title: Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin.
abstract: We studied 21 patients, from 18 families, with L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic disorder with a homogeneous presentation: progressive neurodegeneration with extrapyramidal and cerebellar signs, seizures, and subcortical leukoencephalopathy. Increased levels of L-2-hydroxyglutaric acid in body fluids proved the diagnosis of L-2-HGA in all 21 patients. We analyzed the L-2-HGA gene (L2HGDH), recently found to be mutated in consanguineous families with L-2-HGA, and identified seven novel mutations in 15 families. Three mutations appeared to be particularly prevalent in this Portuguese panel: a frameshift mutation (c.529delC) was detected in 12 out of 30 mutant alleles (40%), a nonsense mutation (c.208C>T; p.Arg70X) in 7/30 alleles (23%), and a missense mutation (c.293A>G; p.His98Arg) in four out of 30 mutant alleles (13%), suggesting that common origin may exist. Furthermore, two novel missense (c.169G>A; p.Gly57Arg, c.1301A>C; p.His434Pro) and two splice error (c.257-2A>G, c.907-2A>G) mutations were found. All the mutations presumably lead to loss-of-function with no relationship between clinical signs, progression of the disease, levels of L-2-HGA and site of the mutation. In the three remaining families, no pathogenic mutations in the L-2-HGA were found, which suggests either alterations in regulatory regions of the gene or of its intervening sequences, compound heterozygosity for large genomic deletion and, or further genetic heterogeneity.
authors.affiliation: Clinical Biology Unit, Medical Genetics Institute, Porto, Portugal. laura.vilarinho@igm.min-saude.pt
authors.forename: L
authors.initials: L
authors.lastname: Vilarinho
authors.forename: M L
authors.initials: ML
authors.lastname: Cardoso
authors.forename: P
authors.initials: P
authors.lastname: Gaspar
authors.forename: C
authors.initials: C
authors.lastname: Barbot
authors.forename: L
authors.initials: L
authors.lastname: Azevedo
authors.forename: L
authors.initials: L
authors.lastname: Diogo
authors.forename: M
authors.initials: M
authors.lastname: Santos
authors.forename: I
authors.initials: I
authors.lastname: Carrilho
authors.forename: I
authors.initials: I
authors.lastname: Fineza
authors.forename: F
authors.initials: F
authors.lastname: Kok
authors.forename: R
authors.initials: R
authors.lastname: Chorão
authors.forename: P
authors.initials: P
authors.lastname: Alegria
authors.forename: E
authors.initials: E
authors.lastname: Martins
authors.forename: J
authors.initials: J
authors.lastname: Teixeira
authors.forename: H
authors.initials: H
authors.lastname: Cabral Fernandes
authors.forename: N M
authors.initials: NM
authors.lastname: Verhoeven
authors.forename: G S
authors.initials: GS
authors.lastname: Salomons
authors.forename: F M
authors.initials: FM
authors.lastname: Santorelli
authors.forename: P
authors.initials: P
authors.lastname: Cabral
authors.forename: A
authors.initials: A
authors.lastname: Amorim
authors.forename: C
authors.initials: C
authors.lastname: Jakobs
mesh_terms: D000293:Adolescent; D000328:Adult; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003241:Consanguinity; D005192:Family Health; D005260:Female; D005977:Glutarates / Q000652:urine*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011174:Portugal; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D000429:Alcohol Oxidoreductases; C023858:2-hydroxyglutarate dehydrogenase