RESUMO
Four different mutations in the GTP cyclohydrolase I gene were found (P199L, M211V, IVS5+1G>A, G203R) in 6 out of 33 families with dopa-responsive dystonia. A splice mutation (IVS5+1G>A) located at the border of exon 5 to intron 5 was found in one of these families. Three members of the family carry the IVS5+1G>A mutation on one allele, inherited from the father to the daughter and son. Examination of the mRNA showed an exon 5 skipping that results in a reduction of enzyme activity in cultured fibroblasts to 4-17% compared to controls. The father and daughter never had clinical symptoms of dopa-responsive dystonia. The son was symptomatic at the age of 3 years and was treated successfully with L-dopa/carbidopa. After 20 years this therapy was terminated and for the next 6 years he was free of symptoms. With increased motoric activity, symptoms reappeared and the therapy was reintroduced.
Assuntos
Di-Hidroxifenilalanina/uso terapêutico , Distonia/genética , GTP Cicloidrolase/genética , Mutação , Splicing de RNA , Alelos , Sequência de Aminoácidos , Inibidores das Descarboxilases de Aminoácidos Aromáticos , Sequência de Bases , Benserazida/uso terapêutico , Biopterinas/metabolismo , Células Cultivadas , Pré-Escolar , Combinação de Medicamentos , Distonia/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Éxons , Feminino , Fibroblastos/metabolismo , GTP Cicloidrolase/química , Humanos , Íntrons , Levodopa/uso terapêutico , Masculino , Neopterina/biossíntese , RNA Mensageiro/análiseRESUMO
Autosomal dominant DOPA-responsive dystonia (DRD) is usually caused by mutation in the gene encoding guanosine triphosphate-cyclohydrolase I (GTPCH I). We studied 22 families with a phenotype of levodopa-responsive dystonia by sequencing the six coding exons, the 5'-untranslated region and the exon-intron boundaries of the GTPCH I gene. Eleven heterozygous mutations were identified, including five missense mutations, one splice site mutation, two small deletions and two nonsense mutations, in 12 families that included 27 patients and 13 asymptomatic carriers. Six mutations were new and five had already been reported. Four of the mutations caused truncation of the GTPCH I protein. One family carried a base-pair change in the 5'-untranslated region, not detected in controls, that could be responsible for the phenotype. Three of the remaining 10 families had deletions in the parkin gene on chromosome 6, underlining how difficult it is to distinguish, in some cases, between DRD and parkin mutations. No mutations were identified in seven families. The clinical spectrum extended from the classical DRD phenotype to parkinsonism with levodopa-induced dyskinesias, and included spastic paraplegia as well as the absence of dystonia.
