L-2-hydroxyglutarate Dehydrogenase Research Articles

L-2-hydroxyglutarate dehydrogenase (L2HGDH)

l-2-hydroxyglutarate dehydrogenase (L2HGDH)

Adult manifestation of l -2-hydroxyglutarate dehydrogenase deficiency by a novel mutation

l-2-Hydroxyglutaric aciduria (L2HGA) is a rare, autosomal recessive disease caused by a deficiency of l-2-hydroxyglutarate dehydrogenase (L2HGDH). This membrane-bound mitochondrial enzyme is prominently expressed in the brain1 and catalyzes the conversion of l-2-hydroxyglutaricacid (L2HG) to 2-ketoglutarate. The exact function is unknown, but the lack of L2HGDH is toxic by inducing oxidative stress and inhibiting mitochondrial creatine kinase in the cerebellum.2 Commonly, symptoms appear during infancy as slowly progressing deficits including psychomotor retardation, cerebellar ataxia, and epilepsy3; however, an acute worsening in adulthood has been described.4 A diagnosis can be achieved through the detection of elevated L2HG in the urine3,5 and although no treatment guidelines exist, positive effects were reported following treatment with flavin adenine dinucleotide in combination with levocarnitine or riboflavin.6,7 We report the case of a young woman with L2HGA, presenting with a fast progressive cerebellar syndrome that could be halted by a low lysine diet. ### Case report. A 24-year-old patient presented with a progressive movement disorder and a disabling tremor of the right hand that began 1.5 years ago. Her mother reported delayed motor and mental development …

L-2-hydroxyglutaric aciduria diagnosed in a young adult with progressive cerebellar ataxia and facial dyskinesia

IntroductionL-2-hydroxyglutaric aciduria is a rare metabolic disorder with quite typical radiological abnormalities and various clinical symptoms. ObservationA 19-year-old girl presented with ataxia, facial dyskinesia, and mild cognitive impairment. Cerebral magnetic resonance imaging demonstrated subcortical white matter T2 abnormalities and a suggestive rim hyperintensity around the caudate nuclei and the putamen. Diagnosis was confirmed by increased 2-hydroxyglutaric acid in urine and a genetic study (Gly260Ala mutation in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene). DiscussionThis case highlights the movement disorder onset and radiological aspects that should indicate the L-2-hydroxyglutaric aciduria diagnosis.

Development and implementation of a novel assay for l-2-hydroxyglutarate dehydrogenase (l-2-HGDH) in cell lysates: l-2-HGDH deficiency in 15 patients with l-2-hydroxyglutaric aciduria

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by mutations in the gene encoding L-2-hydroxyglutarate dehydrogenase. An assay to evaluate L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) activity in fibroblast, lymphoblast and/or lymphocyte lysates has hitherto been unavailable. We developed an L-2-HGDH enzyme assay in cell lysates based on the conversion of stable-isotope-labelled L-2-hydroxyglutarate to 2-ketoglutarate, which is converted into L-glutamate in situ. The formation of stable isotope labelled L-glutamate is therefore a direct measure of L-2-HGDH activity, and this product is detected by liquid chromatography-tandem mass spectrometry. A deficiency of L-2-HGDH activity was detected in cell lysates from 15 out of 15 L-2-HGA patients. Therefore, this specific assay confirmed the diagnosis unambiguously affirming the relationship between molecular and biochemical observations. Residual activity was detected in cells derived from one L-2-HGA patient. The L-2-HGDH assay will be valuable for examining in vitro riboflavin/FAD therapy to rescue L-2-HGDH activity.