L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

Abstract

L-2-Hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. In this study, we generated L2hgdh knockout (KO) mice and observed a robust increase of L-2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis, with a corresponding increase in histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. Our data provide in vivo evidence that L2hgdh mutation leads to L-2-HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thereby offering new insights into the pathophysiology of L-2-HGA in humans.KEYWORDS L2HGDH, 2-HG, leukoencephalopathy, gliosis, neurodegeneration T he rare, autosomal recessive neurometabolic disorders D-2-hydroxyglutaric aciduria (D-2-HGA) and L-2-hydroxyglutaric aciduria (L-2-HGA) are characterized by the accumulation of D-2-hydroxyglutarate (D-2-HG) and L-2-hydroxyglutarate (L-2-HG), respectively, in body fluids. Genetic characterization has shown that 50% of the D-2-HGA population and the majority of L-2-HGA patients harbor pathogenic mutations in D2HGDH and L2HGDH genes, respectively (1-3). The other half of D-2-HGA patients have a gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2) at the residue of R140 (R140Q), which leads to abnormally high accumulation of D-2-HG (4). Based on phenotypic severity in patients, D-2-HGA is classified as mild type I (D2HGDH mutation) and severe type II (IDH2 mutation) (4, 5). Of note, 2-HG concentrations are 2-to 8-fold higher for type II D-2-HGA than type I D-2-HGA patients (4, 6, 7), suggesting that

Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates

“…However, we do not yet have definitive evidence of 2-HG addiction by IDH-mutant tumors. Although several investigators have reported that inhibiting 2-HG production resulted in reduced tumor growth [ 103 – 105 ], one study reported that, in some contexts, cell transformation by mutant IDH1 was not easily reversed by 2-HG depletion [ 106 ]. Presently, there are 19 registered clinical trials (see ClinicalTrials.gov) testing the responses of advanced hematological malignancies (AML, MDS/MPN, and AITL) and advanced solid tumors (glioma, cholangiocarcinoma, and chondrosarcoma) to six inhibitors of mutant IDH enzymes, four targeting mutant IDH1 (AG-120, IDH-305, FT-2102, and BAY-1436032), one targeting mutant IDH2 (AG-221), and one pan-inhibitor targeting both mutant IDH1 and mutant IDH2 (AG-881).…”

A 7-year-old boy with hand tremors and a novel mutation for L-2-hydroxyglutaric aciduria

“…Although the underlying mechanisms are largely unclear, in animal models, L2HG acid has been shown to impair the activities of the enzymes cytochrome C-oxidase and ATP-synthase that play a major role in the oxidative phosphorylation. To date, there are approximately 100 documented cases in the medical literature [1][2][3]. Varying levels of urine L2HG levels have been previously reported (ranging from 350.0 to 3357.0 mmol/mmol creatinine).…”

“…Although there are no specific therapeutic approaches, supplementation of and flavin adenin dinucleotide (FAD) and riboflavin (precursor of FAD) have been reported to be effective in some patients, especially in the ones with mild mutations [1][2][3]. Unfortunately, these do not improve the leukoencephalopathy.…”

“…The dysfunction of this enzyme leads to accumulation of L2HG in urine, cerebrospinal fluid and plasma, which is the biochemical hallmark. The disease has a slowly progressive course and clinical signs are predominantly neurological symptoms, rarely leading to early loss of gross motor skills [1][2][3]. We present the case of a 7-year-old boy with L2HGA, with a novel mutation in the L2HGDH gene.…”

“…L-2-Hydroxyglutaric aciduria (L2HGA) is a rare cerebral organic aciduria occurring due to defects in L-2-hydroxyglutarate dehydrogenase (L2HGDH), encoded by the L2HGDH gene, a mitochondrial enzyme that catalyses the oxidation of L-2-hydroxyglutaric acid (L2HG acid) to α-ketoglutarate [1][2][3]. The dysfunction of this enzyme leads to accumulation of L2HG in urine, cerebrospinal fluid and plasma, which is the biochemical hallmark.…”