4 weeks
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L-2-hydroxyglutaric aciduria (L2HGA) [OMIM #147920] is a rare neurometabolic disease associated with accumulation of L-2-hydroxyglutaric aciduria in urine. L2HGA is a slowly progressive disorder with average age of onset of 2 years (range 0-7). The most commonly observed clinical features are developmental delay, epilepsy and cerebellar ataxia. Other features that can be observed in some patients include macrocephaly, hypotonia, extrapyramidal signs, behavioral problems and spasticity. Patients typically have a characteristic pattern of findings on brain MRI, including subcortical cerebral white matter abnormalities, signal intensities of the caudate nucleus, putamen, dentate nucleus and globus pallidus, and atrophy of the cerebral white matter, cerebellar vermis and hemispheres.

Mutations of the L2HGDH gene [OMIM #609584] gene are associated with L2HGA. Missense, nonsense, frameshift and splice site mutations have been described. The L2HGDH gene encodes for the enzyme L-2- hydroxyglutarate dehydrogenase (L-2-HGDH). Typically, L-2-hydroxyglutaric acid (L-2-HG) is converted to 2- ketoglutarate (2-KG) by L-2-HGDH. Mutations in L2HGDH are associated with accumulation of L-2-HG in the urine and cerebral spinal fluid. L-2-HG has no known physiological function, however its accumulation appears to lead to the clinical manifestations seen in L2HGA. Conventional urine organic acid screening with gas chromatography mass spectrometry (GC-MS) can detect increased 2-HG (2-hydroxyglutaric acid), but does not differentiate between enantiomeric D-2-HG and L-2-HG.