title: L-2-hydroxyglutaric aciduria: identification of ten novel mutations in the L2HGDH gene.
abstract: L-2-hydroxyglutaric aciduria (L-2-HGA) is a metabolic disease with an autosomal recessive mode of inheritance. It was first reported in 1980. Patients with this disease have mutations in both alleles of the L2HDGH gene. The clinical presentation of individuals with L-2-HGA is somewhat variable, but affected individuals typically suffer from progressive neurodegeneration. Analysis of urinary organic acids reveals an increased signal of 2-hydroxyglutaric acid, mainly as the L-enantiomer. L-2-HGA is known to occur in individuals of various ethnic backgrounds, but up to now mutation analysis has been mainly focused on patients of Turkish and Portuguese origin. This led us to confirm the diagnosis on the DNA level and undertake the corresponding mutation analysis in individuals of diverse ethnicity previously diagnosed with L-2-HGA on the basis of urinary metabolites and clinical/neuroimaging data. In 24 individuals from 17 families with diverse ethnic and geographic origins, 13 different mutations were found, 10 of which have not been reported previously. At least eight of the patients were compound heterozygotes. The identification of two mutations (c.751C > T and c.905C > T in exon 7) in patients with different origins supports the view that they occurred independently in different families. In contrast, the mutation c.788C > T was detected in all six Venezuelan patients originating from the same Caribbean island of Margarita, but not in other patients, thus rendering a founder effect likely. None of the mutations was found in the control population, indicating that they are most probably causative. Mutation analysis may improve the quality of diagnosis and prenatal diagnosis of L-2-HGA.
authors.affiliation: Labor für Klinische Biochemie und Stoffwechsel, Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Freiburg, Mathildenstr. 1, 79106, Freiburg, Germany. joern.oliver.sass@uniklinik-freiburg.de
authors.forename: J O
authors.initials: JO
authors.lastname: Sass
authors.forename: F
authors.initials: F
authors.lastname: Jobard
authors.forename: M
authors.initials: M
authors.lastname: Topçu
authors.forename: A
authors.initials: A
authors.lastname: Mahfoud
authors.forename: E
authors.initials: E
authors.lastname: Werlé
authors.forename: S
authors.initials: S
authors.lastname: Cure
authors.forename: N
authors.initials: N
authors.lastname: Al-Sannaa
authors.forename: S A
authors.initials: SA
authors.lastname: Alshahwan
authors.forename: M
authors.initials: M
authors.lastname: Bataillard
authors.forename: L
authors.initials: L
authors.lastname: Cimbalistiene
authors.forename: C
authors.initials: C
authors.lastname: Grolik
authors.forename: V
authors.initials: V
authors.lastname: Kemmerich
authors.forename: H
authors.initials: H
authors.lastname: Omran
authors.forename: L
authors.initials: L
authors.lastname: Sztriha
authors.forename: M
authors.initials: M
authors.lastname: Tabache
authors.forename: J
authors.initials: J
authors.lastname: Fischer
mesh_terms: D000328:Adult; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D015415:Biomarkers / Q000652:urine; D020739:Brain Diseases, Metabolic, Inborn / Q000175:diagnosis / Q000201:enzymology* / Q000208:ethnology / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005060:Europe / Q000208:ethnology; D005260:Female; D020022:Genetic Predisposition to Disease; D005977:Glutarates / Q000652:urine; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010154:Pakistan / Q000208:ethnology; D010641:Phenotype; D011237:Predictive Value of Tests; D012529:Saudi Arabia / Q000208:ethnology; D012720:Severity of Illness Index; D014687:Venezuela / Q000208:ethnology
chemical_list: D015415:Biomarkers; D005977:Glutarates; C019417:alpha-hydroxyglutarate; D000429:Alcohol Oxidoreductases; C506763:L2HGDH protein, human