Evaluation of clinical, neuroradiologic, and genotypic features of patients with L-2-hydroxyglutaric aciduria

L-2-hydroxyglutaric aciduria is a slowly progressive neurometabolic disorder caused by an enzymatic deficiency of L-2-hydroxyglutarate dehydrogenase. Here, we aimed to evaluate the clinical, neuroradiologic, and genotypic characteristics of patients with L-2-hydroxyglutaric aciduria who were followed in our outpatient clinic.

Twenty-five patients with L-2-hydroxyglutaric aciduria were enrolled in the study. Data regarding demographic, clinical, and neuroradiologic findings and molecular analysis were evaluated retrospectively.

The mean age of patients at the time of diagnosis was 12.09±8.02 years, whereas the mean age at the time of the first symptoms was 39.47±29.96 months. Diagnostic delay was found as 9.95±7.78 years. Developmental delay, decrease in school success, and seizures were the most common initial symptoms; however, behavioral problems and seizures became more prominent in the disease course. At the time of diagnosis, mental retardation and at least one pathologic cerebellar finding were detected in all symptomatic patients. Three patients developed brain tumors. The most common neuroimaging findings were subcortical white matter changes and cerebellar dentate nucleus involvement. In one patient, there was only isolated basal ganglia involvement without white matter lesions. Patients with similar genotypic features exhibited different clinical and radiologic findings.

Although clinical symptoms appear early in L-2-hydroxyglutaric aciduria, there is approximately a ten-year delay in diagnosis. In subjects in whom brain tumor is detected in early childhood, L-2-hydroxyglutaric aciduria should be considered in the differential diagnosis in the presence of mental retardation accompanied by developmental delay, cerebellar and pyramidal findings, and behavior disorders in a wide spectrum ranging from autism spectrum disorder to psychosis. In patients with L-2-hydroxyglutaric aciduria, incipient headache, tinnitus, altered consciousness, and seizures can be indicative of brain tumors.