GTP-cyclohydrolase I gene mutations in hereditary progressive amd dopa-responsive dystonia

Ann Neurol. 1996 May;39(5):609-17. doi: 10.1002/ana.410390510.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antioxidants / administration & dosage
  • Base Sequence
  • Biopterin / administration & dosage
  • Biopterin / analogs & derivatives
  • Biopterin / cerebrospinal fluid
  • Brain / enzymology
  • Brain / physiopathology
  • Child
  • Cloning, Molecular
  • Codon, Nonsense / genetics
  • Dopamine Agents / administration & dosage
  • Dystonia / drug therapy
  • Dystonia / genetics*
  • England
  • Female
  • GTP Cyclohydrolase / genetics*
  • Humans
  • Ireland
  • Japan
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Neopterin
  • Point Mutation / genetics


  • Antioxidants
  • Codon, Nonsense
  • Dopamine Agents
  • Biopterin
  • Neopterin
  • GTP Cyclohydrolase
  • sapropterin