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From the Department of Neurology (Drs. Moseley, Schut, Gomez, Koob, and Ranum, and K.A. Benzow) and the Institute of Human Genetics (Drs. Gomez and Ranum), University of Minnesota, Minneapolis, MN; Department of Veterans Affairs Medical Center (Dr. Bird), Seattle, WA; Medical College of Wisconsin and VA Medical Center (Drs. Barkhaus and Blindauer), Milwaukee, WI; Department of Medicine and Centre Hospitalier de l'Université de Montréal (Drs. Labuda and Pandolfo); and Department of Neurology and Neurosurgery (Dr. Pandolfo), McGill University, Montreal, Quebec, Canada.
Address correspondence and reprint requests to Dr. Laura P.W. Ranum, Department of Neurology, Box 295 UMHC, 420 Delaware Street SE, Minneapolis, MN 55455.
Objective: To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich's ataxia (FA) among a large panel of ataxia families.
Background: The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism for five dominantly inherited SCAs as well as FA.
Methods: We collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded from our collection.
Results: Among the 178 dominant kindreds, we found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, with one or more of the following characteristics: adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensory perceptions.
Conclusions: Pathogenic trinucleotide repeat expansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Because of the significant implications that a dominant versus recessive inheritance pattern has for future generations, it is important to screen patients who do not have a clearly dominant inheritance pattern for expansions at both the FA and the dominant ataxia loci.
Supported in part by the Bob Allison Ataxia Research Center, the National Ataxia Foundation, and the National Institutes of Health (grant no. NS33718).
Received May 28, 1998. Accepted in final form August 21, 1998.
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