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Etsuro Ohta; Manabu Funayama, PhD; Hiroshi Ichinose, PhD; Itaru Toyoshima, MD; Fumi Urano; Mitsuhiro Matsuo, MD; Nishida Tomoko, MD; Konishi Yukihiko, MD; Syuji Yoshino, MD; Hiroyuki Yokoyama, MD; Hideki Shimazu, MD; Koji Maeda, MD; Kazuko Hasegawa, MD; Fumiya Obata, PhD

Arch Neurol. 2006;63:1605-1610.

Objectives  To better understand the relationship between mutation of the guanosine triphosphate cyclohydrolase I (GCH1) gene and the etiology of DYT5 dystonia and to accumulate data on the mutation in the Japanese population for genetic diagnosis of the disease.

Setting  Japanese population.

Patients  Eight Japanese patients with suspected DYT5 dystonia were analyzed.

Intervention  Direct genomic sequencing of 6 exons of GCH1 was performed.

Main Outcome Measures  For patients who did not exhibit any abnormality in the sequence analysis, the possibility of exon deletions was examined. In cases for which cerebrospinal fluid was available, the concentrations of neopterin and biopterin were measured as an index of GCH1 enzyme activity.

Results  In 2 patients, we found a new T106I mutation in exon 1 of GCH1, a position involved in the helix-turn-helix structure of the enzyme. In the third patient, we found a new mutation (a 15–base pair nucleotide deletion) in exon 5 that may cause a frameshift involving the active site. In the fourth patient, we detected a known nucleotide G>A substitution in the splice site of intron 5, which has been reported to produce exon 5–skipped messenger RNA. The concentrations of both neopterin and biopterin in the cerebrospinal fluid of the third and fourth patients were markedly lower than the normal range, indicating that the GCH1 enzyme was functionally abnormal in these mutations. Gene dosage analysis showed that the fifth patient had a deletion of both exon 3 and exon 4, whereas the sixth patient had a deletion of exon 3.

Conclusions  We found several novel, as well as known, GCH1 mutations in Japanese patients with DYT5 dystonia. In some of them, the GCH1 enzyme activity was proved to be impaired.

Author Affiliations: Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University (Drs Funayama and Obata and Mr Ohta) and Department of Neurology, National Sagamihara Hospital (Drs Funayama and Hasegawa), Kanagawa, Department of Life Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Tokyo (Dr Ichinose and Ms Urano), Department of Neurology, Akita University School of Medicine, Akita (Dr Toyoshima), Department of Pediatrics, Nagasaki Prefectural Medical Rehabilitation and Welfare Center for Children, Nagasaki (Dr Matsuo), Department of Pediatrics, Kagawa University, Takamatsu (Drs Tomoko, Yukihiko, and Yoshino), Department of Pediatrics, Tohoku University School of Medicine, Sendai (Dr Yokoyama), and Department of Neurology, Tokushima University School of Medicine, Tokushima (Drs Shimazu and Maeda), Japan.

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