This project is focused on locating the gene for """"""""dopa-responsive dystonia"""""""" (DRD), an autosomal dominant disorder. This disorder is a distinct subset of childhood-onset, idiopathic torsion dystonia (ITD), but has several features that separate it from ITD. In some cases it may have features suggestive of cerebral palsy, before clinical progression should allow separation of the disorders. Analysis of two families suggests that adult onset parkinsonism may be the clinical phenotype of gene carriers who do not manifest dystonia in childhood. This finding may have clinical relevance in some cases of hereditary parkinsonism. We propose to do linkage analysis on """"""""Family S,"""""""" the largest known kindred affected with DRD, to identify a chromosomal region linked to DRD. We will then use saturation mapping with known markers in the region or develop new markers by selective cloning methods to further delimit an obligate genetic region (OGR) for the DRD gene. We can then test for genetic heterogeneity with other smaller DRD families. A physical map of the OGR will be constructed by techniques such as pulse field gel electrophoresis and chromosome """"""""walking."""""""" Coding sequences will be identified by several cloning and hybridization strategies and """"""""candidate regions"""""""" compared in DNA between normal and affected individuals in an attempt to identify the disease locus. Identification of the gene for DRD may allow better understanding of the biochemical defect in DRD. Improved diagnostic reliability in childhood dystonic conditions and some forms of adult-onset parkinsonism should be possible.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HD000914-01
Application #
3081444
Study Section
Mental Retardation Research Committee (HDMR)
Project Start
1990-08-01
Project End
1993-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Takahashi, H; Levine, R A; Galloway, M P et al. (1994) Biochemical and fluorodopa positron emission tomographic findings in an asymptomatic carrier of the gene for dopa-responsive dystonia. Ann Neurol 35:354-6
Lasser, D M; Wilhelmsen, K C; Nygaard, T G et al. (1993) Characterization of microsatellite polymorphisms DXS691 and DXS692: genetic mapping to Xq26.2-Xq27 and Xq25-Xq26.2. Genomics 16:785-6
Nygaard, T G (1993) Dopa-responsive dystonia. Delineation of the clinical syndrome and clues to pathogenesis. Adv Neurol 60:577-85
Nygaard, T G; Wilhelmsen, K C; Risch, N J et al. (1993) Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q. Nat Genet 5:386-91
Snow, B J; Nygaard, T G; Takahashi, H et al. (1993) Positron emission tomographic studies of dopa-responsive dystonia and early-onset idiopathic parkinsonism. Ann Neurol 34:733-8
Waters, C H; Takahashi, H; Wilhelmsen, K C et al. (1993) Phenotypic expression of X-linked dystonia-parkinsonism (lubag) in two women. Neurology 43:1555-8
Nygaard, T G; Takahashi, H; Heiman, G A et al. (1992) Long-term treatment response and fluorodopa positron emission tomographic scanning of parkinsonism in a family with dopa-responsive dystonia. Ann Neurol 32:603-8