L-2-HYDROXYGLUTARIC ACIDEMIA - CLINICAL AND BIOCHEMICAL FINDINGS IN 12 PATIENTS AND PRELIMINARY-REPORT ON L-2-HYDROXYACID DEHYDROGENASE

L-2-Hydroxyglutaric acidaemia represents a newly defined inborn error of metabolism, with increased levels Of L-2-hydroxyglutaric acid in ur ine, plasma and cerebrospinal fluid. The concentration in cerebrospina l fluid is higher than in plasma. The other consistent biochemical fin ding is an increase of lysine in blood and cerebrospinal fluid, but ly sine loading does not increase L-2-hydroxyglutaric acid concentration in plasma. This autosomal recessively inherited disease is expressed a s progressive ataxia, mental deficiency with subcortical leukoencephal opathy and cerebellar atrophy on magnetic resonance imaging. Since the se features were described in 8 patients by Barth and co-workers in 19 92, 4 more patients with similar findings have been diagnosed and adde d to the present series. L-2-Hydroxyglutaric acid is found in only tra ce amounts on routine gas chromatographic screening in normal persons, and its origin, its fate and even its relevance to normal metabolism are unknown. Therefore its catabolism was studied in normal liver. Inc ubation of rat liver with L-2-hydroxyglutaric acid did not produce H2O 2, which excluded (peroxisomal) L-2-hydroxyacid oxidase as the main ro ute of catabolism. However, L-2-hydroxyglutaric acid is rapidly dehydr ogenated if NAD+ is added as a co-factor to the standard reaction medi um. This could also be demonstrated in human liver. The preliminary ev idence for this enzyme activity in rats and humanS, L-2-hydroxyglutari c acid dehydrogenase, is given. Further investigations are required to clarify the possible relevance to the metabolic defect in L-2-hydroxy glutaric acidaemia.