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Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin

2005; Wiley; Volume: 26; Issue: 4 Linguagem: Inglês

10.1002/humu.9373

1098-1004

Laura Vilarinho, Maria Luı́s Cardoso, Paulo Gaspar, Clara Barbot, Luı́sa Azevedo, Luísa Diogo, Maria Lúcia Barbosa Maia dos Santos, Inês Carrilho, Isabel Fineza, Fernando Kok, Rui Chorão, Paulo Alegria, Esmeralda Martins, Julia de Abreu Teixeira, Helena C. Fernandes, Nanda M. Verhoeven, Gajja S. Salomons, Filippo M. Santorelli, Pedro Cabral, António Amorim, C. Jakobs,

Amino Acid Enzymes and Metabolism

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.