TY - JOUR
T1 - Genotype-phenotype correlations in THAP1 dystonia
T2 - Molecular foundations and description of new cases
AU - LeDoux, Mark S.
AU - Xiao, Jianfeng
AU - Rudzińska, Monika
AU - Bastian, Robert W.
AU - Wszolek, Zbigniew K.
AU - Van Gerpen, Jay A.
AU - Puschmann, Andreas
AU - Momčilović, Dragana
AU - Vemula, Satya R.
AU - Zhao, Yu
N1 - Funding Information:
This study was supported by the Neuroscience Institute at the University of Tennessee Health Science Center (M.S.L.), Dystonia Medical Research Foundation (M.S.L. and Z.K.W.), NIH grants R01NS048458 and R01NS069936 (M.S.L.), NIH U54 Dystonia Coalition ( 1U54NS065701 ) Pilot Projects Program (M.S.L.), and the Parkinson’s & Movement Disorder Foundation (M.S.L.). At Mayo Clinic Florida, work was supported by the NIH National Institute of Neurological Disease and Stroke Morris K. Udall Center of Excellence for Parkinson Disease Research grant ( P50-NS57567 and P50 NS072187-01S2 ) (Z.K.W. and J.A.VG.), NINDS R01 NS057567 (Z.K.W.), NINDS 1RC2NS070276 (Z.K.W.), and CR 90052030 Mayo Clinic Jacksonville Research Committee (Z.K.W. and J.A.VG). A.P. received funding from the Swedish Parkinson Academy . The Swedish patient was cared for by the Clinical Movement Disorders Team at Skåne University Hospital, Lund, Sweden, where Dr. Lars Wictor, Department of Neurology, recorded the pre-operative video, and Dr. Hjalmar Bjartmarz, Department of Neurosurgery, performed the surgical procedure and was responsible for clinical follow-up and DBS adjustments.
PY - 2012/6
Y1 - 2012/6
N2 - An extensive variety of THAP1 sequence variants have been associated with focal, segmental and generalized dystonia with age of onset ranging from 3 to over 60 years. In previous work, we screened 1114 subjects with mainly adult-onset primary dystonia (Neurology 2010; 74:229-238) and identified 6 missense mutations in THAP1. For this report, we screened 750 additional subjects for mutations in coding regions of THAP1 and interrogated all published descriptions of THAP1 phenotypes (gender, age of onset, anatomical distribution of dystonia, family history and site of onset) to explore the possibility of THAP1 genotype-phenotype correlations and facilitate a deeper understanding of THAP1 pathobiology. We identified 5 additional missense mutations in THAP1 (p.A7D, p.K16E, p.S21C, p.R29Q, and p.I80V). Three of these variants are associated with appendicular tremors, which were an isolated or presenting sign in some of the affected subjects. Abductor laryngeal dystonia and mild blepharospasm can be manifestations of THAP1 mutations in some individuals. Overall, mean age of onset for THAP1 dystonia is 16.8 years and the most common sites of onset are the arm and neck, and the most frequently affected anatomical site is the neck. In addition, over half of patients exhibit either cranial or laryngeal involvement. Protein truncating mutations and missense mutations within the THAP domain of THAP1 tend to manifest at an earlier age and exhibit more extensive anatomical distributions than mutations localized to other regions of THAP1.
AB - An extensive variety of THAP1 sequence variants have been associated with focal, segmental and generalized dystonia with age of onset ranging from 3 to over 60 years. In previous work, we screened 1114 subjects with mainly adult-onset primary dystonia (Neurology 2010; 74:229-238) and identified 6 missense mutations in THAP1. For this report, we screened 750 additional subjects for mutations in coding regions of THAP1 and interrogated all published descriptions of THAP1 phenotypes (gender, age of onset, anatomical distribution of dystonia, family history and site of onset) to explore the possibility of THAP1 genotype-phenotype correlations and facilitate a deeper understanding of THAP1 pathobiology. We identified 5 additional missense mutations in THAP1 (p.A7D, p.K16E, p.S21C, p.R29Q, and p.I80V). Three of these variants are associated with appendicular tremors, which were an isolated or presenting sign in some of the affected subjects. Abductor laryngeal dystonia and mild blepharospasm can be manifestations of THAP1 mutations in some individuals. Overall, mean age of onset for THAP1 dystonia is 16.8 years and the most common sites of onset are the arm and neck, and the most frequently affected anatomical site is the neck. In addition, over half of patients exhibit either cranial or laryngeal involvement. Protein truncating mutations and missense mutations within the THAP domain of THAP1 tend to manifest at an earlier age and exhibit more extensive anatomical distributions than mutations localized to other regions of THAP1.
KW - DYT6
KW - Dystonia
KW - Spasmodic dysphonia
KW - THAP1
KW - Tremor
UR - http://www.scopus.com/inward/record.url?scp=84862807301&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862807301&partnerID=8YFLogxK
U2 - 10.1016/j.parkreldis.2012.02.001
DO - 10.1016/j.parkreldis.2012.02.001
M3 - Review article
C2 - 22377579
AN - SCOPUS:84862807301
SN - 1353-8020
VL - 18
SP - 414
EP - 425
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
IS - 5
ER -