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Idiopathic torsion dystonia (ITD) is a neurological disorder characterized by sustained muscle contractions that appear as twisting movements of the limbs, trunk, and/or neck, which can progress to abnormal postures. Most familial forms of ITD follow autosomal dominant transmission with reduced penetrance. The frequency of ITD in the Ashkenazi Jewish population is five to ten times greater than that in other groups. Recently, a gene for ITD (DYT1) in a non-Jewish kindred was located on chromosome 9q32-34, with tight linkage to the gene encoding gelsolin (GSN). In the present study linkage analysis using DNA polymorphisms is used to locate a gene responsible for susceptibility to ITD in 12 Ashkenazi Jewish families. This dystonia gene exhibits close linkage with the gene encoding argininosuccinate synthetase (ASS), and appears by multipoint analysis to lie in the q32-34 region of chromosome 9, a region that also contains the loci for gelsolin and dopamine-beta-hydroxylase. The same gene may be responsible for ITD both in the non-Jewish kindred mentioned above and in the Ashkenazi Jewish families presented here. However, because there is substantial difference between the penetrance of the dominant allele in these two groups, two different mutations may be operating to produce susceptibility to this disease in the two groups.

Medical treatment of dystonia usually results in an incomplete response and is frequently unsuccessful. Peripheral surgical therapy is available for some focal dystonias, but may only offer temporary relief and may have unacceptable complications. We have used local injections of botulinum toxin into the appropriate muscles for treatment of disabling focal or segmental dystonia in 93 patients with torticollis, blepharospasm, oromandibular dystonia (OMD), limb dystonia, lingual dystonia, and dystonia adductor dysphonia, in addition to four patients with hemifacial spasm. Significant relief of motor symptoms was seen in 69% of the patients with blepharospasm and 64% of patients with torticollis; 74% of the latter group with pain experience relief. Relief of symptoms was noted in most patients with OMD and limb dystonia, and all with lingual dystonia, dystonic adductor spastic dysphonia, and those with hemifacial spasm. Benefit averaged 2 1/2-3 months initially; however some patients experienced longer relief with subsequent injections. Adverse effects were transient, although 2 patients developed antibodies against the toxin, and we documented evidence for distant effects in others. This approach of chemically weakening contracting muscles in focal dystonia offers many advantages over pharmacotherapy and surgical therapy. Additional experience is needed to explore the proper doses, and potential for long term adverse effects.

We studied families to clarify the mode of inheritance of idiopathic torsion dystonia among the Ashkenazim. Probands had symptoms before 28 years of age, had at least one Ashkenazi grandparent, and were ascertained independently of family history and not referred by another relative. All available first- and second-degree relatives were examined, and videotapes were made. Examination notes and blinded review of videotapes led to rating of dystonia as definite, probable, possible, or absent. We determined rates of illness for first- and second-degree relatives and calculated age-adjusted lifetime risks. The methods of maximum likelihood and likelihood ratio goodness-of-fit tests were used to estimate parameters and to test dominant and recessive models of inheritance. We studied 43 probands, 146 (90.1%) of 162 living first-degree relatives, and 96 (40.2%) of 239 living second-degree relatives. Nineteen relatives had definite dystonia, and 2 had probable dystonia. Using definite cases only, the age-adjusted risk for all first-degree relatives was 15.5% and for all second-degree relatives 6.5%, with no significant sex differences; parent, offspring, and sibling risks did not differ significantly. The risks were consistent with autosomal dominant inheritance with a penetrance estimated at 29.4% using definite cases only or 32.2% using definite and probable cases. Assuming a disease frequency of 1/15,000, the gene frequency was estimated to be 1/9000.