title: GTP-cyclohydrolase I gene mutations in hereditary progressive amd dopa-responsive dystonia.
abstract: Recently, mutations of the GTP-cyclohydrolase I (GTP-CH I) gene, which catalyzes the first step in the tetrahydrobiopterin (BH4) biosynthesis, were discovered in Japanese patients with hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD). However, it has not been confirmed that non-Japanese patients also contain mutations in the same gene, or whether these mutations are specific to HPD/DRD. In this study, two novel nonsense mutations in exon I of the GTP-CH I gene and a new mutation at the splice acceptor site of intron I were identified in an autopsied case of English-Irish descent and 2 Japanese patients with HPD/DRD. In the latter, cerebrospinal fluid (CSF) neopterin levels (which may reflect the GTP-CH I activity in the brain) were reduced to 18% and 37% of controls. A therapeutic trial of oral BH4 was ineffective, however, in a genetically proven patient. In contrast, no mutations in any exons of the GTP-CH I gene were found in 2 patients with early-onset parkinsonism with dystonia (EOP-D) who developed dopa-responsive parkinsonism and dystonia at 6 and 8 years old, respectively. Neopterin levels in CSF were well preserved in 6 EOP-D patients. These data suggest that, among patients of different racial backgrounds, the pathogenesis of HPD/DRD, unlike EOP-D, involves partial reduction of the brain GTP-CH I activity consequent to mutations in the GTP-CH I gene. Measurement of CSF neopterin concentration may be useful for the differential diagnosis between HPD/DRD and EOP-D.
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Furukawa
authors.forename: M
authors.initials: M
authors.lastname: Shimadzu
authors.forename: A H
authors.initials: AH
authors.lastname: Rajput
authors.forename: Y
authors.initials: Y
authors.lastname: Shimizu
authors.forename: T
authors.initials: T
authors.lastname: Tagawa
authors.forename: H
authors.initials: H
authors.lastname: Mori
authors.forename: M
authors.initials: M
authors.lastname: Yokochi
authors.forename: H
authors.initials: H
authors.lastname: Narabayashi
authors.forename: O
authors.initials: O
authors.lastname: Hornykiewicz
authors.forename: Y
authors.initials: Y
authors.lastname: Mizuno
authors.forename: S J
authors.initials: SJ
authors.lastname: Kish
mesh_terms: D000293:Adolescent; D000328:Adult; D000975:Antioxidants / Q000008:administration & dosage; D001483:Base Sequence; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000134:cerebrospinal fluid; D001921:Brain / Q000201:enzymology / Q000503:physiopathology; D002648:Child; D003001:Cloning, Molecular; D018389:Codon, Nonsense / Q000235:genetics; D015259:Dopamine Agents / Q000008:administration & dosage; D004421:Dystonia / Q000188:drug therapy / Q000235:genetics*; D004739:England; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D006801:Humans; D007494:Ireland; D007564:Japan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D019798:Neopterin; D017354:Point Mutation / Q000235:genetics
chemical_list: D000975:Antioxidants; D018389:Codon, Nonsense; D015259:Dopamine Agents; D001708:Biopterins; D019798:Neopterin; D006136:GTP Cyclohydrolase; C003402:sapropterin