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From the Department of Neurology (Drs. O’Riordan and Hutchinson), St. Vincent’s University Hospital and University College Dublin, Department of Neurology (Dr. Lynch), Mater Misericordiae University Hospital, and Department of Public Health Medicine and Epidemiology (Dr. Daly), University College Dublin, National University of Ireland; and Department of Neurology (Drs. Saunders-Pullman and Bressman, D. Raymond), Beth Israel Medical Center, New York.
Address correspondence and reprint requests to Dr. M. Hutchinson, Department of Neurology, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland; e-mail: mhutchin{at}iol.i.e
Background: The genetic basis of most forms of primary torsion dystonia (PTD) is unknown; multiplex families are uncommon due to low penetrance. Intrafamilial, age-related, phenotypic heterogeneity was noted in 14 PTD families. The authors hypothesized that the clinical presentation of PTD was modulated by the age at onset of the dystonia, irrespective of the genotype.
Methods: This hypothesis was addressed in a study of 14 PTD families and a meta-analysis of 83 published series of PTD.
Results: In 12 families with adult-onset PTD, the index cases presented with cervical dystonia (CD); of the 22 affected relatives, 17 had CD, 2 had writer’s cramp, 1 had blepharospasm, and 2 had spasmodic dysphonia. In the two other PTD families, the probands and all 10 symptomatic relatives had limb-onset dystonia at <20 years of age. There were differences between the median ages at onset of the different phenotypes (p = 0.0037). Analysis of 83 published series including 5,057 patients indicated significant differences in the mean age at onset of five phenotypes of PTD (mean age at onset; 95% CI): DYT1 dystonia (11.3 years; 10.3 to 12.2), writer’s cramp (38.4; 36.9 to 39.9), CD (40.8; 40.3 to 41.3), spasmodic dysphonia (43.0; 42.2 to 43.9), and blepharospasm–oromandibular dystonia (55.7; 55.1 to 56.4).
Conclusion: Phenotypic variation in PTD presentation is due to the effect of age at onset modulating the expression of a genetic disorder with a caudal-to-rostral change in the site of onset.
Received February 2, 2004. Accepted in final form June 18, 2004.
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 October 26 issue to find the title link for this article.
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