2

M1

SECOND IIK"AII0NAL CONGRESS OF MOVEMEhT DISORDERS

Principles of molecular genetics/Dystonia

X.O. Breakefield, L. Ozelius, P. Kramer, D. de Leon, S. Bressman, N. Risch, D. Schuback, M. Brin, D. Kwiatkowski, J. Hewett, T. Gasser, J.F. Gusella, and S. Fahn Massachusetts General Hosp., Boston, MA , Oregon Health Sciences Univ., Portland, OR, Columbia Presbyterian Med. Ctr., New York, NY, Yale Sch. of Medicine, New Haven, CT USA

alcohol-responsive, myoclonic-dystonia (one in collaboration Dystonia is a syndrome characterized by sustained, with Drs. Jan Wahlstrom [Univ. Gbtheburg] and GSsta involuntary movements of a twisting or repetitive nature. Holmgren), and a family wth dystonia accompanied with Muscle spasms can be eneralized, as in tomon dystonia, or developmental delays. focal, as in torticollis, bfepharospasm, dysphonia and writer's cramp. A substantial fradon of p r i m e dystonias appear to have a genetic basis, with the highest frequency of the disease gene in the Ashkenazic Jewish population. Various distinct dystonic syndromes have been described in different pedigrees, including the early onset, generalized form torsion dystonia); paroxysmal dystonia; myoclonic dystonia alcohol-responsive); dystonia with Parkinsonian features dopa-responsive); and various late onset, focal dystonias. In

most types, including the Jewish form, inheritance follows an autosomal dominant mode with reduced penetrance (Breakefield and Bressman, 1987; Muller and Kupke, 1990; Risch et al, 1990; Pauls and Korayn, 1990), althou X- linked (Kupke et al, 1990; Wilhelmsen et al, 199lpand autosomal recessive forms have been described (Gimenez- Roldan et a1 1988; Eldridge, 1970).

Linkage analysis has been carried out b our grou to determine how man different genes un;fkrlie hereltary dystonia and where Key are located in the human enome. Initial studies revealed a disease gene, A, on chromosome 9 in the 934 band re ion for early onset, generalized d tonia in a non-Jewish $amily (Ozelius et al, 1989 and in k s h families (Kramer et al, 1990). This gene was Iodized to a 6 cM region between gene loci &$J and esS based on obligate recombination events in these families (Kwiatkowski et al, 1991a). Further resolution of the location of this gene was determined by analysis of normal variations in DNA se uenCe around it in the Ashkenazic Jewish population, &ere most cases are believed to be caused by the same mutation. These normal polymorphism near the mutation will tend to remain associated with it through succeedin generations. Usin highly informative ~ l y m o r p k s ~ defined by (GT(G8n repeat sequences, it as been ossible to define a haplotype which is present on 69% of t& disease-bearing chromosomes among affected Ashkenazic Jewish individuals (with and without a famil history of the illness) and less than 1% of control Jewisg chromosomes (Ozelius et al, in press). This finding su ports the idea that most cases of dystonia in the Ashkenazic fewish population are caused by the same mutation and su ests that most "S radic" cases in this population are actualf genetic, with a g k of family history being due to low penetrance and the fact that mild symptoms can go undi as well as e idemiologic analysis of Asrzt %E%s in the New?ork - New Jersey area,.increases the estimated fre uency of disease gene carriers in this population to about I/&. Further, most affected individuals were found to be heterozygous for the haplo associated with the disease gene, supporting a u t o s o d Z L x m t inheritance.

Linkage analysis has also been carried out in a number of non-Jewish families manifesting various forms of dystonia. Preliminary data suggest that this same gene on 9q34 is responsible for early onset, generalized dystonia in four families (one in collaboration with Dr. Anthony h g , Univ. Toronto) and for late onset, focal dystonia in one family (in collaboration with Dr. G6sta Holm en and Lars Forsgren, Univ. Hospital, Umea). In most of &se cases, the haplotype around the disease gene is different am0 families and distinct from that found in Ashkenazic Jews. % several other families with clinically distinct forms of tonia, this gene does not appear to be responsible; these in%de a family with early onset, dopa-responsive dystonia and parkinsonism in later life (Kwiatkowski et al, 1991b), two families with

In summary, our studies indicate that most familial cases of

that can cause familial dystonia with distinct clinical features.

R e f e r e m

Breakefield, X.O. and Bressman, S. In Movemnt D i s o r b Vol. 2. Eds. C.D. Marsden and S. Fahn) Butterworth Scienti $ ic, Boston, 1987.

Eldridge, R. Neurology 20 1078,1970.

Gimenez-Roldan, S., Delgado, G., Marin, M., Villanueva, J.A., and Mateo, D. Adv. Neurol. 5 0 73-81, 1988.

Kramer, P.L. de Leon, D., Ozelius, L, Risch, M., Brin, M.F., Bressman, S.B., Burke, R.E., Kwiatkowski, DJ., Schuback, D.E., Shale, H., Gusella, J.F., Breakefield, X.O. and Fahn, S. Ann. Neurol. 27: 114-120,1990.

Kupke, KG., Lee, LV., and Muller, U. Neurology 4 0 1438- 1442,1990.

Kwiatkowski, DJ., Ozelius, L, Kramer, P.L, Perman, S., Gusella, J.F., Fabn, S. and Breakefield, XO. Am. J. Hum. Gen. 49 366-371,1991&

Kwiatkowski, DJ., Nygaard, T.G., Scbuback, D.E., Perman, S., Bfessman, S., Burke, RE. Brin, M., Trugman, J., Ozehus, L, Breakefield, X.O., Fahn, S. and Kramer, P.L Am. J. Hum. Genet. 48: 121-128,1991b.

Muller, U. and Kupke, KG. Human Genet. 84: 107-115, 1990.

Ozelius, L, Kramer, P., de Leon, D., Risch, N., Bressman, S.B., Schuback, D.E., Brin, M.F., Kwiatkowski, DJ., Burke, R.E., Gusella, J.F., Fahn, S. and Breakefield, X.O. Am. J. Hum. Genet., in press.

Pauls, D. and Korayn, A. Neurology 40 1107-1110,1990.

Risch, N., Bressman, S.B., de Leon, D., Brin, M.F., Burke, R.E., Greene, P.E., Shale, H., Claus, E.G., Cu ples, LA., and Fahn, S. Am. J. Hum. Genet. 46 53l-538, 1990.

Wilhelmsen, KC., Weeks, D.E., Nygaard, T.G., Moskowitz, C.B., Rosales, R.L, dela Paz, D.C., Sobrevega, E.E., Fahn, S., and Gilliam, T.C. AM. Neurol. 29 124-31, 1991.

Movement Disorders, Vol. 7, Suppkm?U 1 (I%??)