Non-DYT1 dystonia in a large Italian family

Downloaded from jnnp.bmj.com on July 14, 2011 - Published by group.bmj.com 357 J7oumnal of Neurology, Neurosurgery, and Psychiatry 1997;62:357-360 Non-DYTl dystonia in a large Italian family A R Bentivoglio, N Del Grosso, A Albanese, E Cassetta, P Tonali, M Frontali Abstract A large non-Jewish Italian family affected by idiopathic torsion dystonia with autosomal dominant transmission and almost complete penetrance is reported. The prevalent phenotype was characterised by early onset with cranial-cervical involvement and progression to a segmental distribution; progression to generalisation was also found. Among 45 people examined, 14 were considered definitely or probably affected by idiopathic torsion dystonia. Eight definitely affected members had mean age (SD) at onset of 15t6 (12-5); idiopathic torsion dystonia started in the cranial-cervical region in six of them, in the upper limbs in two; in four cases dystonia progressed to other body regions, in two cases a generalisation was seen. Linkage analysis with 9q34 markers excluded the region containing the DYTI locus in this family; linkage to the doparesponsive dystonia markers was also excluded. A comparison of the phenotype in the present family and other non-DYTI families shows stiking overlapping features differing from those of DYT1 idiopathic torsion dystonia. Istituto di Neurologia, Universita Cattolica del Sacro Cuore, Roma A R Bentivoglio A Albanese E Cassetta P Tonali Istituto di Medicina Sperimentale, Consiglio Nazionale delle Ricerche, Roma N Del Grosso M Frontali Correspondence to: Dr Alberto Albanese, Department of Movement Disorders, Istituto di Neurologia, Universita Cattolica, Largo A Gemelli 8, 1-00168 Roma, Italy. Received 27 August 1996 Accepted 11 November 1996 We report here the genetic study of an Italian family affected by non-DYT1 idiopathic torsion dystonia and provide evidence that most heterogeneous families have common distinct clinical features, differing from DYT1 idiopathic torsion dystonia. Materials and methods FAMILY DATA The family under study comprised 109 members. They were white and were ascertained through an index case seen at the movement disorders clinic of the Gemelli hospital. The ancestors were from a small countryside area close to Perugia (on the preApennine highlands) and all the family members were still living in that region. Family members older than 18 years and participating to the study were requested to sign an informed consent. Minors were not included in the study for ethical reasons. All the examined subjects provided detailed information on the following topics: delivery, growth and development, education, past and present use of medications, drug misuse, work, pregnancies, exposure to toxins or chemicals, previous illnesses, previous admissions to hospital, any neurological or psychiatric disease, and head and body injuries. All (JNeurolNeurosurg Psychiatry 1997;62:357-360) subjects were also requested to check out a detailed list of symptoms related to dystonia or Keywords: idiopathic torsion dystonia; DYT1 gene; other movement disorders. chromosome 9 Participating family members had a complete on site neurological examination by two Idiopathic torsion dystonia is a neurological dis- neurologists experienced in movement disororder characterised by sustained muscle con- ders (ARB, EC). To disclose dystonia, tremor, tractions, often causing twisting and repetitive or other involuntary movements, subjects were movements or abnormal postures, in the requested to perform the following tasks (lastabsence of other neurological signs and without ing for about 20 seconds each): to sit quietly, any known cause. Three genes for well characto speak trivially, to spell the alphabet, and to terised forms of dystonia have been located. count quickly from 1 to 20, to move the neck, DYT2 for dopa responsive dystonia and DYT3 to hold the upper limbs outstretched, to perfor Filipino dystonia-parkinsonism mapped on form a finger to nose sequence, to perform chromosomes 14 and X respectively.' 2 DYT1, rapid sequential movements with upper and responsible for idiopathic torsion dystonia, was lower limbs, to walk, to stand against a backmapped on chromosome 9q32-34.3 Sub- ward pull, to write, and to draw a spiral with sequently, a small region, spanning 6 cM and either hand. Each subject was videotaped durdelimited by markers AKi and ASS, was ing the assessment. The on site assessors, who reported for the DYT1 gene, with a disease interviewed and examined all the available gene location closer to the telomeric boundary, subjects, established a diagnosis of dystonia as suggested by linkage dysequilibrium with (yes, no, probable) and identified the body ABL/ASS haplotype in Jewish families.4 Idio- segments involved. A senior neurologist (AA) pathic torsion dystonia linked to 9q34 markers reviewed the videotapes (blinded on the diagwas found both in Jewish and in non-Jewish nosis and on the history). When the examiners families. However, genetic heterogeneity among disagreed, the videotapes were re-examined idiopathic torsion dystonias was reported in sev- jointly to reach a final decision. eral families not linked to the DYTl markers.5-9 The diagnosis of dystonia was considered Downloaded from jnnp.bmj.com on July 14, 2011 - Published by group.bmj.com 358 Bentivoglio, Del Grosso, Albanese, Cassetta, Tonali, Frontali IV Figure 1 Pedigree of a non-Jewish, Italian family with early onset idiopathic torsion dystonia. Black symbols denote affected persons; hatched symbols denote probable cases; unfilled symbols denote healthy members; dots indicate visit and blood sample for DNA analysis; asterisks indicate clinical evaluation only. definite when dystonic posturing and slow torsion movements were evident to all the examiners. A definite diagnosis of blepharospasm was established when all the examiners found at least two prolonged spasms of the orbicularis oculi muscle. A definite diagnosis of writer's cramp was established when at least three of the following occurred: (1) a progressive change in handwriting; (2) a progressive change of hand grip; (3) hand posturing and increased pressure on the sheet during handwriting, as noted by all the evaluators; (4) abnormal contraction of brachial or antebrachial muscles during handwriting; (5) hand posturing associated with abnormal proximal movements of the arm or shoulder while writ- dCTP. Pairwise and multipoint linkage analyses were performed using the LINKAGE package'2 assuming autosomal dominant inheritance with 50% and 75% penetrance respectively before and after the age of 24. Although penetrance of idiopathic torsion dystonia in non-Jewish families was estimated at between 0 3013 14 and 0-75,1 the highest value was considered in the present family since penetrance seemed to be almost complete at age 25 (fig 1). Alleles were reduced according to Ott.'5 Results CLINICAL FEATURES Figure 1 shows the pedigree of the family. The diagnosis was considered probable Inheritance of the disease was clearly autosowhen unanimity could not be reached or when mal dominant with a possible case of reduced rapid, jerky movements were detected, but no penetrance (III:3 being the healthy parent of a clear dystonic postural or slow movements subject with probable dystonia). We examined occurred. Excessive blinking, or mild postur- 56 subjects, including 45 family members and ing of the neck or of one arm while writing also 11 spouses, of whom 37 and 11 respectively, led to a diagnosis of probable dystonia. had blood samples taken. Eight children were Isolated postural or action tremor was not also examined but not sampled; they were unaffected and are not reported further. considered a dystonia phenotype. Twenty three subjects had no signs of dysDNA ANALYSIS tonia; their mean (SD) age was 43-3 (17-2) Blood samples were taken from thirty seven (range 18-74) years. Some of them showed an family members and 11 spouses; DNA was isolated postural or action tremor. Eight subjects received a diagnosis of defiextracted by standard methods. Five cases of GT polymorphism, GSN, D9S60, D9S63, nite idiopathic torsion dystonia (table 1). ASS, and D9S64 were analysed as Their mean age at the time of study was 56-8 (SD 12-7). Age at onset was 15-6 (SD 12-5). described,'011 using 35S-dGTP instead of 32Ping. Table 1 Clinicalfeatures of subjects affected by idiopathic torsion dystonia (ITD) At time of evaluation At onset Subject (sex) Definite cases: III:2 (F) III:5 (M) III:9 (F) III:20 (F) III:22 (F) III:23 (M) IV: 1 (M) IV:3 (M) Probable cases: III:7 (M) III:25 (F) IV:2 (F) IV: 5 (F) IV:6 (F) IV:23 (F) ITD Age Presentation Age Presentation Segmental Segmental Segmental Segmental 14 Cranial-cervical Cervical Cranial-cervical Upper limbs Cervical Cervical Right upper limb Cranial-cervical 71 67 63 61 Generalised Focal 5 10 26 5 5 20 40 Cranial-cervical, upper limbs Cranial-cervical, upper limbs Cranial-cervical, upper limbs Cranial-cervical, trunk, limbs Cranial-cervical, trunk Cranial-cervical, limbs Right upper limb Cervical Cervical 64 52 47 31 29 29 Generalised Segmental Segmental Segmental Segmental Focal Focal Focal Upper limbs Cervical Cervical Cervical 59 56 45 32 Cranial-cervical Cervical, larynx, right upper limb Cranial-cervical, right upper limb Upper limbs Cervical Cervical Cervical Downloaded from jnnp.bmj.com on July 14, 2011 - Published by group.bmj.com Non-DYT1 dystonia in a large Italian family 359 Table 2 Pairvise lod scores for idiopathic torsion dystonia and 9q markers with data of condition A posturing and clumsiness in the upper limbs; in one of these, a mild postural abnormality of the neck was also seen. Marker 00 00 0 01 GSN D9S60 D9S63 D9S64 - 6-00 - 5-68 - 5-20 -4-88 -2 -1 -1 -1 84 30 49 68 0 05 0 10 0-20 0 30 0 40 -1 90 -0-64 -0-79 -1 00 -1-34 - 0-43 - 0-52 - 0-76 - 0-69 - 0-32 - 0 35 -0 57 - 0-36 - 0-28 - 0-27 - 040 -0 16 -0-17 -0-14 -0-17 MOLECULAR GENETIC ANALYSIS The average duration of disease was 41-3 (SD 21 2) (range 5-66) years. Table 1 shows the main clinical features. Most subjects (six out of eight) had their first symptom in the cervical or cranial-cervical segment, and two in the upper limbs, including a focal onset (writer's cramp) and a segmental onset (both upper limbs). All the patients with more than 18 years of duration of disease had a progression of dystonia to other body regions, and just two cases had a generalisation with a relatively mild clinical picture which did not impair daily living activities. No progression was seen in two subjects with a shorter history of the disease. The proband and subiect III:22 (who had the most severe clinical presentation) were treated with levodopa/benserazide (200/50 mg four times daily) for one month, without clinical benefit. Six family members received a diagnosis of probable idiopathic torsion dystonia (table 1). Their mean age at the time of the study was 42-3 (SD 14-6) (range 29-64). The age at onset was unknown, as they all denied having any disease and considered the abnormal movements of the head as part of their gestures. Three subjects presented only jerky movements of the head, similar to those found in other members with a definite diagnosis; one subject presented with jerky movements of the head, vocal hoarseness, and an abnormal right hand grip. Two had mild action induced To test whether the disease locus in this family is mapping in the same region of DYTI gene, subjects were typed for five microsatellite markers encompassing the critical area: cen-GSN-5cM-D9S60-8cM-D9S63-lcM-ASS2cM-D9S64-tel. The marker ASS was not informative in this family and was excluded from further analysis. Pairwise and multipoint linkage analysis were performed considering the subjects with probable dystonia either as unknown phenotype (condition A) or as affected (condition B). Table 2 shows pairwise lod scores between the disease and each of the markers under condition A. No positive lod scores were obtained. More negative values were obtained under condition B (data not shown). A four point linkage analysis with the disease against a fixed map D9S60-8cMD9S63-3cM-D9S64 (fig 2) provided odds in favour of a disease location outside the D9S60-D9S64 interval greater than 10 000: 1 under condition A. When condition B was used the odds favouring the exclusion of the disease locus from the above mentioned interval were increased. Multipoint linkage analysis with a penetrance reduced to 30% was still excluding the gene from the D9S60-D9S64 interval with 1000:1 odds. Although the phenotype in the present family is very different from dopa responsive dystonia, and levodopa treatment in two affected family members was completely ineffective, family members were genotyped for D14S52 marker, linked to the dopa responsive dystonia gene.' A two point linkage analysis between the disease and the marker loci produced highly negative lod scores excluding gene location from an inter- Recombination (%) Figure 2 Four point linkage analysis of idiopathic torsion dystonia and 9q markers. Lod scores are plotted with data of condition A (see text). 0.70 -1 -2 -3 en o Q) U' -4 0 -5 -6 -7 Downloaded from jnnp.bmj.com on July 14, 2011 - Published by group.bmj.com Bentivoglio, Del Grosso, Albanese, Cassetta, Tonali, Frontali 360 Table 3 Clinicalfeatures of cervical and upper limb idiopathic torsion dystonia in families unrelated to DYT1 Definitely affected membranes Ancestry and origin Ethnic origin Age at onset: mean (range) Duration (y): mean (range) Age at examination: mean (range) Site of onset: Arm Leg Neck Cranial Disease progression: No progression Progression to segmental or multifocal Progression to generalisation Parker'8 Bressman et al Parker Holmgren et al This family 10 English-Australian Non-Jewish NG (13-37) NG NG 7 German-American Non-Jewish 28-4 (7-50) 28-2 (10-50) NG (37-75) 7 Non-Jewish 14 7 (5-34) 30-2 (10-65) NG (15-78) 7t Swedish Non-Jewish 27-3 (17-50) 14 3 (0-47) NG (20-64) 8 Italian Non-Jewish 15 6 (5-40) 41 3 (5-66) 56-8 (32-71) 0 1 9t 0 0 1 2 0 1 3 2 0 1 3 1 1 2 1 1 8 0 6 1 0 4 3 2 2 3 2 4 2 65 Germnan-American 6¶ 3 *One obligate gene carrier was possibly affected by dystonia.t Presenting signs were not reported in one subject affected by generalised dystonia.t Dysphonia was the presenting sign in seven subjects.§ One case had cranial-cervical dystonia.¶ Three cases had cranial-cervical dystonia; NG = not given. val of about 3 cM around D14S52 using condition A, and an even larger interval using condition B. exception,'8 all non-DYT1 families so far described have common features, such as onset in the cranial-cervical segment or upper limb, milder course, and only occasional generalisation. The large number of meioses span- Discussion We report a large Italian family affected by non-DYTI idiopathic torsion dystonia with onset in the cranial-cervical region or in upper limbs and with slow progression to other segments and relatively mild severity. The above results provide further evidence that idiopathic torsion dystonia is aetiologically heterogeneous and confirm previous findings that the DYTl gene does not underlie idiopathic torsion dystonia in all families. The typical DYT1 phenotype presents with dystonia first affecting a limb (preferentially the lower limbs) during childhood or adolescence before spreading to other limbs and to axial muscles. Although DYTI idiopathic torsion dystonia does not show a unique pattern of presentation or progression, it does not commonly affect cranial-cervical segments as the first site of onset or as a site of progression3' 16; however, adult onset cases with cranial-cervical presentation have been described on occasion.'7 When progressing to generalisation, DYT1 idiopathic torsion dystonia is usually highly incapacitating. Four non-Jewish idiopathic torsion dystonia families, unrelated to the DYT 1 gene have been reported so far (table 3).5 79' All of them and the present one show overlapping features, distinct from DYTI dystonia. Onset is most likely in the cranial-cervical segment or in an upper limb; with the exception of one case'8 the clinical course is relatively mild with only occasional generalisation and a very variable age at onset, on average later than that of DYT1 idiopathic torsion dystonia. However, differences among these families are also present. In particular, in most patients of the English-Australian family'8 dysphonia was the presenting sign and generalisation was more common than in the other four families (including the present one). Some differences in the mean age at onset have also been reported, but variations of the age at onset were not significant when compared statistically in the four families for which these data are available (table 3). On the whole, it seems that, with one ning three generations and the high penetrance of the disease make the present family a good candidate for localising a new idiopathic torsion dystonia gene, possibly responsible for the disease in the other heterogeneous families. This research was supported by Comitato Promotore Telethon grant E 113 to AA. 1 Nygaard TG, Wilhelmsen KC, Risch NJ, et al. Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q. Nat Genet 1993;5:386-91. 2 Kupke KG, Graeber MB, Muller U. Dystonia-parkinsonism syndrome (XDP) locus: flanking markers in Xql2q21 1. Am J Hum Genet 1992;50:808-15. 3 Ozelius L, Kramer PL, Moskowitz CB, et al. Human gene for torsion dystonia located on chromosome 9q32-q34. Neuron 1989;2:1427-34. 4 Ozelius L, Kramer PL, de Leon D, et al. Strong allelic association between the torsion dystonia gene (DYTI) and loci on chromosome 9q34 in Ashkenazi Jews. Am _7 Hum Genet 1992;50:619-28. 5 Ahmad F, Davis MB, Waddy HM, Oley CA, Marsden CD, Harding AE. Evidence for locus heterogeneity in autosomal dominant torsion dystonia. Genomics 1993;15:9-12. 6 Warner TV, Fletcher NA, Davis MB, et al. Linkage analysis in British and French families with idiopathic torsion dystonia. Brain 1993;116:739-44. 7 Bressman SB, Heiman GA, Nygaard TG, et al. A study of idiopathic torsion dystonia in a non-Jewish family: evidence for genetic heterogeneity. Neurology 1994;44: 283-7. 8 Bressman SB, Hunt AL, Heiman GA, et al. Exclusion of the DYTI locus in a non-Jewish family with early-onset dystonia. Mov Disord 1994;9:626-32. 9 Holmgren G, Ozelius L, Forsgren L, et al. Adult onset idiopathic torsion dystonia is excluded from the DYTI region (9q34) in a Swedish family. _7 Neurol Neurosurg Psychiatry 1995;59: 178-81. 10 Kwiatkowski DJ, Ozelius L, Kramer PL, et al. Torsion dystonia genes in 2 populations confined to a small region on chromosome 9q32-34. Am 7 Hum Genet 199 1; 49:366-71. 11 Kwiatkowski DJ, Enske EP, Weimer K, Ozelius L, Gusella JF, Haines J. Construction of a GT polymorphism map of human 9q. Genomics 1992;12:229-40. 12 Lathrop GM, Lalouel J-M, Julier C, Ott J. Strategies for multilocus linkage analysis in humans. Proc Nat Acad Sci USA 1984;81:3443-6. 13 Pauls DL, Korczyn A. Complex segregation analysis of dystonia pedigrees suggests autosomal dominant inheritance. Neurology 1990;40:1107-10. 14 Risch NJ, Bressman SB, deLeon D, et al. Segregation analysis of idiopathic torsion dystonia in Ashkenazi Jews suggests autosomal dominant inheritance. Am Y Hum Genet 1990;46:533-8. 15 Ott J. A simple scheme for the analysis of HLA linkages in pedigrees. Ann Hum Genet 1978;42:255-7. 16 Kramer PL, de Leon D, Ozelius L, et al. Dystonia gene in Ashkenazi Jewish population is located on chromosome 9q32-34. Ann Neurol 1990;27:114-20. 17 Bressman SB, de Leon D, Brin MF, et al. Idiopathic dystonia among Ashkenazi Jews: evidence for autosomal dominant inheritance. Ann Neurol 1989;26:612-20. 18 Parker N. Hereditary whispering dysphonia. .7 Neurol Neurosurg Psychiatry 1985;48:218-24. Downloaded from jnnp.bmj.com on July 14, 2011 - Published by group.bmj.com Non-DYT1 dystonia in a large Italian family. A R Bentivoglio, N Del Grosso, A Albanese, et al. J Neurol Neurosurg Psychiatry 1997 62: 357-360 doi: 10.1136/jnnp.62.4.357 Updated information and services can be found at: http://jnnp.bmj.com/content/62/4/357 These include: References Article cited in: http://jnnp.bmj.com/content/62/4/357#related-urls Email alerting service Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article. Notes To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/