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BACKGROUND: 2-HydroxyGlutaric Acid (2HGA) is a dicarboxylic acid synthesized from 2-ketoglutarate and 4-hydroxybutyrate via malate dehydrogenase and ALDHFE1 respectively. Urinary excretion of small quantities of 2HGA is normal in healthy individuals. Known disorders of 2HGA metabolism associated with significantly elevated urinary excretion include: D, L and combined 2 hydroxyglutaric aciduria. Clinical phenotypes of these neurometabolic syndromes include neonatal/early-infantile onset encephalopathy, severe developmental delays, hypotonia, seizures, muscle weakness, cardiomyopathy, apnea and multifocal cerebral white matter abnormalities.  Current investigational therapies include AG-221 (Agios) for type II D-2 hydroxyglutaric aciduria and Taurine in SSADH deficiency. OBJECTIVE: To report on a large cohort of patients with 2-hydroxyglutaric aciduria diagnosed at KFSHRC. METHODS: Random urine samples from Saudi children with static as well as progressive neurodevelopmental disorders were evaluated by GC-MS analysis followed by LC-MSMS chiral analysis of the D and L enantiomers of 2-hydroxyglutaric acid. RESULTS: Since 1995 and among 3197 samples which were abnormal for various inborn errors of metabolism, 27 patients (8.4/1000) with significant 2-hydroxyglutaric aciduria were identified. Chiral analysis confirmed L-2HGA (15 patients), D-2HGA (3 patients) and combined D, L-2HGA (5 patients). One patient had D2-HGA in combination with 4-hydroxybytric aciduria.                                                                                                                                                                                                                                                      CONCLUSION: L-2HGA is more common among Saudi patients with 2HGA. D-2HGA in combination with 4-hydroxybutyric aciduria likely results from altered activity of ALDHFE1 in combination with recessive germline mutations in SSADH. Accurate diagnosis of the specific etiology of 2HGA is essential for proper management, prognosis, genetic counseling and more recently, potential enrollment in prospective clinical trials.

2hydroxyglutaric aciduria, organic aciduria, GC-MS, LC-MSMS, clinical trials