GCH1 mutations in dopa-responsive dystonia and Parkinson’s disease
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Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson’s disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms.
KeywordsGenetics Dopa-responsive dystonia GCH1 Parkinson’s disease Dystonia
This work was supported by JSPS KAKENHI Grant numbers, 16K09678 (to KN), 16K09700 (to YL), 16K09676 (to MF), 15KK0354 (to MF), 15H04842 (to NH), 23111003 (to NH), 22390181 (to YU), 25293206 (to YU), and 15H05881 (to YU). We are very grateful for these grants: AMED-CREST (Japanese Association of Medical Research and Development) (to N.H.), Practical Research Project for Rare/Intractable Diseases from AMED; 15ek0109029s0202 to NH.
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Conflicts of interest
The authors report no conflicts of interest relevant to the manuscript.
This study was performed in compliance with the Helsinki Declaration and its later amendments.