Heterogeneity in primary dystonia: Lessons from THAP1, GNAL, and TOR1A in Amish‐Mennonites. Issue 6 (5th February 2014)

• Record Type: Journal Article
• Authors: Saunders‐Pullman, Rachel; Fuchs, Tania; San Luciano, Marta; Raymond, Deborah; Brashear, Alison; Ortega, Robert; Deik, Andres; Ozelius, Laurie J.; Bressman, Susan B.
• Is Part Of: Movement disorders. Volume 29:Issue 6(2014)
• Page Start: 812
• Page End: 818
• Publication Date: 2014-02-05
• Subjects: Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.25818
• Languages: English
• ISSNs: 0885-3185

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>A founder mutation in the Thanatos‐associated (THAP) domain containing, apoptosis associated protein 1 (<italic>THAP1</italic>) gene causing primary dystonia was originally described in the Amish‐Mennonites. However, there may be both genotypic and phenotypic heterogeneity of dystonia in this population that may also inform studies in other ethnic groups. Genotyping for <italic>THAP1</italic> and for guanine nucleotide binding protein (G protein), α‐activating activity polypeptide, olfactory type (<italic>GNAL</italic>) mutations and genotype‐phenotype comparisons were performed for 76 individuals of Amish‐Mennonites heritage with primary dystonia. Twenty‐seven individuals had mutations in <italic>THAP1</italic>—most with the founder indel mutation—but two had different <italic>THAP1</italic> mutations, 8 had mutations in <italic>GNAL</italic>, and 1 had a de novo GAG deletion in torsin 1A (<italic>TOR1A</italic>) (dystonia 1 [<italic>DYT1</italic>]). In the primary analysis comparing <italic>THAP1</italic> carriers versus all non‐<italic>THAP1</italic>, non‐<italic>GNAL</italic>, non‐<italic>TOR1A</italic> individuals, age at onset was lower in <italic>THAP1</italic> carriers (mean age ± standard deviation, 15.5 ± 9.2 years [range, 5‐38 years] vs. 39.2 ± 17.7 years [range, 1‐70 years]; <italic>P</italic> < 0.001), and <italic>THAP1</italic> carriers were more likely to have onset of dystonia in an arm (44.4% vs. 15.0%; <italic>P</italic> = 0.02) and to have arm involvement (88.9% vs. 22.5%; <italic>P</italic> < 0.01), leg involvement (51.9% vs. 10.0%; <italic>P</italic> = 0.01), and jaw/tongue involvement (33.3% vs. 7.5%; <italic>P</italic> = 0.02) involvement at their final examination. Carriers were less likely to have dystonia restricted to a single site (11.11% in carriers vs. 65.9% in noncarriers; <italic>P</italic> < 0.01) and were less likely to have dystonia onset in cervical regions (25.9% of <italic>THAP1</italic> carriers vs. 52.5% of noncarriers; <italic>P</italic> = 0.04). Primary dystonia in the Amish‐Mennonites is genetically diverse and includes not only the <italic>THAP1</italic> indel founder mutation but also different mutations in <italic>THAP1</italic> and <italic>GNAL</italic> as well as the <italic>TOR1A</italic> GAG deletion. Phenotype, particularly age at onset combined with final distribution, may be highly specific for the genetic etiology. © 2014 International Parkinson and Movement Disorder Society</p> </abstract>