Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1

Redefining DYT14 as DYT5

C. Wider, S. Melquist, M. Hauf, A. Solida, S. A. Cobb, J. M. Kachergus, J. Gass, K. D. Coon, M. Baker, A. Cannon, D. A. Stephan, D. F. Schorderet, J. Ghika, P. R. Burkhard, G. Kapatos, M. Hutton, M. J. Farrer, Zbigniew K Wszolek, F. J G Vingerhoets

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1377-1383
Number of pages7
JournalNeurology
Volume70
Issue number16 PART 2
DOIs
StatePublished - Apr 2008

Fingerprint

Gene Dosage
Dystonia
Parkinsonian Disorders
GTP Cyclohydrolase
Genome
Dihydroxyphenylalanine
Mutation
Penetrance
Levodopa
Gene Frequency
Microsatellite Repeats
Foot
Exons
Genes
Dopa-Responsive Dystonia

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Wider, C., Melquist, S., Hauf, M., Solida, A., Cobb, S. A., Kachergus, J. M., ... Vingerhoets, F. J. G. (2008). Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: Redefining DYT14 as DYT5. Neurology, 70(16 PART 2), 1377-1383. https://doi.org/10.1212/01.wnl.0000275527.35752.c5

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1 : Redefining DYT14 as DYT5. / Wider, C.; Melquist, S.; Hauf, M.; Solida, A.; Cobb, S. A.; Kachergus, J. M.; Gass, J.; Coon, K. D.; Baker, M.; Cannon, A.; Stephan, D. A.; Schorderet, D. F.; Ghika, J.; Burkhard, P. R.; Kapatos, G.; Hutton, M.; Farrer, M. J.; Wszolek, Zbigniew K; Vingerhoets, F. J G.

In: Neurology, Vol. 70, No. 16 PART 2, 04.2008, p. 1377-1383.

Research output: Contribution to journalArticle

Wider, C, Melquist, S, Hauf, M, Solida, A, Cobb, SA, Kachergus, JM, Gass, J, Coon, KD, Baker, M, Cannon, A, Stephan, DA, Schorderet, DF, Ghika, J, Burkhard, PR, Kapatos, G, Hutton, M, Farrer, MJ, Wszolek, ZK & Vingerhoets, FJG 2008, 'Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: Redefining DYT14 as DYT5', Neurology, vol. 70, no. 16 PART 2, pp. 1377-1383. https://doi.org/10.1212/01.wnl.0000275527.35752.c5
Wider C, Melquist S, Hauf M, Solida A, Cobb SA, Kachergus JM et al. Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: Redefining DYT14 as DYT5. Neurology. 2008 Apr;70(16 PART 2):1377-1383. https://doi.org/10.1212/01.wnl.0000275527.35752.c5
Wider, C. ; Melquist, S. ; Hauf, M. ; Solida, A. ; Cobb, S. A. ; Kachergus, J. M. ; Gass, J. ; Coon, K. D. ; Baker, M. ; Cannon, A. ; Stephan, D. A. ; Schorderet, D. F. ; Ghika, J. ; Burkhard, P. R. ; Kapatos, G. ; Hutton, M. ; Farrer, M. J. ; Wszolek, Zbigniew K ; Vingerhoets, F. J G. / Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1 : Redefining DYT14 as DYT5. In: Neurology. 2008 ; Vol. 70, No. 16 PART 2. pp. 1377-1383.
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AU - Solida, A.

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