title: Heterogeneity in primary dystonia: lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites.
abstract: A founder mutation in the Thanatos-associated (THAP) domain containing, apoptosis associated protein 1 (THAP1) 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 THAP1 and for guanine nucleotide binding protein (G protein), α-activating activity polypeptide, olfactory type (GNAL) mutations and genotype-phenotype comparisons were performed for 76 individuals of Amish-Mennonites heritage with primary dystonia. Twenty-seven individuals had mutations in THAP1-most with the founder indel mutation-but two had different THAP1 mutations, 8 had mutations in GNAL, and 1 had a de novo GAG deletion in torsin 1A (TOR1A) (dystonia 1 [DYT1]). In the primary analysis comparing THAP1 carriers versus all non-THAP1, non-GNAL, non-TOR1A individuals, age at onset was lower in THAP1 carriers (mean age ± standard deviation, 15.5 ± 9.2 years [range, 5-38 years] vs. 39.2 ± 17.7 years [range, 1-70 years]; P < 0.001), and THAP1 carriers were more likely to have onset of dystonia in an arm (44.4% vs. 15.0%; P = 0.02) and to have arm involvement (88.9% vs. 22.5%; P < 0.01), leg involvement (51.9% vs. 10.0%; P = 0.01), and jaw/tongue involvement (33.3% vs. 7.5%; P = 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; P < 0.01) and were less likely to have dystonia onset in cervical regions (25.9% of THAP1 carriers vs. 52.5% of noncarriers; P = 0.04). Primary dystonia in the Amish-Mennonites is genetically diverse and includes not only the THAP1 indel founder mutation but also different mutations in THAP1 and GNAL as well as the TOR1A GAG deletion. Phenotype, particularly age at onset combined with final distribution, may be highly specific for the genetic etiology.
authors: Department of Neurology, Beth Israel Medical Center, New York, New York, USA; Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Rachel
authors: R
authors: Saunders-Pullman
authors: Tania
authors: T
authors: Fuchs
authors: Marta
authors: M
authors: San Luciano
authors: Deborah
authors: D
authors: Raymond
authors: Alison
authors: A
authors: Brashear
authors: Robert
authors: R
authors: Ortega
authors: Andres
authors: A
authors: Deik
authors: Laurie J
authors: LJ
authors: Ozelius
authors: Susan B
authors: SB
authors: Bressman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061365:Amish; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D020821:Dystonic Disorders / Q000208:ethnology / Q000235:genetics*; D005192:Family Health; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D044385:GTP-Binding Protein alpha Subunits; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C474080:THAP1 protein, human; C108175:TOR1A protein, human; C084618:olfactory G protein subunit alpha olf
keywords: Amish, Mennonites; GNAL; THAP1; dystonia; genetics