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Mutations in DYT1

Extension of the phenotypic and mutational spectrum

From the Departments of Neurology (Drs. Kabakci, Hedrich, Vieregge, Hagenah, and Klein, and J. Garrels), Human Genetics (Drs. Kabakci, Hedrich, and Klein, and J. Garrels), and Psychiatry and Psychotherapy (Dr. Lencer), University of Lübeck, Germany; Department of Neurology (J.C. Leung and Drs. Friedman and Breakefield), Massachusetts General Hospital and Harvard Medical School, Boston; Department of Transfusion Medicine (Dr. Mitterer), Hospital Merano, Italy; Department of Neurology (Dr. Vieregge), Hospital of Lippe-Lemgo, Lemgo, Germany; Department of Neurology (Dr. Witt), Christian-Albrechts-University of Kiel, Germany; Department of Neurology (Dr. Klostermann), Freie Universität of Berlin, Germany; Department of Neurology (Drs. Svetel and Kostic), University of Belgrade, Yugoslavia; Department of Neurology (Dr. Bressman), Beth Israel Medical Center, New York, NY; Department of Molecular Genetics (Dr. Ozelius), Albert Einstein College of Medicine, New York, NY; and Department of Neurology (Dr. Pramstaller), Regional General Hospital Bolzano, Italy.

Address correspondence and reprint requests to Dr. Christine Klein, Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; e-mail: klein_ch{at}neuro.mu-luebeck.de

Background: Most cases of early-onset primary torsion dystonia (PTD) are caused by the same three–base pair (bp) (GAG) deletion in the DYT1 gene. Exon rearrangements are a common mutation type in other genes and have not yet been tested for in DYT1. Several lines of evidence suggest a relationship of the DYT1 gene with Parkinson disease (PD).

Objective: To investigate the frequency and type of DYT1 mutations and explore the associated phenotypes in a mixed movement disorders patient cohort and in controls.

Methods: The authors screened 197 patients with dystonia (generalized: n = 5; focal/segmental: n = 126; myoclonus-dystonia: n = 34; neuroleptic-induced: n = 32), 435 with PD, and 42 with various other movement disorders, along with 812 healthy controls, for small deletions in exon 5 of DYT1 and tested for exon rearrangements by quantitative, duplex PCR in 51 GAG deletion-negative dystonia cases.

Results: The GAG deletion was detected in five patients: three with early-onset PTD, one with generalized jerky or clonic dystonia, and one with generalized dystonia and additional features (developmental delay, pyramidal syndrome). A novel out-of-frame four-bp deletion (934_937delAGAG) in exon 5 of the DYT1 gene was found in a putatively healthy blood donor. No exon rearrangements were identified in DYT1.

Conclusions: In this mixed patient sample, the GAG deletion was rare and in two out of five cases associated with an unusual phenotype. In addition, a novel DYT1 truncating mutation of unknown clinical relevance was found in a putatively unaffected individual. DYT1 exon rearrangements, however, do not seem to be associated with PTD.

Received July 31, 2003. Accepted in final form October 6, 2003.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the February 10 issue to find the title link for this article.

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