indeed, the described mutation was not found in parent’s DNA, leading to the diagnosis of the autosomal dominant form of D-2 hydroxyglutaric aciduria (D-2-HGA) type II