In IDH -mutant gliomas, the accumulation of 2-hydroxyglutarate (2-HG) induces widespread epigenetic disruption and drives gliomagenesis. L-2-hydroxyglutaric aciduria (L-2-HGA) is a metabolic disorder causing L-2-HG accumulation, resulting in myelin toxicity, and increased brain tumor risk. Gliomas arising in L-2-HGA remain poorly characterized. We report a new case of high-grade glioma in a L-2-HGA patient, including methylome profiling, and review previously published cases to clarify glioma characteristics and provide hypothesis regarding 2-HG–driven gliomagenesis.

A new case of high-grade glioma in a L-2-HGA patient was locally identified. A literature review was conducted following PRISMA guidelines.

A 45-year-old L-2-HGA woman developed a diffuse anaplastic glioma harboring a TERT p C228 T mutation, revealed by progressive neurological decline. Methylation profiling assigned the tumor to the “Diffuse pediatric-type high-grade gliomas” superfamily (score ≥0.9). Despite chemotherapy, the patient died 5 months post-diagnosis. Literature review yielded 20 documented cases of glioma in L-2-HGA patients, with a mean age at diagnosis of 18 ± 9.5 years. Tumor location was relatively stereotyped, with 75% in the temporal lobe or thalamus/basal ganglia. Molecular alterations typical of glioblastoma were observed ( EGFR amplification, partial 10q loss) and the epigenetic profile was similar. Although some tumors misleadingly harbored the microscopic features of low-grade gliomas, the median overall survival was 6 months.

Although gliomas associated with L-2HGA predominantly affect young patients, their characteristics differ from those of IDH -mutant gliomas. These tumors may possibly be related to diffuse pediatric-type high-grade glioma H3 -wildtype and IDH -wildtype, which is consistent with their highly aggressive clinical course.