title: Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5.
abstract: 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.
authors.affiliation: Department of Neurology, Cannaday Building 2E, Mayo Clinic, San Pablo Road 4500, Jacksonville, FL 32246, USA. wider.christian@mayo.edu
authors.forename: C
authors.initials: C
authors.lastname: Wider
authors.forename: S
authors.initials: S
authors.lastname: Melquist
authors.forename: M
authors.initials: M
authors.lastname: Hauf
authors.forename: A
authors.initials: A
authors.lastname: Solida
authors.forename: S A
authors.initials: SA
authors.lastname: Cobb
authors.forename: J M
authors.initials: JM
authors.lastname: Kachergus
authors.forename: J
authors.initials: J
authors.lastname: Gass
authors.forename: K D
authors.initials: KD
authors.lastname: Coon
authors.forename: M
authors.initials: M
authors.lastname: Baker
authors.forename: A
authors.initials: A
authors.lastname: Cannon
authors.forename: D A
authors.initials: DA
authors.lastname: Stephan
authors.forename: D F
authors.initials: DF
authors.lastname: Schorderet
authors.forename: J
authors.initials: J
authors.lastname: Ghika
authors.forename: P R
authors.initials: PR
authors.lastname: Burkhard
authors.forename: G
authors.initials: G
authors.lastname: Kapatos
authors.forename: M
authors.initials: M
authors.lastname: Hutton
authors.forename: M J
authors.initials: MJ
authors.lastname: Farrer
authors.forename: Z K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: F J G
authors.initials: FJ
authors.lastname: Vingerhoets
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D004421:Dystonia / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D040641:Quantitative Trait Loci / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics*; D013557:Switzerland