Background: Guanosine triphosphate cyclohydrolase I (GTPCH) catalyzes the first step in the synthesis of tetrahydrobiopterin (BH4). Autosomal dominantly inherited defects in the GTPCH gene (GCH1) cause a form of dystonia that is responsive to treatment with levodopa (dopa-responsive dystonia [DRD]).
Objective: To investigate molecular and clinical aspects of DRD in a large Danish family.
Methods: For analysis of the GCH1 gene, a mutation-scanning method based on denaturing gradient gel electrophoresis (DGGE) was used. A novel mutation, X251R, was identified in the GCH1 gene of 2 distantly related Danish patients with DRD, one of whom also had Tourette syndrome (TS). Thirty-five additional family members were investigated for this mutation, and 16 of them underwent clinical neurological examination.
Results: A total of 18 patients were heterozygous for the X251R allele, 16 of whom had neurological complaints spanning from very mild parkinsonism to severe invalidism due to dystonia. Of 13 symptomatic heterozygotes who had been neurologically examined, 10 had signs of dystonia or parkinsonism. Sixteen of the heterozygotes were treated with levodopa, and 13 reported a treatment benefit. Three of the symptomatic heterozygotes had signs of TS.
Conclusions: This study confirms the large variability in DRD symptoms and emphasizes the usefulness of molecular analysis for diagnosis and treatment of DRD. The presence of TS is suggested to be coincidental, though the development of TS-like symptoms due to mutations in GCH1 cannot be excluded.