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

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 dystonial 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 1 of the GTP-CH I gene and a new mutation at the splice acceptor site of intron 1 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.