Dystonia in Ashkenazi Jews: Clinical characterization of a founder mutation

Susan B. Bressman, Deborah De Leon, Patricia L. Kramer, Laurie J. Ozelius, Mitchell F. Brin, Paul E. Greene, Stanley Fahn, Xandra O. Breakefield, Neil J. Risch

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Abstract

A gene (DYT1) for idiopathic torsion dystonia maps to chromosome 9q34 in Ashkenazi Jewish families with early onset of symptoms. Further, there is linkage disequilibrium between DYT1 and a particular haplotype of alleles at 9q34 loci in this population. This implies that a large proportion of early- onset idiopathic torsion dystonia in Ashkenazi Jews is due to a founder mutation in DYT1. To characterize the phenotypic range of this mutation, we studied 174 Ashkenazi Jewish individuals affected with idiopathic torsion dystonia. We used GT(n) markers on chromosome 9q34 (D9S62, D9S63, and ASS) and classified individuals as having ('carriers'), not having ('noncarriers'), or being ambiguous with respect to a DYT1-associated haplotype. We assessed clinical features and found marked clinical differences between haplotype carriers and noncarriers. There were 90 carriers, 70 noncarriers, and 14 ambiguous individuals. The mean age at onset of symptoms was significantly lower in carriers than in noncarriers (12.5 ± 8.2 vs 36.5 ± 16.4 years). In 94% of carriers, symptoms began in a limb (arm or leg equally), rarely the disorder started in the neck (3.3%) or larynx (2.2%). In contrast, the neck, larynx, and other cranial muscles were the sites of onset in 79% of noncarriers; onset in the arms occurred in 21% and onset in the legs never occurred. Limb onset, leg involvement in the course of disease, and age at onset distinguished haplotype carriers from noncarriers with 90% accuracy. In conclusion, there are clinical differences between Ashkenazi Jewish individuals with idiopathic torsion dystonia who do or do not have a unique DYT1 mutation, as determined by a DYT1-associated haplotype of 9q34 alleles. These differences suggest that early, limb-onset idiopathic torsion dystonia and late, cervical cranial-onset idiopathic torsion dystonia are genetically distinct entities.

Original languageEnglish (US)
Pages (from-to)771-777
Number of pages7
JournalAnnals of Neurology
Volume36
Issue number5
DOIs
StatePublished - Nov 1994

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Dystonia Musculorum Deformans
Jews
Dystonia
Haplotypes
Mutation
Leg
Extremities
Larynx
Age of Onset
Arm
Neck
Alleles
Linkage Disequilibrium
Genetic Markers
Chromosomes
Muscles
Population

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Bressman, S. B., De Leon, D., Kramer, P. L., Ozelius, L. J., Brin, M. F., Greene, P. E., ... Risch, N. J. (1994). Dystonia in Ashkenazi Jews: Clinical characterization of a founder mutation. Annals of Neurology, 36(5), 771-777. https://doi.org/10.1002/ana.410360514

Dystonia in Ashkenazi Jews : Clinical characterization of a founder mutation. / Bressman, Susan B.; De Leon, Deborah; Kramer, Patricia L.; Ozelius, Laurie J.; Brin, Mitchell F.; Greene, Paul E.; Fahn, Stanley; Breakefield, Xandra O.; Risch, Neil J.

In: Annals of Neurology, Vol. 36, No. 5, 11.1994, p. 771-777.

Research output: Contribution to journalArticle

Bressman, SB, De Leon, D, Kramer, PL, Ozelius, LJ, Brin, MF, Greene, PE, Fahn, S, Breakefield, XO & Risch, NJ 1994, 'Dystonia in Ashkenazi Jews: Clinical characterization of a founder mutation', Annals of Neurology, vol. 36, no. 5, pp. 771-777. https://doi.org/10.1002/ana.410360514
Bressman SB, De Leon D, Kramer PL, Ozelius LJ, Brin MF, Greene PE et al. Dystonia in Ashkenazi Jews: Clinical characterization of a founder mutation. Annals of Neurology. 1994 Nov;36(5):771-777. https://doi.org/10.1002/ana.410360514
Bressman, Susan B. ; De Leon, Deborah ; Kramer, Patricia L. ; Ozelius, Laurie J. ; Brin, Mitchell F. ; Greene, Paul E. ; Fahn, Stanley ; Breakefield, Xandra O. ; Risch, Neil J. / Dystonia in Ashkenazi Jews : Clinical characterization of a founder mutation. In: Annals of Neurology. 1994 ; Vol. 36, No. 5. pp. 771-777.
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abstract = "A gene (DYT1) for idiopathic torsion dystonia maps to chromosome 9q34 in Ashkenazi Jewish families with early onset of symptoms. Further, there is linkage disequilibrium between DYT1 and a particular haplotype of alleles at 9q34 loci in this population. This implies that a large proportion of early- onset idiopathic torsion dystonia in Ashkenazi Jews is due to a founder mutation in DYT1. To characterize the phenotypic range of this mutation, we studied 174 Ashkenazi Jewish individuals affected with idiopathic torsion dystonia. We used GT(n) markers on chromosome 9q34 (D9S62, D9S63, and ASS) and classified individuals as having ('carriers'), not having ('noncarriers'), or being ambiguous with respect to a DYT1-associated haplotype. We assessed clinical features and found marked clinical differences between haplotype carriers and noncarriers. There were 90 carriers, 70 noncarriers, and 14 ambiguous individuals. The mean age at onset of symptoms was significantly lower in carriers than in noncarriers (12.5 ± 8.2 vs 36.5 ± 16.4 years). In 94{\%} of carriers, symptoms began in a limb (arm or leg equally), rarely the disorder started in the neck (3.3{\%}) or larynx (2.2{\%}). In contrast, the neck, larynx, and other cranial muscles were the sites of onset in 79{\%} of noncarriers; onset in the arms occurred in 21{\%} and onset in the legs never occurred. Limb onset, leg involvement in the course of disease, and age at onset distinguished haplotype carriers from noncarriers with 90{\%} accuracy. In conclusion, there are clinical differences between Ashkenazi Jewish individuals with idiopathic torsion dystonia who do or do not have a unique DYT1 mutation, as determined by a DYT1-associated haplotype of 9q34 alleles. These differences suggest that early, limb-onset idiopathic torsion dystonia and late, cervical cranial-onset idiopathic torsion dystonia are genetically distinct entities.",
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