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134 PROGRESSIVE ATAXIA AND MENTAL RETARDATION ASSOCIATED WITH LEUCODYSTROPHY IN 4 PATIENTS WITH L-2-HYDROXY-GLUTARIC ACIDURIA

We present the clinical, neuroradiological and biochemical data of 4 patients with L-2-hydroxy-glutaric aciduria, which appears to be a new neurometabolic disorder. Two male siblings of Marocco ancestry presented with psychomotor retardation and dystrophy in early childhood. Consequently they developed a progressive ataxia, slight extrapyramidal signs and mental retardation (IQ< 48 at the age of 18 y and IQ= 48 at the age of 12y). One of them suffered from convulsions. Two additional female patients (To., A., age 15y, and Fi., A., age 19y) of Turkish and Greek ancestry followed a similar course with short stature, progressive ataxia and mental retardation. In addition, To, A., developed an oligoepilepsy with generalized seizures in early infancy and showed pyramidal signs with the age of 10 y. Neuroradiological investigations revealed distinct extensive subcortical hypodensities, resembling spongy degeneration and a (sub)cortical and cerebellar atrophy in all four patients. Urinary excretion of L-2-hydroxyglutaric acid was in the order of 1-3 mol/mol of erea, in all patients as determined by GCMS and III-NMR spectroscopy (controls < 0.002 mol/mol of crea.). Plasma levels of L-2-hydroxyglutaric acid were 20-30 μmol/l and in the CSF 40-50 μmol/l (controls n. d.). The very similar clinical findings as well as the distinct neuroradiological picture in 4 patients from 3 families pinpoint a hitherto unrecognized neurometabolic disorder. The relation of L-2-hydroxyglutaric acid to human metabolic pathways is unknown. In patient Fi.. A., we observed a small decrease in ihe urinary excretion of L-2-hydroxyglutaric acid under a carbohydrate rich diet and an increase after an oral load with plant oil. In To., A., a 24h last produced a +fold increase in L-2-hydroxyglutaric aciduria. A therapeutic trial of a carbohydrate rich, low fat diet did not result in any clinical improvement. A number of other in vivo loading experiments and in vitro investigations in fibroblasts using radiolabeled precursors were unrewarding.