Lindex #1602

Kwiatkowski DJ, Nygaard TG, Schuback DE, Perman S, Trugman JM, Bressman SB, Burke RE, Brin MF, Ozelius L, Breakfield XO, Fahn S, Kramer PL

Identification of a Highly Polymorphic Microsatellite VNTR within the Argininosuccinate Synthetase Locus: Exclusion of the Dystonia Gene on 9q32-34 as the Cause of Dopa-response Dystonia in a Large Kindred

American Journal of Human Genetics

1991; 48(1): 121-128

Torsion dystonia is a syndrome characterized by sustained, involuntary muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The occurrence of such symptoms in the absence of a known disease or identifiable biochemical disorder is classified as idiopathic torsion dystonia (ITD).

ITD occurs in both hereditary and sporadic forms. The inherited forms of the disease are generally autosomal dominant in nature although X-linked and autosomal recessive forms have been reported. ITD occurs with a ten-fold higher frequency among Ashkenazi Jews then in the general population. Disease expression is variable with penetrance estimates ranging from .3-.4 for Ashkenazi Jews and .75 for non-Jewish populations.

Dopa responsive dystonia (DRD) represents a variant of ITD that is clinically distinguished by frequent co occurrence of parkinsonism, diurnal fluctuation of symptom severity, and dramatic responsiveness to L-dopa treatments.

The authors demonstrated previously the linkage between the gene for dystonia (DYTZ) and the gelsolin (GSN) locus in non-Jewish families and between DYT1 and the argininosuccinate synthetase (ASS) locus in Jewish families. Since both the GSN and ASS loci have been mapped to I q32 - q34 with a recombination distance of only 14 centiMorgans, it has been proposed that the same gene is responsible for both of these hereditary forms of dystonia.

The authors investigated 110 members and 14 spouses of a family with DRD. Affected status for dystonia was assigned by at least two blinded neurologists with specialization in movement disorders. Demonstration of a response to L-dopa therapy in addition was required to assure conformity to the DRD phenotype before an assignment of definite DRD was made. Using the above protocol for clinical evaluation, nine of the 124 individuals were assessed to have definite DRD.

The DNA of these nine individuals in addition to 51 other members of the family was obtained for analysis. The authors discovered a (GT)n repeat sequence in the ASS locus and designed flanking sequence primers for PCR amplification of the region. Using the newly defined (GT)n microsatellite VNTR polymorphism within the ASS locus and six other conventional RFLPs from the 9q32-34 region, they calculating lod scores between each DNA marker and the DRD trait based on penetrance estimates of.35 an .05.

Three point analysis was carried out with the DRD trait and the D9S26 and ASS loci. These two loci were chosen because they were the most informative markers and they encompass the GSN locus, which proved to be uninformative.

The lod score was - 2 between the DRD trait and a region of 9q encompassing the 40 centiMorgans from 5cM proximal to D9S26 to llcM distal to ASS making the odds against linkage greater than 100:1. The authors excluded therefore the two previously identified loci responsible for ITD GSN and ASS as the site responsible for the DRD variant.