An Overview of L-2-Hydroxyglutarate Dehydrogenase Gene (L2HGDH) Variants: A Genotype-Phenotype Study

WOS: 000276810600002PubMed ID: 20052767L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH. About 200 patients with elevated concentrations of 2-hydroxyglutarate (2HG) in the urine were referred for chiral determination of 2HG and L2HGDH mutational analysis. All patients with increased L2HG (n = 106; 83 families) were included. Clinical information on 61 patients was obtained via questionnaires. In 82 families the mutations were detected by direct sequence analysis and/or multiplex ligation dependent probe amplification (MLPA), including one case where MLPA was essential to detect the second allele. In another case RT-PCR followed by deep intronic sequencing was needed to detect the mutation. Thirty-five novel mutations as well as 35 reported mutations and 14 nondisease-related variants are reviewed and included in a novel Leiden Open source Variation Database (LOVD) for L2HGDH variants (http://www.LOVD.nl/L2HGDH). Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype genotype relationship. Hum Mutat 31:380-390, 2010. (C) 2010 Wiley-Liss, Inc.Dutch Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [9120.6002]; Optimix Foundation for Scientific Research; European CommunityEuropean Community (EC) [FP7/2007-2013]; Ministery of Science, Education, and Sport of the Republic of Croatia [108-1081870-1885]The authors express their gratitude toward all scientists and doctors for taking care and referring of the patients affected with L2HGA to Amsterdam, including Drs. Parul Jayakar, Medical Genetics, Miami Children's, Hospital, FL, USA; Leyla Turner; Tuba F. Eminoglu; Ilyas Okur, Department of Pediatric Metabolism and Nutrition, At Gazi University Faculty of Medicine, Turkey; Mehmet Gunduz, Pediatric Nutrition and Metabolism Department, SSK Ankara Children's Hospital, Diskapi, Turkey; Dr. Marie-Therese Zabot, France. We are grateful to Ofir T. Betsalel for preparation of Supp. Figure SI (alignment of the L2HGDH species). M.E.S. and M.S.v.d.K. received financial support from the Dutch Organization for Scientific Research (Zon MW, TOP Grant 9120.6002) and the Optimix Foundation for Scientific Research. J.T.d.D. was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 200754-the GEN2PHEN project. I.B. received financial support by grant 108-1081870-1885 of The Ministery of Science, Education, and Sport of the Republic of Croatia