Cerebral neoplasms in L-2 hydroxyglutaric aciduria: 3 new cases and meta-analysis of literature data

Abstract

Increasing evidence suggests that patients with L2-HGA have a predisposition to cerebral neoplasms. This may be related to the pathologic accumulation of L2-HG because high amounts of 2-HG have been found in brain neoplasms that have IDH1 mutations. Our experience, on the basis of 11 previously unreported cases of L2-HGA, 3 of which developed cerebral neoplasms during the course of the disease, also supports an association between L2-HGA and cerebral neoplasms. We conducted a meta-analysis of published data, and we identified 295 patients (including our 11 patients) with L2-HGA. In 14 patients, the metabolic disorder was associated with cerebral neoplasms, suggesting an approximately 5% prevalence rate of CNS neoplasms in patients with L2-HGA; nonetheless, it may still be an underestimate. L2-HGA is an important disease "model" that provides further evidence to support the recently proposed pathogenetic role of 2-HG in the development of cerebral neoplasms.

Fig 1.

Axial T2-weighted MR images of our patients, Patient 1 (A) had anaplastic astrocytoma in the right hippocampal area (Fig 2), patient 2 (B) was diagnosed with oligodendroglioma, and patient 3 (C) had a low-grade glioma in the left thalamus. Besides the obvious intra-axial mass lesions in all 3 cases, extensive, leukodystrophy-like changes, showing a centripetal gradient are clearly conspicuous; and in conjunction with additional abnormalities found in basal ganglia and dentate nuclei (not shown), these are pathognomonic for L2-HGA.

Fig 2.

Histopathologic specimen of patient 1 diagnosed with right hippocampal neoplasm. It revealed a diffuse astrocytic tumor characterized by mildly pleomorphic neoplastic cells, microcysts, and some mitotic figures. Hematoxylin-eosin staining, 200× magnification.

Fig 3.

The diagram shows the derivation of 2-HG. With an IDH1 mutation and gain of enzyme function, there is an overproduction of 2-HG beyond the capacity of L2HGDH to convert it to alpha-ketoglutarate. In the setting of L2-GA (ie, L2HGDH deficiency), a normal amount of 2-HG is produced, but it accumulates because it is not converted to alpha-ketoglutarate. It is, therefore, excess 2-HG that is both myelinotoxic and carcinogenic. Also shown is the dual function of malate dehydrogenase-2, which converts malate to oxaloacetate as well as alpha-ketoglutarate to 2-HG (there is also a cytosolic form of MDH, which plays a role in gluconeogenesis).