title: Clinical, neuroimaging, and genetic features of L-2-hydroxyglutaric aciduria in Arab kindreds.
abstract: OBJECTIVE
  L-2-hydroxyglutaric aciduria is a neurometabolic disorder with autosomal recessive mode of inheritance in which patients exhibit elevated L-2-hydroxyglutaric acid in body fluids, central nervous system manifestations, and increased risk of brain tumor formation. Mutations in L2HGDH gene have been described in L-2-hydroxyglutaric aciduria patients of different ethnicities. The present study was conducted to perform a detailed clinical, imaging and genetic analysis.
  
  
  METHODS
  A cross-sectional clinical genetic study of 16 L-2-hydroxyglutaric aciduria patients from 4 Arab consanguineous families examined at the metabolic clinic of the hospital.
  
  
  METHODS
  Genomic DNA was isolated from the blood of 12 patients and 10 unaffected family members, and the L2HGDH gene was sequenced. DNA sequences were compared to the L2HGDH reference sequence from GenBank.
  
  
  RESULTS
  All patients exhibit characteristic clinical, biochemical, and imaging features of L-2-hydroxyglutaric aciduria, and 4 patients exhibited increased incidence of brain tumors. The sequencing of the L2HGDH gene revealed the c.1015delA, c.1319C > A, and c.169G > A mutations in these patients. These mutations encode for the p.Arg339AspfsX351, p.Ser440Tyr, and p.Gly57Arg changes in the L2HGDH protein, respectively. The c.169G > A mutation, which was shown to have a common origin in Italian and Portuguese patients, was also discovered in Arab patients. Finding of the homozygous c.159T SNP associated with the c.169G > A mutation in Arab patients points to an independent origin of this mutation in Arab population.
  
  
  CONCLUSIONS
  The detailed description of clinical manifestations and L2HGDH mutation in this study is useful for diagnosis of L-2-hydroxyglutaric aciduria in Arab patients. While reoccurrence of an L2HGDH mutation in L-2-hydroxyglutaric aciduria patients of different ethnicity is extremely rare, the c.169G mutation has an independent origin in Arab patients. It is likely that this mutation may also be present in patients of other ethnicities.
authors.affiliation: Dr. Muhammad Faiyaz-Ul-Haque, Department of Pathology,, College of Medicine,, King Khaled University Hospital,, King Saud University, T: 966-11-4699377, F: +966-11-4672462, mfhaque@ksu.edu.sa.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Faiyaz-Ul-Haque
authors.forename: Moeenaldeen D
authors.initials: MD
authors.lastname: Al-Sayed
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.forename: Masood
authors.initials: M
authors.lastname: Jamil
authors.forename: Anjum
authors.initials: A
authors.lastname: Saeed
authors.forename: Mohamed Saleh
authors.initials: MS
authors.lastname: Amoudi
authors.forename: Namik
authors.initials: N
authors.lastname: Kaya
authors.forename: Halah
authors.initials: H
authors.lastname: Abalkhail
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al-Abdullatif
authors.forename: Mohamed
authors.initials: M
authors.lastname: Rashed
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Owain
authors.forename: Iskra
authors.initials: I
authors.lastname: Peltekova
authors.forename: Syed H E
authors.initials: SH
authors.lastname: Zaidi
mesh_terms: D000293:Adolescent; D000328:Adult; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D018912:Arabs / Q000235:genetics*; D020739:Brain Diseases, Metabolic, Inborn / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D001932:Brain Neoplasms / Q000209:etiology; D002648:Child; D003241:Consanguinity; D003430:Cross-Sectional Studies; D005190:Family; D005260:Female; D016368:Frameshift Mutation; D005820:Genetic Testing; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D020125:Mutation, Missense; D059906:Neuroimaging / Q000379:methods; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D000429:Alcohol Oxidoreductases; C506763:L2HGDH protein, human