title: Wide expressivity variation and high but no gender-related penetrance in two dopa-responsive dystonia families with a novel GCH-I mutation.
abstract: We describe the clinical and molecular correlates in two Italian families with dopa-responsive dystonia (DRD) and the same novel mutation of GTP-cyclohydrolase I (GCH-I) gene. Thirty-five subjects were examined and the genotype correlated to phenotype. Childhood onset foot dystonia is present in 7 subjects currently under the age of 40. In 1 patient bilateral foot dystonia was evident at birth suggesting that dystonia may be active as early as in utero. In another patient, dystonia spontaneously remitted in adolescence, to relapse 8 years later, as writer's cramp. Dystonia and parkinsonian signs are present in 5 other patients. In 2 subjects an isolated parkinsonism started over the age of 45. A 5-base pair insertion at codon 242 within exon 6 of GTP-cyclohydrolase I (GCH-I) gene that shifts the reading frame and results in a premature stop at codon 247 with truncation of the polypeptide has been detected in 21 subjects. Considering dystonia and parkinsonism the overall penetrance is 0.71 and not significantly different in men (0.69) and women (0.75). Genealogical studies seem to exclude that these families are related but haplotype analysis suggests a single founder. Our findings in subjects with the same mutation indicate a wide intrafamilial variation in expressivity and high penetrance in DRD but do not confirm the reported influence of gender on GCH-I gene mutation penetrance.
authors.affiliation: Neurodegenerative Diseases Unit, Institute of Aging, University G d'Annunzio, Chieti, Italy. uncini@unich.it
authors.forename: Antonino
authors.initials: A
authors.lastname: Uncini
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: De Angelis
authors.forename: Patrizia
authors.initials: P
authors.lastname: Di Fulvio
authors.forename: Michele
authors.initials: M
authors.lastname: Ragno
authors.forename: Grazia
authors.initials: G
authors.lastname: Annesi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Filla
authors.forename: Liborio
authors.initials: L
authors.lastname: Stuppia
authors.forename: Domenico
authors.initials: D
authors.lastname: Gambi
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D004277:DNA, Single-Stranded / Q000235:genetics; D018491:Dopamine Agonists / Q000627:therapeutic use*; D004421:Dystonia / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: D004277:DNA, Single-Stranded; D018491:Dopamine Agonists; D007980:Levodopa; D006136:GTP Cyclohydrolase