Mutations in GTP-cyclohydrolase 1 (GCH1) cause autosomal dominant dopa-responsive dystonia (DRD), characterized by childhood-onset foot dystonia that later generalizes. DRD patients frequently present with associated Parkinsonism. Conversely, early-onset Parkinson's disease (EOPD) patients commonly display dystonia. Herein, we investigated the frequency of GCH1 mutations in a series of 53 familial EOPD patients (21 with dystonia) and screened them for mutations in PRKN, PINK1, and DJ-1. In addition, we examined a matched EOPD patient-control series for association of common variability at the GCH1 locus and EOPD susceptibility. No GCH1 coding change or copy-number abnormality was identified in familial EOPD patients. A novel 18-bp deletion was found in the proximal promoter (two patients, one control), which is expected to knock out two regulatory elements previously shown to regulate GCH1 transcription. No association was found between GCH1 variability and risk of EOPD. Fourteen (26.4%) familial EOPD patients had homozygous or compound heterozygous PRKN mutations. PRKN-positive patients were 10 years younger than PRKN-negative patients and had a twofold higher prevalence of dystonia. This study does not support a significant role for genetic variation at the GCH1 locus in EOPD. However, our results further highlight the relevance of PRKN screening in familial EOPD.
(c) 2009 Movement Disorder Society.