Dystonia is a disabling neurological disorder characterized by involuntary twisting movements and postures. Dystonia may be idiopathic or secondary to known environmental or metabolic factors. No marker, pathological or biochemical, has been identified in idiopathic dystonia. However based on clinical and ethnic criteria and familial patterns, subtypes have been described and genetic heterogeneity proposed. Included in these subtypes are (1) Ashkenazi Jews, (2) non- Jewish caucasians and (3) non-Ashkenazi caucasians with dopa responsiveness. Because of our rich resource of patients, clinical expertise, and team of experienced geneticists, we are in a unique position to locate and ultimately identify the defective gene(s) underlying idiopathic dystonia and establish whether the same locus is involved in each group through linkage heterogeneity test. We propose to perform linkage studies on families that are representative of the three subtypes of dystonia described above. Detailed and unbiased clinical assessment of informative large and small families will be performed. Blood samples from informative family members will be collected for DNA and protein marker determination. We will search for a linked marker within individual large families ethnic subtype. We will test for genetic heterogeneity both within and between subgroups. Once a linked marker to one or more disease subtypes is found, we will define further the genomic region containing the dystonia gene with the ultimate aim of identification of the defective gene. The results of this study are directly applicable in the clinical setting. Finding a closely linked marker will allow for reliable risk assessment in counseling of families. Further identification of the mutant gene will ultimately elucidate the mechanism(s) underlying this mysterious disorder and could provide a basis for specific treatment.
| Mirelman, Anat; Alcalay, Roy N; Saunders-Pullman, Rachel et al. (2015) Nonmotor symptoms in healthy Ashkenazi Jewish carriers of the G2019S mutation in the LRRK2 gene. Mov Disord 30:981-6 |
| Saunders-Pullman, Rachel; Fuchs, Tania; San Luciano, Marta et al. (2014) Heterogeneity in primary dystonia: lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites. Mov Disord 29:812-8 |
| Fuchs, Tania; Saunders-Pullman, Rachel; Masuho, Ikuo et al. (2013) Mutations in GNAL cause primary torsion dystonia. Nat Genet 45:88-92 |
| Bressman, Susan B; Raymond, Deborah; Fuchs, Tania et al. (2009) Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study. Lancet Neurol 8:441-6 |
| Raymond, Deborah; Saunders-Pullman, Rachel; de Carvalho Aguiar, Patricia et al. (2008) Phenotypic spectrum and sex effects in eleven myoclonus-dystonia families with epsilon-sarcoglycan mutations. Mov Disord 23:588-92 |
| Risch, Neil J; Bressman, Susan B; Senthil, Geetha et al. (2007) Intragenic Cis and Trans modification of genetic susceptibility in DYT1 torsion dystonia. Am J Hum Genet 80:1188-93 |
| Bressman, Susan B (2007) Genetics of dystonia: an overview. Parkinsonism Relat Disord 13 Suppl 3:S347-55 |
| Saunders-Pullman, Rachel; Raymond, Deborah; Senthil, Geetha et al. (2007) Narrowing the DYT6 dystonia region and evidence for locus heterogeneity in the Amish-Mennonites. Am J Med Genet A 143A:2098-105 |
| Heiman, Gary A; Ottman, Ruth; Saunders-Pullman, Rachel J et al. (2007) Obsessive-compulsive disorder is not a clinical manifestation of the DYT1 dystonia gene. Am J Med Genet B Neuropsychiatr Genet 144B:361-4 |
| Hess, C W; Raymond, D; Aguiar, P de Carvalho et al. (2007) Myoclonus-dystonia, obsessive-compulsive disorder, and alcohol dependence in SGCE mutation carriers. Neurology 68:522-4 |
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