2nd Workshop Neurogenetics in Germany, Munich, October 19-21, 1995
Idiopathic torsion dystonia (ITD)
Idiopathic torsion dystonia (ITD) is a movement disorder characterized by sustained muscle contractions, causing twisting movements and postures that are not attributed to exogenous factors (i.e. trauma, neuroleptics) or other neurological disorders (i.e. Wilsonís disease, Parkinsonís disease) (Fahn et al., 1987). Clinical variation is extreme, ranging from focal involvement of a single body region, to generalized involvement of the limbs and trunk. This clinical variation most probably leads to the underestimation of the prevalence of ITD as many patients go undiagnosed. The frequency of the disease has been estimated at 1/160,000 in the general population (Zeman and Dykan, 1967) with a higher frequency of 1/15,000 in the Ashkenazi Jews (AJ)(Zilber et al., 1984). Recently, using our genotyping data and patient database, we have determined that the frequency of the disease in the Ashkenazi population is likely to lie in the range of 1/6000 to 1/2000 (Risch et al, 1995).
The molecular etiology of ITD is unknown and clues garnered from pathological, biochemical and pharmacological studies provide few insights. Brains from patients with ITD do not display any marked neuropathologic changes (Zeman and Dyken, 1967; Zeman, 1970; Hedreen et al, 1988), although brains from individuals with nongenetic dystonia frequently reveal abnormalities in the basal ganglia (Marsden et al, 1985; Rothwell and Obeso, 1987), which implicates this area of the brain as being involved in the development of ITD. Results of studies measuring the concentration of various neurotransmitters and their metabolites in the cerebral spinal fluid of patients with ITD have not revealed any consistently marked abnormalities (Tabaddor et al, 1978; Perry et al, 1982), but in several cases of early onset dystonia, increased levels of norepinephrine (NE) have been reported in various nuclei of the brainstem (Hornykiewizc et al, 1988;). L-DOPA, D2 receptor antagonists and anticonvulsants can all induce dystonic symptoms (Fahn et al., 1987). Anticholinergics, benzodiazepines and carbamazepine can alleviate symptoms in some patients but overall, there is no consistently effective drug treatment.
There are at least seven clinically distinct types of hereditary dystonia: early onset, generalized dystonia; late onset, focal dystonia; dopa-responsive dystonia; alcohol-responsive myoclonic dystonia; rapid onset dystonia with Parkinsonism; paroxysmal dystonia and an X-linked recessive form with parkinsonian features (for review see Kramer et al, 1995; Gasser et al, 1992). Except for the X-linked form, all are inherited as autosomal dominant traits with low penetrance. Dopa-responsive dystonia (DRD) has been mapped to chromosome 14q (Nygaard et. al, 1993) and mutations in the GTP cyclohydrolase I gene have been found in DRD families (Ichinose et. al, 1994) suggesting that this is the causative gene for this disorder. The X-linked form has been linked to markers in Xq13.1 (Haberhausen et. al, 1995)while the early onset form maps to 9q34 (Ozelius et. al, 1989).
Having established linkage between a gene for ITD and DNA markers in the 9q34 region in a large non-Jewish (NJ) pedigree (Ozelius et al, 1989) and in a collection of AJ families (Kramer et al, 1990), we subsequently identified strong allele association between the DYT1 locus and a particular haplotype at the ASS/ABL loci in early onset affected Ashkenazi Jews (Ozelius et al., 1992). This observation suggested that these loci were within 1-2 cM of the DYT1 gene and lent support to the idea that a single mutational event is responsible for most cases of early onset dystonia in the AJ population. Extending the linkage disequilibrium study to surrounding markers, a six allele haplotype was defined that marks the primordial chromosome on which the original mutation occurred in this population. Using this haplotype we were able to gain several insights into its origin and manifestations. The mutation arose about 350 years ago in the AJ population somewhere near Lithuania and Byelorussia (Risch et al., 1995). The founder haplotype correlates with a phenotype, i.e. 90% of affected haplotype carriers had early limb-onset dystonia, whereas those AJ affecteds without the haplotype had late, cervical cranial-onset dystonia (Bressman et al., 1994). Non-Jewish families with the early onset phenotype show linkage to the DYT1 gene but have distinct haplotypes, supporting the idea that different mutations in the DYT1 gene are responsible for ITD in the AJ and NJ populations (Kramer et al., 1994). Lastly, it has been possible to define the region containing the DYT1 gene by identifying early onset affected AJ individuals who retain only a portion of the haplotype and therefore represent historic recombination events occurring sometime in the last 350 years. A yeast artificial chromosome (YAC) contig has been constructed encompassing the critical region which spans 500-600 kb. Seven new polymorphic markers generated and physically localized on the contig have been used to reassess the position of historic recombination events. This analysis placed the DYT1 gene within a small interval. Cosmids containing this interval were isolated from chromosome 9 specific libraries and then subcloned into an exon amplification vector (Buckler et al., 1991; Church et al., 1994) to identify exons from this region. Various cDNA libraries were screened with the exons and five transcripts were obtained that map to the minimal genetic region implicated by the haplotype analysis. Mutational analysis of these transcripts is underway.
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