title: Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations?
abstract: 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.
authors.affiliation: INSERM U289, Hôpital de la Salpêtrière, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Tassin
authors.forename: A
authors.initials: A
authors.lastname: Dürr
authors.forename: A M
authors.initials: AM
authors.lastname: Bonnet
authors.forename: R
authors.initials: R
authors.lastname: Gil
authors.forename: M
authors.initials: M
authors.lastname: Vidailhet
authors.forename: C B
authors.initials: CB
authors.lastname: Lücking
authors.forename: J Y
authors.initials: JY
authors.lastname: Goas
authors.forename: F
authors.initials: F
authors.lastname: Durif
authors.forename: M
authors.initials: M
authors.lastname: Abada
authors.forename: B
authors.initials: B
authors.lastname: Echenne
authors.forename: J
authors.initials: J
authors.lastname: Motte
authors.forename: A
authors.initials: A
authors.lastname: Lagueny
authors.forename: L
authors.initials: L
authors.lastname: Lacomblez
authors.forename: P
authors.initials: P
authors.lastname: Jedynak
authors.forename: B
authors.initials: B
authors.lastname: Bartholomé
authors.forename: Y
authors.initials: Y
authors.lastname: Agid
authors.forename: A
authors.initials: A
authors.lastname: Brice
mesh_terms: D000293:Adolescent; D000328:Adult; D000978:Antiparkinson Agents / Q000008:administration & dosage; D002648:Child; D004252:DNA Mutational Analysis; D004421:Dystonia / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D005192:Family Health; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage; D008025:Ligases; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases
chemical_list: D000978:Antiparkinson Agents; D011506:Proteins; D007980:Levodopa; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D006136:GTP Cyclohydrolase; D008025:Ligases