ORIGINAL ARTICLES

Dystonia Gene in Ashkenazi Jewish Population Is Located on Chromosome 9~32-34 Patricia L. Kramer, PhD," Deborah de Leon, MS,? Laurie Ozelius, BS,$ll Neil Fbsch, PhD,' Susan B. Bressman, MD,? Mitchell F. Brin, MD,? Deborah E. Schuback, BS,$ Robert E. Burke, MD,? David J. Kwiatkowski, PhD,§ Heidi Shale, MD,? James F. Gusella, PhD,$II" Xandra 0. Breakefield, PhD,$"" and Stanley Fahn, MD'F

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 (DYTI) in a nonJewish 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. Kramer PL, de Leon D, Ozelius L, Risch N, Bressman SB, Brin MF, Schuback DE, Burke RE, Kwiatkowski DJ, Shale H, Gusella JF, Breakefield XO, Fahn S. Dystonia gene in Ashkenazi Jewish population is located on chromosome 9q32-34. Ann Neurol 1990;27:114-120

Idiopathic torsion dystonia (ITD)is a neurological disorder characterized, by sustained muscle contractions that appear as twisting repetitive movements of the limbs, trunk, neck, or cranial muscles, which can progress to abnormal postures. The etiology remains unclear. Onset can occur in childhood, adolescence, or adulthood. Early-onset cases tend to cluster around age 9 and frequently progress to generalized physical impairment; later onset cases cluster around age 48 and symptoms often appear in more restricted or focal regions I l l . Accurate estimates of population prevalence of ITD are difficult to obtain, given variation in expression of the disease in terms of symptomatology, severity, and ethnic background. As is often the case, those individuals who seek medicai attention are more severely af-

fected, whereas those with milder manifestations of dystonic symptoms are underreported. ITD is estimated to be approximately five to ten times more common in Ashkenazi Jews (cumulative incidence of about 1/15,000 to 1/23,000 (2, 31) than in non-Ashkenazi Jews [2} or non-Jews 141. The genetics of inherited dystonia has been the subject of a number of recent studies. Nearly all forms appear to exhibit autosomal dominant inheritance with reduced penetrance. Ozelius and associates 15, 61 and Kramer and colleagues 171 have investigated a large, non-Jewish kindred in which the mode of inheritance is consistent with autosomal dominant transmission and penetrance is 0.75. Other recent studies of Ashkenazi Jewish populations give evidence for autosomal dominant transmission with penetrance estimates of

From the 'Neurology Department, Oregon Health Sciences University, Portland O R t Dystonia Clinical Research Center and Neurology Department, Columbia University College of Physicians and Surgeons, New York, NY; $Molecular Neurogenetics Laboratory (Neurology) and $Hematology-Oncology Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA; "Genetics Department and "Neuroscience Program, Harvard Medical School, Boston, MA; 'Department of Epidemiology and Public Health and Department of Human Genetics, Yale University Medical School, New Haven, CT; and **Molecular Neurogenetics Division, Eunice K. Shriver Center, Waltham, MA.

Received Sep 15, 1989, and in revised form Oct 18. Accepted for publication Oct 20, 1989. Address correspondence to Dr Kramer, Neurology Dept L-226, OHSU, 3181 SW Sam Jackson Park Rd, Portland, OR 97201.

114 Copyright 0 1990 by the American Neurological Association

0.30 to 0.40 C3, 8-10], although an earlier study suggested an autosomal recessive form of ITD in some Jewish families [4]. In addition, Lee and co-workers [ l l ]and Fahn and Moskowin C12) have reported an X-linked Filipino form of dystonia. These studies provide substantial evidence that different forms of ITD are single-locus disorders. Genetic linkage analysis, using DNA polymorphisms and protein markers, can be used to determine whether one gene is responsible for susceptibility to several forms of ITD or whether different genes are responsible for different forms. Ozelius and associates [ S , 61 performed genetic linkage analysis o n a large, nonJewish kindred in which 40 to 50% of the genome previously had been excluded for linkage with dystonia [13, 141. They found significant evidence for linkage of a gene responsible for susceptibility to dystonia (DYTI) o n chromosome 9, in the q32-34 region between ABO and D9S26. Location of a gene responsible for ITD in the Ashkenazi Jewish population would constitute a major step toward understanding the etiology and managing the symptoms of this disease, since the occurrence of ITD in this population is five to ten times higher than in other populations. We report results of a linkage study based o n 12 Ashkenazi Jewish families. Because of strong evidence for dominant transmission across study samples and because the Ashkenazi Jewish population is a genetic isolate, it is likely that the relatively high frequency of the ITD gene in this population is the result of random genetic drift E91. Thus, these families can be assumed to be a homogeneous group. T h e clinical syndrome of affected individuals in this group is similar to that in the non-Jewish kindred already discussed.

Methods Clinical Methods Ten families were ascertained for this study from a computerized database file of patients with ITD followed by members of the Movement Disorder Group at Columbia Presbyterian Medical Center, and 2 families were ascertained through the Dystonia Medical Research Foundation. The criteria for the diagnosis of primary versus secondary dystonia and designation as Ashkenazi Jewish were the same as those described by Bressman and colleagues 18). In each family, at least 1 family member had onset of dystonia symptoms before the age of 12 years. Ancestry was 100% Ashkenazi Jewish in 9 of the 12 families included in this study. In 1 family 1 grandparent of the affected individuals was Sephardic, in another family 1 grandparent of an affected member was non-Jewish, and in another family the mother of 2 affected individuals was non-Jewish; in no family was there evidence of inheritance through the non-Ashkenazi ancestor. Informed consent was obtained from 135 cooperative members of the 12 families. Complete on-site neurological

examinations were performed by neurologists (M.F.B., S.B.B., H.S.) experienced in evaluating dystonia; venous blood samples were obtained for lymphoblast transformation. On-site examination included evaluation of the face, jaw, tongue, voice, neck, trunk, and limbs, at rest and with action. Rapid successive and alternating movements of the limbs, finger-to-nose test, handwriting with each hand, and speaking and walking were assessed. All but 2 individuals also received a standardized videotape examination. Videotape examinations were reviewed by at least 2 nonexamining investigators (S.B.B., R.E.B., S.F., M.F.B.) who were blinded to the identity of the subjects. Each subject was classified as having definite dystonia, probable dystonia, possible dystonia, no dystonia, or unrateable. Definite dystonia was defined by twisting movements or postures that were characteristic of ITD and were apparent to all examiners. All individuals classified as definitely affected had both on-site and video examinations. Probable dystonia was diagnosed if (1) there were twisting movements or postures that were apparent to some but not all examiners (e.g., video rater versus onsite examiner), (2) if there was abnormal posturing of the arm with writing or excessive eye-blinking or foot posturing that was not sufficient to merit classification as definite dystonia, or (3) if detailed historical information indicated definite dystonia but the subject was no longer living or unable to undergo complete examination. Possible dystonia implied suggestive abnormalities that were not diagnostic of dystonia (e.g., clumsy, effordul, rapid foot-tapping or abnormally tense handwriting). Scoliosis alone was not considered diagnostic of dystonia unless there was also definite dystonia of another body part. When there were significant neurological abnormalities, such as stroke or Parkinson’s disease, that might mask the presence of dystonia, or when dystonia was present but there was a question as to etiology (e.g., neuroleptic exposure or birth injury), the designation unrateable was used. In 1 case (Family 1l),a definitely affected member had meconium staining and variable decelerations at birth, but a normal Apgar score, no history of resuscitation or neonatal seizures, and normal developmental milestones. On the basis of birth records and subsequent normal development, she was not considered to have had birth injury.

DNA Probes and Labeling DNA probes were labeled routinely with C3’P)dATP (3,000 CUmmol; Amersham, Arlington Heights, IL) by random oligonucleotide priming 115). Gel-purified insert fragments were used as probes for ASS, D9S29, GSN, AKl; dilutions were used for D9S26 and D9SlO. In some cases human placenta DNA was hybridized to labeled probes prior to hybridization with genomic DNA to saturate repeat sequences. The following polymorphic marker probes on 9q were used: ASSGl and ASSG3 (Hind111 and Prt I) for the argininosuccinate synthetase locus (ASS; q34-qter) 116, 17); pMCT136 (Pst I) for random VNTR (variable number of tandem repeats) locus D9SlO (q34 by linkage mapping) 118, 191; CRI-L659 (Taq I) for random locus D9S26 (q31-34 by linkage mapping) 120); M1D (Stu I) for the gelsolin locus (GSN;q32-34) [21,22}; Lamp92 (Taq I and Puu 11) for the random locus D9S29 (q31) 123); pAKlB3.25 (Taq I) for the

Gamer et ak Dystonia Gene on 9432-34 in Jews

115

Table I . Clinical Characteristics of Affected Individuals At Onset Family No.

Sex

Definite Dystonia" 1 F F 2 M M 3 M M 4 F

5

6 7 8

9 10 11 12

F F M F F M F M M F M M F F M F M M F F F F

Probable Dystonia" 4 M 8 F M 10 M

At Examination

Age (yr)

Site

Age (yr)

Regions Affected

8 14 7 15 8 16 7

R arm L arm R leg R arrn L leg R arm R leg

48 53 29 81 31 32 26

8 35 8 11 8 8 8 7 8 10 8 12 18 38 46 7

50 55 17 25 52 18 23 8 12 31 23 18 41 75 58

21

R leg R arm Both legs R leg R arm L leg L leg R leg R arm L leg R arm L leg Larynx R arm R arm Neck L arm L leg or R arm R leg L leg R arm Neck

34 28 45 12 38 65

Arms, neck, legs Arms, neck, trunk, legs Jaw, arms, legs R arm, legs Upper face, jaw, arms, legs, trunk Arms Upper and lower face, jaw, pharynx, larynx, neck, trunk, arms, legs Arms, neck, trunk, legs R arrn Lower face, arms, legs Arms, legs Neck, arms, trunk, R leg Larynx, R arm, trunk, R leg Tongue, arms, legs R arm, R leg Arms, legs Neck, arms, trunk, legs R arm R arm, L leg Larynx, R arm, L leg Jaw, lower face, neck, R arm Upper and lower face, neck, R arm Neck L arm, trunk R arm, L leg Arms, R leg Arms, trunk, legs Arms, trunk Neck, R arm

40

R arm

86 62 10 31

R arm Upper face Arms, trunk, legs L arm, trunk, R leg

?

11 7 6 10

? 7 ?

70

?

L leg ?

~

~

~~

~~~

"Definite and probable dystonia are explained in Clinical Methods section. R = right; L = left.

adenylate kinase-1 locus (MI; q32-34) [24, 251. References for map positions and restriction fragment length polymorphisms (RFL.Ps) for all loci except D9S29, ASS, and GSN are cited in 1261 or E271.

Denhardt's solution, 6 x sodium chloride/sodium citrate (SSC) containing salmon sperm DNA at 65°C; washed at 65°C in decreasing concentrations of SSC to 0.5 x , and exposed to x-ray film, as previously described [ 131.

RFLP Analyses

Linkage Analysis

DNA was extracted from lymphoblastoid lines 1281 or whole blood, as previously described [13, 291. Samples of DNA (5-10 p,g) were digested to completion with restriction enzymes according to the manufacturers' instructions. Electrophoresis was carried out routinely in 0.8% agarose gels at 70 to 90 V for 16 hours. DNA fragments were blotted onto Genetran nylon membranes (Plasco, Woburn, MA) by the method of Southern 1301. Filters were prehybridized and hybridized in 0.3% sodium dodecyl sulfate, 1x

Two strategies were used for designating status in the linkage analyses. First, only those individuals considered to have definite dystonia were designated as affected. These 29 individuals are distributed among the 12 families as indicated in Table 1. Second, analyses were done in which those individuals with probable dystonia were added to the group of 29, which resulted in 33 individuals designated as affected. The additional 4 cases occurred in Families 4, 8, and 10 (crosshatched in Fig 1). Results of the 2 sets of analyses were

116 Annals of Neurology Vol 27 N o 2 February 1990

I

2

4

3

w w w w

v

Multi-point analysis was done using the LINKMAP program from the LINKAGE computer package, version 4.7 1341. The stepwise age correction incorporated into this analysis is technically more precise than the correction used in the two-point analysis; in practice, however, differences are negligible. In these families, about 50% of affected individuals had onset by late childhood (8-9 years) and 75% had onset by late adolescence (16-17 years). This distribution was specified in terms of six liability classes, in which penetrance increased from 0.0 at age 5 to 0.30 at age 35, after which it remained constant at 0.30. No interference was assumed. The genetic map used as the basis for LINKMAP was generated using the Venezuelan Reference Pedigrees 1333. The maximum likelihood order and map distance estimates (6) were determined using the MAPMAKER program, version 1.0 1351. Other maps of various regions of chromosome 9q have been generated by Lathrop and co-workers { 197 and Donis-Keller and associates 120). Northrup and colleagues 1171recently localized the ASS gene within this region. With the exception of GSN, the markers we considered here are represented in at least one of these other maps. To the extent that comparisons can be made, the order of the markers and the map distances are generally consistent across published maps. Heterogeneity between families was examined by means of an admixture test and a beta test described in Risch 1361.

p"I.a""Jg+& . ... . ... ..

5

7

6

Dr0

0@

m

9

8

.. . . . . . . II

$ ..

12

..... LEGEND

0 = No definite dyslonia (includes unaffected, possible.and unraleable)

=.

Definite dyslonia = Probable dyslonia

a=Examined

a=

Deceased

Fag I . Pedigrees of 12 AshkenaziJewish families with idiopathic torsion dystonia.

similar. Thus, we report here only the results of the first strategy (i.e., individuals with definite dystonia considered affected). Individuals designated with possible dystonia were considered "unknown" with respect to status in all analyses. Two-point linkage analysis for the dystonia-to-marker comparisons was carried out using the LIPED program, version 3 131, 321, which incorporates an age correction. Autosomal dominant inheritance of a rare gene (frequency, 0.01%) was assumed, and penetrance was estimated at 0.30 [S, 91. Parameters for the age correction were based on empirical age-of-onset data on affected individuals in the 12 families presented here. Specifically,penetrance between the ages of 5 and 35 years increased in a straight line fashion from 0.0 to 0.30, respectively. Penetrance prior to age 5 was set at 0.0 and that after 35 was held constant to 0.30. Allele frequencies for the various markers used were estimated by counting alleles in these 12 families among founders and individuals who married into the families. Estimates were roughly comparable to those based on the Venezuelan Reference Pedigrees 1331 and the large non-Jewish kindred 151.

Results The 29 individuals classified as having definite dystonia are characterized in Table 1. Their ages at onset range from 6 to 46 years, with an average of 13.2 ? 1.9 and a median of 8.0. Four individuals were rated with probable dystonia; 2 of these had both on-site and video examinations, 1 refused a video examination and 1 was deceased prior to this study (a diagnosis of generalized dystonia had been made by treating neurologists and confirmed through medical records). These 4 individuals are characterized at the bottom of Table 1. Nine individuals were diagnosed with possible dystonia, and one was designated unrateable. Pedigree plots for all 12 families are presented in Figure 1. Given the recent finding of linkage between a dystonia locus (DYTI) and chromosome 9q markers in a non-Jewish kindred, in which the clinical profile of affected individuals was similar to that of affected individuals in these 12 Ashkenazi Jewish families, attention was focused in this study on chromosome 9. Linkage between the dystonia locus and a number of DNA marker probes on 9q, including those shown in Table 2, was evaluated by two-point analysis. Highest lod scores were obtained with a probe for the argininosuccinate synthetase locus, ASS. The dystonia and ASS loci showed significant evidence for linkage with a maximum likelihood estimate of theta (6) at 0.03 with a lod score (2) of 3.49. This corresponds to odds for linkage of 3090:l. The 1-lod-unit confidence interval for this estimate [i.e., the extent of the region o n either Kramer et al: Dystonia Gene on 9q32-34 in Jews

117

Table 2. Results of Pairwise Linkage Analysis of Idiopathic Torsion Dystonia and Chromosome 96 Markers -

Gene Symbol D9S29 D9S26 GSN AKl ASS D9SlO

~~

.oo

.05

.10

0.35

1.75 0.28 0.35 0.60 3.45 - 0.54

1.73 0.40 0.26 0.50 3.15 - 0.22

- 1.45

0.44 0.69 2.48 - 0.92

.20

.30

.40

1.37 0.36 0.11 0.32 2.27 0.00

0.90 0.23 0.02 0.17 1.36 0.03

0.43 0.10 -0.01 0.06 0.58 0.01

side of ASS within which the odds for linkage range from 309:l (2 = 2.49) to 3090:l) is approximately 0- 17 centiMorgans (cM). Two-point linkage results with other informative 9q markers in this region are included in Table 2. Positive lod scores were obtained for D9S29, D9S26, GSN, and MI. Negative lod scores were obtained with D9S10, which lies 5 to 10 cM distal to the ASS locus (1171; L. Ozelius, unpublished data, 1989). Multipoint analysis was carried out with the dystonia locus and D9S26, GSN, AKl, and ASS. These loci were chosen for several reasons. First, results of the two-point analyses gave suggestive evidence for linkage with this contiguous group of markers. Second, these markers encompass the region in which linkage for the DYTl locus was found in a non-Jewish family. Third, “working” linkage maps are available for this region of 94. Results of the multi-point analysis are presented graphically in Figure 2. On the basis of the data presented here, the most likely position of the dystonia locus is midway between AKl and ASS (2 = 3.54, odds of 3467 :1). The 1-lod-unit confidence interval for this estimate is approximately 0-18 cM; within this interval, odds for linkage range from 347 :1 (9 = 2.54) to 3467:l. There was no significant evidence for linkage heterogeneity ( p < 0.05) among the families reported here for any of the markers tested. The admixture test and the beta test used are discussed in detail by Risch

1361. Discussion Dystonia among Ashkenazi Jewish populations is a significant medical problem for several reasons: ( 1 ) the relatively high frequency of this dominant allele, (2) the low penetrance of the allele (about 0.30) that masks carrier status, and (3) the generally early age of onset, which is frequently associated with a more severe form of illness 1373. This study provides strong evidence that a gene causing susceptibility to ITD in a sample of Ashkenazi Jewish families is located in the 118 Annals of Neurology Vol 27

No 2 February 1990

&nax

Maximum Lod Score

0.07 0.13 0.00 0.00 0.03 0.30

1.77 0.41 0.44 0.69 3.49 0.03

map location

Fig 2. Multipoint analysis of ITD and 9q markers. Location map summarizing lod scores for dystonia at various map positions in a fixed marker map. Genetic distances between markers are given in centiMorgans (cM)and are calculated on the basis of sex-average recombination estimates. Marker names are given at top offigure.

q32-34 region of chromosome 9. Pairwise linkage analysis gives evidence for close linkage of this gene to the gene encoding argininosuccinate synthetase (ASS) (6 = 0.03, 2 = 3.49). Multipoint analysis suggests that the most likely position of this dystonia locus is within the interval between AKl and ASS (2 = 3.54). The 1-lod-unit confidence interval for this estimate spans the region from 2 cM distal to D9S26 to approximately 18 cM distal to ASS (see Fig 2). This finding corroborates evidence from previous work on a nonJewish kindred with a clinically similar form of ITD, which localized a dystonia gene (DYTl) to within 36 cM of GSN. GSN maps approximately 10 cM centromeric to AKl and 15 cM centromeric to ASS. The same gene may be responsible for susceptibility to ITD in these two populations. However, there is a substantial difference in the penetrance of the dominant allele (0.75 in the non-Jewish family, 0.30 in the Jewish families). One explanation may be that two different mutations at the same gene locus produce susceptibility to this disease in the two groups, a situation which characterizes a number of genetic disorders (e.g., hemoglobinopathies, Duchenne and Becker muscular dystrophy 138, 391).

As discussed by Ozelius and co-workers 151, this region of chromosome 9q contains 2 candidate genes: GSN, which encodes the actin-binding protein gelsolin, and DBH, which encodes the enzyme dopamine beta-hydroxylase that converts dopamine to norepinephrine. Linkage relationships of GSN and DBH with dystonia in these families is currently under study. It is encouraging that our results are compatible with previous linkage results on a different population. Further analysis is required to assess the role of genes in this region in other forms of inherited dystonia, including that in a large Swedish family with late onset 1401, dopa-responsive (several forms) 14 1-4 31, paroxysmal 1441, and myoclonic dystonia 145, 461. Nonetheless, these results establish the genomic region containing a dystonia gene that accounts for the occurrence of ITD in a major portion of the affected population. Characterization of this gene and its encoded protein should clarify the factors that confound the molecular basis of this disorder. This work was supported by the Dystonia Medical Research Foundation (X.O.B., J.F.G., P.L.K., and S.F.), the Henry J. Kaiser Family Foundation (X.O.B.), the Jim Pattison Foundation (X.O.B.), and National Institutes of Health grants NS26656 (S.F.), NS20012 (J.F.G.), HL01582 (D.J.K.), GM39812 (N.R.), and NS00746 (R.E.B.). The authors thank Ms Wendy Hobbs and Heather MacFarlane for establishment of lymphoblastoid lines; Drs Hope Northrup and Arthur Beaudet for supplying us with RFLP probes for the ASS locus; Dr Yusuke Nakamura for the VNTR probe pMCT136; Dr Moyra Smith for the probe for D9S29; Dr N. T. Bech-Hansen for the probe for MI;Dr Jonathan Haines for assistance in running the MAPMAKER program and for sharing his expertise in generating linkage maps; Drs Paul Greene, Un Kang and Torbjoern Nygwd for examining some of the family members; Ms Carol Moskowin and Linda Winfield for assistance with collecting blood samples; members of the families for their generous cooperation and for donating blood samples for study; and the Belzberg family for their continued encouragement, confidence, and unqualified support.

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39. McKusick VA. Mendelian inheritance in man. 8th ed. Baltimore: Johns Hopkins Press, 1988 40. Forsgren L, Holmgren G, Almay BGA, Drugge U. Autosomal dominant torsion dystonia in a Swedish family. Adv Neurol 1988;50:83-92 41. de Yebenes JG, Moskowitz C, Fahn S, Saint-Hilaire M-H. Long-term treatment with levodopa in a family with autosomal dominant torsion dystonia. Adv Neurol 1988;50:101-111 42. Nygaard TG, Marsden CD, Duvoisin RC. Dopa-responsive dystonia. Adv Neurol 1988;50:377-384 43. Segawa M, Hosake A, Miyyawa F. Hereditary progressive dystonia with marked diurnal fluctuation. Adv Neurol 1976;14: 215-233 44. Bressman SB, Fahn S, Burke RE. Paroxysmal non-kinesigenic dystonia. Adv Neurol 1988;50:403-413 45. Quinn NP, Rothwell JC, Thompson PD, Marsden CD. Hereditary myoclonic dystonia, hereditary torsion dystonia and hereditary essential myoclonus: an area of confusion. Adv Neurol 1988;50:391-401 46. Kurlan R, Behr J, Medved L, Shoulson I. Myoclonus and dystonia: a family study. Adv Neurol 1988;50:385-389

Correction A copyediting error was made in an abstract that appeared in the September issue of Annals (Leber SM, Breedlove SM, Sanes JR. Lineage of motoneurons in chick spinal cord studied with a retroviral marker. Ann Neurol 1989;26:447A). The sentence that reads:

“Clones were usually radial or planar in shape, with rostrocaudal spread of greater than 150 pm . . .” should read “. . . less than 150 p m . . .” Annals apologizes for this error.

120 Annals of Neurology

Vol 27

No 2 February 1990

Dystonia gene in Ashkenazi Jewish population is located on chromosome 9q32-34.

Idiopathic torsion dystonia (ITD) is a neurological disorder characterized by sustained muscle contractions that appear as twisting movements of the l...
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