Valerija Dobričić1, Aleksandra Tomić1, Vesna Branković2, Nikola Kresojević1, Milena Janković1, Ana Westenberger3, Vedrana Milić Rašić2, Christine Klein3, Ivana Novaković4, Marina Svetel1, Vladimir S Kostić5. 1. Institute of Neurology CCS, School of Medicine, University of Belgrade, Belgrade, Serbia. 2. Clinic for Neurology and Psychiatry for Children and Youth, School of Medicine, University of Belgrade, Belgrade, Serbia. 3. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. 4. Institute for Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. 5. Institute of Neurology CCS, School of Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: vladimir.s.kostic@gmail.com.
Abstract
BACKGROUND: GTP cyclohydrolase 1-deficient DOPA-responsive dystonia, caused by autosomal dominant mutation in the gene coding for GTP cyclohydrolase 1, is a rare disorder with a reported prevalence of 0.5 per million. A correct diagnosis of DRD is crucial, given that this is an exquisitely treatable neurogenetic disorder. Although genetic testing is now widely available, we hypothesize that DRD is still underdiagnosed and its prevalence underestimated. METHODS: Molecular genetic analysis of the GCH1 gene was performed in a representative cohort of 47 Serbian patients with clinical features of DRD and in their 16 available relatives. The DRD prevalence rate in Serbia was estimated based on population size, catchment area, and the centralized Serbian referral system for rare diseases. RESULTS: We identified 9 different GCH1 mutations in 23 individuals from 11 families, 5 of which are novel. Patients displayed a broad range of clinical phenotypes. The estimated prevalence of GCH1-related DOPA-responsive dystonia in Serbia was 2.96 per million individuals and there was no evidence for a common founder. CONCLUSIONS: Our data expand the genotypic spectrum of GCH1 and confirm the broad phenotypic spectrum of DRD in the Serbian population. The number of detected mutation carriers in this sample implies that the frequency of DRD in the Serbian population is considerably higher than expected based on published prevalence rates, suggesting that the prevalence of this treatable disease should be revisited also in other populations.
BACKGROUND: GTP cyclohydrolase 1-deficient DOPA-responsive dystonia, caused by autosomal dominant mutation in the gene coding for GTP cyclohydrolase 1, is a rare disorder with a reported prevalence of 0.5 per million. A correct diagnosis of DRD is crucial, given that this is an exquisitely treatable neurogenetic disorder. Although genetic testing is now widely available, we hypothesize that DRD is still underdiagnosed and its prevalence underestimated. METHODS: Molecular genetic analysis of the GCH1 gene was performed in a representative cohort of 47 Serbian patients with clinical features of DRD and in their 16 available relatives. The DRD prevalence rate in Serbia was estimated based on population size, catchment area, and the centralized Serbian referral system for rare diseases. RESULTS: We identified 9 different GCH1 mutations in 23 individuals from 11 families, 5 of which are novel. Patients displayed a broad range of clinical phenotypes. The estimated prevalence of GCH1-related DOPA-responsive dystonia in Serbia was 2.96 per million individuals and there was no evidence for a common founder. CONCLUSIONS: Our data expand the genotypic spectrum of GCH1 and confirm the broad phenotypic spectrum of DRD in the Serbian population. The number of detected mutation carriers in this sample implies that the frequency of DRD in the Serbian population is considerably higher than expected based on published prevalence rates, suggesting that the prevalence of this treatable disease should be revisited also in other populations.
Authors: Uladzislau Rudakou; Bouchra Ouled Amar Bencheikh; Jennifer A Ruskey; Lynne Krohn; Sandra B Laurent; Dan Spiegelman; Christopher Liong; Stanley Fahn; Cheryl Waters; Oury Monchi; Edward A Fon; Yves Dauvilliers; Roy N Alcalay; Nicolas Dupré; Ziv Gan-Or Journal: Neurobiol Aging Date: 2018-09-15 Impact factor: 4.673
Authors: Thomas Opladen; Eduardo López-Laso; Elisenda Cortès-Saladelafont; Toni S Pearson; H Serap Sivri; Yilmaz Yildiz; Birgit Assmann; Manju A Kurian; Vincenzo Leuzzi; Simon Heales; Simon Pope; Francesco Porta; Angeles García-Cazorla; Tomáš Honzík; Roser Pons; Luc Regal; Helly Goez; Rafael Artuch; Georg F Hoffmann; Gabriella Horvath; Beat Thöny; Sabine Scholl-Bürgi; Alberto Burlina; Marcel M Verbeek; Mario Mastrangelo; Jennifer Friedman; Tessa Wassenberg; Kathrin Jeltsch; Jan Kulhánek; Oya Kuseyri Hübschmann Journal: Orphanet J Rare Dis Date: 2020-05-26 Impact factor: 4.123