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From the Departments of Neurology (C.W., Z.K.W.) and Neuroscience (C.W., S.M., S.A.B., J.M.K., J.G., M.B., A.C., M. Hutton, M.J.F.), Mayo Clinic Jacksonville, FL; Department of Neurology (C.W., M. Hauf, A.S., J.G., F.J.G.V.), Lausanne University Hospital, Switzerland; Neurogenomics Division (K.D.C., D.A.S.), Translational Genomics Research Institute, Phoenix, AZ; Institut de Recherche en Ophtalmologie (IRO) (D.F.S.), Department of Ophtalmology, University of Lausanne and the Swiss Federal Institute of Technology in Lausanne (EPFL), Switzerland; Department of Neurology (P.R.B.), Geneva University Hospital, Switzerland; and Center for Molecular Medicine and Genetics (G.K.), Wayne State University, Detroit, MI.
Address correspondence and reprint requests to Dr. Christian Wider, Department of Neurology, Cannaday Building 2E, Mayo Clinic, San Pablo Road 4500, Jacksonville, FL 32246
Objective: To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD).
Methods: Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis.
Results: We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy.
Conclusions: This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis.
GLOSSARY: DRD = dopa-responsive dystonia; GCH1 = GTP cyclohydrolase I; SNP = single nucleotide polymorphisms; STR = short tandem repeats.
Supplemental data at www.neurology.org
Editorial, page 1373
e-Pub ahead of print on September 5, 2007, at www.neurology.org.
Supported by the Swiss National Science Foundation (C.W.), by Parkinson Switzerland (C.W.), and by the Robert and Clarice Smith Foundation (S.M., C.W.) through fellowships grants. S.M. was funded by NRSA postdoctoral fellowship #AG24030. G.K., M.J.F., J.M.K., and S.A.C. are supported by National Institute of Neurological Disorders and Stroke R01 # NS26. M.J.F. and Z.K.W. are supported by the Morris K. Udall NIH/NINDS Parkinson Disease Center of Excellence Grant awarded to the Mayo Clinic Jacksonville (P01 NS0256).
Disclosure: The authors report no conflicts of interest.
Received March 11, 2007. Accepted in final form May 23, 2007.
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