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DYT1 mutation in French families with idiopathic torsion dystonia

DYT1 mutation in French families with idiopathic torsion dystonia Abstract A GAG deletion at position 946 in DYT1, one of the genes responsible for autosomal dominant idiopathic torsion dystonia (ITD), has recently been identified. We tested 24 families and six isolated cases with ITD and found 14 individuals from six French families who carried this mutation, indicating that 20% of the affected families carried the DYT1 mutation. Age at onset was always before 20 years (mean, 9 ± 4 years). Interestingly, the site of onset was the upper limb in all but one patient. Dystonia was generalized in seven patients and remained focal or segmental in three patients. The absence of common haplotypes among DYT1 families suggests that at least six independent founder mutations have occurred. In addition, one Ashkenazi Jewish family carried the common haplotype described previously in Ashkenazi Jewish patients, but it was absent in the other family. Moreover, the dystonia remained focal in the latter family when compared with the usual generalized phenotype in patients with the common Ashkenazi Jewish haplotype. This indicates that there are at least two founder mutations in this population. idiopathic torsion dystonia, Ashkenazi Jews, linkage disequilibrium, DYT1, torsin A ITD = idiopathic torsion dystonia Introduction Idiopathic torsion dystonia (ITD) is characterized by involuntary sustained muscle contractions, causing twisting and repetitive movements or abnormal postures. ITD is transmitted as an autosomal dominant disorder with low penetrance (30–40%) (Bressman et al., 1989; Kramer et al., 1994). Clinical expression is highly variable but is partly determined by the age at onset. When onset occurs before the age of 20 the disease is usually severe and generalized, often affecting a leg before progressing to other limbs and the trunk. Late-onset forms are milder and often remain segmental or focal. The first locus (DYT1) of this genetically heterogeneous disease was mapped to chromosome 9q34 (Ozelius et al., 1989), and the corresponding gene, encoding a small polypeptide, torsin A, has recently been identified (Ozelius et al., 1997a). The mutation is a deletion of a GAG codon at position 946. ITD linked to chromosome 9 is particularly prevalent in Ashkenazi Jews due to a founder effect (Ozelius et al., 1997b). The DYT1 phenotype, defined by clinical characterization of carriers of the ancestral haplotype in this population, is early limb-onset generalized dystonia (Bressman et al., 1994). The 946delGAG mutation, linked to chromosome 9, was found in all patients and obligate carriers of 68 ITD families, 64 of whom were of Ashkenazi Jewish origin (Ozelius et al., 1997a). In the present study, we determined the frequency of the DYT1 mutation in 30 French families with ITD and analysed the corresponding phenotype. Method Patients We tested 51 individuals (24 women and 27 men) from 30 families with ITD for the presence of the DYT1 mutation. The families were ascertained at the Hôpital de la Salpêtrière according to the following criteria: (i) clinical evidence of dystonic movements or postures, without pyramidal, cerebellar, sensory or intellectual deficits; (ii) no history of kernicterus, perinatal asphyxia or other predisposing causes of dystonia; (iii) at least two first-degree relatives with ITD cases for the familial cases. There were 14 families with affected individuals in two generations, eight families with at least two patients in one generation and eight isolated cases. In nine families, all patients suffered from focal dystonia, in four from generalized dystonia, and in one dystonia was segmental in all patients (Fahn, 1988). In the other families (n = 8), patients were affected with different types of dystonia. In addition, eight members of two families with autosomal dominant non-alcohol-responsive myoclonic dystonia were tested. We excluded families with dopamine-responsive dystonias and paroxysmal kinesigenic choreoathetosis. The families were classified into three categories according to Ozelius et al. (1997a), where the index case was (i) typical: early onset (under 28 years), limb dystonia with spread to at least one other limb but not to cranial muscles; (ii) atypical: focal or segmental cervical–cranial dystonia of any age of onset, or writer's cramp beginning after age 44; (iii) uncertain: dystonia that did not fit into either of these categories, such as cervical or cranial onset dystonia spreading down to the limbs, or limb onset spreading up to the cranial muscles. The patients' written consent was obtained according to the declaration of Helsinki, and the ethical committee of the Groupe Hospitalier Pitié-Salpêtrière approved the study. Molecular analysis Blood samples were taken, with informed consent, from patients and some of their relatives for extraction of genomic DNA. Mutational analysis was performed by digestion with BseRI of PCR (polymerase chain reaction) fragments generated from genomic DNA (Ozelius et al., 1997a). PCR analysis of the polymorphic markers D9S2160, D9S2161, D9S63 and D9S2162, which span a region of ~320 kb of genomic DNA containing the DYT1 gene, was carried out with the oligonucleotide primers reported previously (Kwiatkowski et al., 1992; Ozelius et al., 1997b). PCR conditions and analysis of the amplified products were as described previously (Ozelius et al., 1992). Comparison of the common haplotype in Ashkenazi Jews with the haplotype of French Canadian DYT1 families was carried out using the data of L. Ozelius (personal communication) on the latter families. Results There were eight index cases with typical, 13 with atypical and nine with uncertain phenotype. The phenotype was concordant among patients in 14 of the 22 families. The 946delGAG mutation in the DYT1 gene was found in four of the typical families (SAL-405, SAL-416, SAL-417 and SAL-420), two of the uncertain families (SAL-449 and SAL-451) and none of the atypical families. The mutation occurred in 10 patients, three unaffected parents aged 71 (SAL-405–2), 42 (SAL-451–7) and 39 (SAL-420–8) years, and one unaffected sibling (SAL-417–15) (Fig. 1). In family SAL-420, the grandfather was reported by the family to have suffered from writers' cramp. Only two families (SAL-416 and SAL-449) were Ashkenazi Jews. The mutation was not detected in families with non-alcohol-responsive myoclonic dystonia. The clinical characteristics of the 10 patients from the six DYT1 families are described in Table 1. All patients had their first dystonic posture at or before the age of 20. The mean age at onset was 9 ± 4 years (range 5–20 years) and patients were examined after a mean disease duration of 22 ± 17 years (range 3–45 years). The site of onset was an upper limb in all but one patient, who had onset in the foot. This is an unusual finding and is perhaps due to the small number of patients. At the time of examination, dystonia was generalized in seven patients. In three patients with disease durations ranging from 3 to 30 years, dystonia remained focal or segmental. Six patients had tremor, which was evident in four of them when writing. The two apparently sporadic cases (in families SAL-449 and SAL-451) were classified as uncertain because of the cranial involvement with facial and oromandibular dystonia in one and blepharospasm in the other. The mean age of onset of dystonia in patients without the DYT1 mutation was significantly later (31 ± 23 years; range 3–74 years, n = 34) than in those with the deletion (P < 0.01). In families with generalized or mixed phenotypes, however, the mean age at onset was similar in DYT1 carriers (10 ± 5 years, n = 7) and in the non-carriers (8 ± 8 years, n = 12). The sites of onset were significantly different in DYT1 carriers and non-carriers: arm (90% versus 32%); leg (10% versus 12%); neck (0% versus 32%); cranial (0% versus 24%) (P < 0.05). No common haplotype that segregated with the disease in the six DYT1 families was detected by haplotype reconstruction with four microsatellite markers (D9S2160, D9S2161, D9S63 and D9S2162), which span 320 kb of DNA, covering the DYT1 locus. An isolated Ashkenazi Jew (SAL-449–16) carried the alleles associated with the common Ashkenazi Jew haplotype at the four loci, but parental information was not available and therefore the phase of the haplotype was unknown. Interestingly, the Ashkenazi Jew family SAL-416 had another haplotype, indicating the existence of at least two independent mutations in the Ashkenazi Jew population. Four other haplotypes were observed in the four non-Ashkenazi Jew families, none of which were similar to those found in two French Canadian families described previously (Kramer et al., 1994; L. Ozelius, personal communication). Discussion We report the screening of 30 families or isolated cases with idiopathic torsion dystonia for the DYT1 mutation, a GAG deletion at position 946. Six out of our 30 families carried the mutation. This indicates that the mutation frequency varies according to the population studied, since the majority of cases with typical early-onset dystonia in both Ashkenazi Jewish and non-Jewish patients carried the mutation studied previously (Ozelius et al., 1997a). In addition, the 946delGAG mutation was excluded in two families with autosomal dominant non-alcohol-responsive myoclonic dystonia. As predicted from previous reports, the DYT1 mutation was associated with early onset. The symptoms at onset differed, however, in patients who were reported in the literature before the DYT1 gene had been identified, but who were identified as haplotype carriers in family studies using linkage analysis with respect to the DYT1 locus on chromosome 9 (Bressman et al., 1994). In that study, 42 out of 90 (47%) patients had onset in the leg and 43 out of 90 (48%) in the arm compared with one out of nine and eight out of nine, respectively, in the present study. The difference observed for the onset of dystonia in the arm may be due to the fact that in the study of Bressman et al. the relatives were not systematically examined and mild arm onset dystonia could have been missed. In addition, our sample of patients with the DYT1 mutation is relatively small. The distribution of dystonia was different between the two Ashkenazi Jewish families, remaining focal in one patient of family SAL-416 without the common Ashkenazi Jew haplotype but generalized in the patient from family SAL-449, which shared alleles of the common Ashkenazi Jew haplotype. Incomplete penetrance of ITD, estimated at 30–40% (Bressman et al., 1989), was confirmed by this study, since four individuals who carried the mutation were still unaffected at ages ranging from 7 to 71, later than the latest onset in three other carriers. However, onset up to 44 years of age was reported in the haplotype carrier study of Bressman et al. (1994). Expression of the disease was also incomplete in several other cases, since the disease did not become generalized in all patients, even after disease durations ranging up to 30 years. This suggests that there are other factors modulating the penetrance and phenotypic expression of the disease in addition to the DYTl gene mutation. For clinical practice, it is important to consider the possibility that the DYT1 mutation is present in patients with focal dystonia. A common founder effect is excluded in the French DYT1 families, which probably all derive from independent founder mutations. Furthermore, one Ashkenazi Jew patient carried the common Ashkenazi Jew haplotype, but it was absent in the other Ashkenazi Jew family, indicating at least another ancestral mutation among the Ashkenazi Jew population. At least six independent ancestral mutations can therefore be suspected in the French population. Genetic counselling for ITD is difficult because of the low penetrance and variable clinical expression in DYT1 gene carriers, as well as the existence of further genetic heterogeneity demonstrated by linkage analysis in large pedigrees. Most of our families with early-onset generalized ITD did not have the 946delGAG mutation, and two new loci have recently been identified on chromosomes 8 (Almasy et al., 1997) and 18p (Leube et al., 1997), which are associated with different dystonic phenotypes. Clinical characteristics of 10 DYT1 patients . Positive family history . Sex . Age at onset (years) . Disease duration (years) . Site of onset . Distribution . Tremor . Other . SAL-405-003 Siblings F 10 40 Hand Arm, both legs Writing SAL-405-004 Siblings M 11 37 Unknown Neck, arms, legs, trunk Writing SAL-405-005 Siblings M Childhood 38 Arm Generalized No Bilateral thalamotomy SAL-416-009 Daughter F 20 22 Hand Foot, arm Writing, head Dysarthria SAL-416-014 Mother F 9 3 Hand Both arms No SAL-417-009 Son M 7 30 Hand Writer's cramp No SAL-417-014 Father M 7 3 Hand Larynx, both arms, trunk Postural SAL-420-011 Grandfather F 6 3 Hand trunk Both arms, leg Postural SAL-449-016 No M 9 45 Foot Cranial, neck, arms, legs, trunk Dysarthria SAL-451-011 No M 5 13 Hand Cranial, neck, legs, arms, trunk Postural, writing Nystagmus, decreased reflexes . Positive family history . Sex . Age at onset (years) . Disease duration (years) . Site of onset . Distribution . Tremor . Other . SAL-405-003 Siblings F 10 40 Hand Arm, both legs Writing SAL-405-004 Siblings M 11 37 Unknown Neck, arms, legs, trunk Writing SAL-405-005 Siblings M Childhood 38 Arm Generalized No Bilateral thalamotomy SAL-416-009 Daughter F 20 22 Hand Foot, arm Writing, head Dysarthria SAL-416-014 Mother F 9 3 Hand Both arms No SAL-417-009 Son M 7 30 Hand Writer's cramp No SAL-417-014 Father M 7 3 Hand Larynx, both arms, trunk Postural SAL-420-011 Grandfather F 6 3 Hand trunk Both arms, leg Postural SAL-449-016 No M 9 45 Foot Cranial, neck, arms, legs, trunk Dysarthria SAL-451-011 No M 5 13 Hand Cranial, neck, legs, arms, trunk Postural, writing Nystagmus, decreased reflexes Open in new tab Clinical characteristics of 10 DYT1 patients . Positive family history . Sex . Age at onset (years) . Disease duration (years) . Site of onset . Distribution . Tremor . Other . SAL-405-003 Siblings F 10 40 Hand Arm, both legs Writing SAL-405-004 Siblings M 11 37 Unknown Neck, arms, legs, trunk Writing SAL-405-005 Siblings M Childhood 38 Arm Generalized No Bilateral thalamotomy SAL-416-009 Daughter F 20 22 Hand Foot, arm Writing, head Dysarthria SAL-416-014 Mother F 9 3 Hand Both arms No SAL-417-009 Son M 7 30 Hand Writer's cramp No SAL-417-014 Father M 7 3 Hand Larynx, both arms, trunk Postural SAL-420-011 Grandfather F 6 3 Hand trunk Both arms, leg Postural SAL-449-016 No M 9 45 Foot Cranial, neck, arms, legs, trunk Dysarthria SAL-451-011 No M 5 13 Hand Cranial, neck, legs, arms, trunk Postural, writing Nystagmus, decreased reflexes . Positive family history . Sex . Age at onset (years) . Disease duration (years) . Site of onset . Distribution . Tremor . Other . SAL-405-003 Siblings F 10 40 Hand Arm, both legs Writing SAL-405-004 Siblings M 11 37 Unknown Neck, arms, legs, trunk Writing SAL-405-005 Siblings M Childhood 38 Arm Generalized No Bilateral thalamotomy SAL-416-009 Daughter F 20 22 Hand Foot, arm Writing, head Dysarthria SAL-416-014 Mother F 9 3 Hand Both arms No SAL-417-009 Son M 7 30 Hand Writer's cramp No SAL-417-014 Father M 7 3 Hand Larynx, both arms, trunk Postural SAL-420-011 Grandfather F 6 3 Hand trunk Both arms, leg Postural SAL-449-016 No M 9 45 Foot Cranial, neck, arms, legs, trunk Dysarthria SAL-451-011 No M 5 13 Hand Cranial, neck, legs, arms, trunk Postural, writing Nystagmus, decreased reflexes Open in new tab Fig. 1 Open in new tabDownload slide Partial pedigrees of six DYT1 families. Black squares and circles represent affected men and women, respectively. Asymptomatic gene carriers are represented by a black dot. Asterisks indicate individuals who were sampled and analysed. Haplotypes segregating with the disease are boxed. Distances between markers are indicated according to Ozelius et al. (1997b). Fig. 1 Open in new tabDownload slide Partial pedigrees of six DYT1 families. Black squares and circles represent affected men and women, respectively. Asymptomatic gene carriers are represented by a black dot. Asterisks indicate individuals who were sampled and analysed. Haplotypes segregating with the disease are boxed. Distances between markers are indicated according to Ozelius et al. (1997b). We wish to thank Professor L. Ozelius for giving us the haplotype for the French Canadian DYT1 families, Dr M. Ruberg for critical reading of this manuscript, Drs M. Abada, S. Belal, H. Chneiweiss, A. Nivelon-Chevallier, P. Pollak, O. Rascol, F. Tison and J.-C. Vernant for referring patients, J. Bou for technical assistance and A. Camuzat, C. Penet and Y. Pothin for their contributions to this study. References Almasy L, Bressman SB, Raymond D, Kramer PL, Greene PE, Heiman GA, et al. Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families. Ann Neurol 1997 ; 42 : 670 –3. Bressman SB, de Leon D, Brin MF, Risch N, Burke RE, Greene PE, et al. Idiopathic dystonia among Ashkenazi Jews: evidence for autosomal dominant inheritance. Ann Neurol 1989 ; 26 : 612 –20. Bressman SB, de Leon D, Kramer PL, Ozelius LJ, Brin MF, Greene PE, et al. Dystonia in Ashkenazi Jews: clinical characterization of a founder mutation [published erratum appears in Ann Neurol 1995; 37: 140]. Ann Neurol 1994 ; 36 : 771 –7. Fahn S. Concept and classification of dystonia. [Review]. Adv Neurol 1988 ; 50 : 1 –8. Kramer PL, Heiman GA, Gasser T, Ozelius LJ, de Leon D, Brin MF, et al. The DYT1 gene on 9q34 is responsible for most cases of early limb-onset idiopathic torsion dystonia in non-Jews. Am J Hum Genet 1994 ; 55 : 468 –75. Kwiatkowski DJ, Henske EP, Weimer K, Ozelius L, Gusella JF, Haines J. Construction of a GT polymorphism map of human 9q. Genomics 1992 ; 12 : 229 –40. Leube B, Hendgen T, Kessler KR, Knapp M, Benecke R, Auburger G. Sporadic focal dystonia in northwest Germany: molecular basis on chromosome 18p. Ann Neurol 1997 ; 42 : 111 –4. Ozelius L, Kramer PL, Moskowitz CB, Kwiatkowski DJ, Brin MF, Bressman SB, et al. Human gene for torsion dystonia located on chromosome 9q32–q34. Neuron 1989 ; 2 : 1427 –34. Ozelius LJ, Kramer PL, de Leon D, Risch N, Bressman SB, Schuback DE, et al. Strong allelic association between the torsion dystonia gene (DYT1) and loci on chromosome 9q34 in Ashkenazi Jews. Am J Hum Genet 1992 ; 50 : 619 –28. Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer PL, Shalish C, et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet 1997 ; 17 : 40 –8. Ozelius LJ, Hewett J, Kramer P, Bressman SB, Shalish C, de Leon D, et al. Fine localization of the torsion dystonia gene (DYT1) on human chromosome 9q34: YAC map and linkage disequilibrium. Genome Res 1997 ; 7 : 483 –94. © Oxford University Press 1999 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Oxford University Press

DYT1 mutation in French families with idiopathic torsion dystonia

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Publisher
Oxford University Press
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© Oxford University Press 1999
ISSN
0006-8950
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1460-2156
DOI
10.1093/brain/122.1.41
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Abstract

Abstract A GAG deletion at position 946 in DYT1, one of the genes responsible for autosomal dominant idiopathic torsion dystonia (ITD), has recently been identified. We tested 24 families and six isolated cases with ITD and found 14 individuals from six French families who carried this mutation, indicating that 20% of the affected families carried the DYT1 mutation. Age at onset was always before 20 years (mean, 9 ± 4 years). Interestingly, the site of onset was the upper limb in all but one patient. Dystonia was generalized in seven patients and remained focal or segmental in three patients. The absence of common haplotypes among DYT1 families suggests that at least six independent founder mutations have occurred. In addition, one Ashkenazi Jewish family carried the common haplotype described previously in Ashkenazi Jewish patients, but it was absent in the other family. Moreover, the dystonia remained focal in the latter family when compared with the usual generalized phenotype in patients with the common Ashkenazi Jewish haplotype. This indicates that there are at least two founder mutations in this population. idiopathic torsion dystonia, Ashkenazi Jews, linkage disequilibrium, DYT1, torsin A ITD = idiopathic torsion dystonia Introduction Idiopathic torsion dystonia (ITD) is characterized by involuntary sustained muscle contractions, causing twisting and repetitive movements or abnormal postures. ITD is transmitted as an autosomal dominant disorder with low penetrance (30–40%) (Bressman et al., 1989; Kramer et al., 1994). Clinical expression is highly variable but is partly determined by the age at onset. When onset occurs before the age of 20 the disease is usually severe and generalized, often affecting a leg before progressing to other limbs and the trunk. Late-onset forms are milder and often remain segmental or focal. The first locus (DYT1) of this genetically heterogeneous disease was mapped to chromosome 9q34 (Ozelius et al., 1989), and the corresponding gene, encoding a small polypeptide, torsin A, has recently been identified (Ozelius et al., 1997a). The mutation is a deletion of a GAG codon at position 946. ITD linked to chromosome 9 is particularly prevalent in Ashkenazi Jews due to a founder effect (Ozelius et al., 1997b). The DYT1 phenotype, defined by clinical characterization of carriers of the ancestral haplotype in this population, is early limb-onset generalized dystonia (Bressman et al., 1994). The 946delGAG mutation, linked to chromosome 9, was found in all patients and obligate carriers of 68 ITD families, 64 of whom were of Ashkenazi Jewish origin (Ozelius et al., 1997a). In the present study, we determined the frequency of the DYT1 mutation in 30 French families with ITD and analysed the corresponding phenotype. Method Patients We tested 51 individuals (24 women and 27 men) from 30 families with ITD for the presence of the DYT1 mutation. The families were ascertained at the Hôpital de la Salpêtrière according to the following criteria: (i) clinical evidence of dystonic movements or postures, without pyramidal, cerebellar, sensory or intellectual deficits; (ii) no history of kernicterus, perinatal asphyxia or other predisposing causes of dystonia; (iii) at least two first-degree relatives with ITD cases for the familial cases. There were 14 families with affected individuals in two generations, eight families with at least two patients in one generation and eight isolated cases. In nine families, all patients suffered from focal dystonia, in four from generalized dystonia, and in one dystonia was segmental in all patients (Fahn, 1988). In the other families (n = 8), patients were affected with different types of dystonia. In addition, eight members of two families with autosomal dominant non-alcohol-responsive myoclonic dystonia were tested. We excluded families with dopamine-responsive dystonias and paroxysmal kinesigenic choreoathetosis. The families were classified into three categories according to Ozelius et al. (1997a), where the index case was (i) typical: early onset (under 28 years), limb dystonia with spread to at least one other limb but not to cranial muscles; (ii) atypical: focal or segmental cervical–cranial dystonia of any age of onset, or writer's cramp beginning after age 44; (iii) uncertain: dystonia that did not fit into either of these categories, such as cervical or cranial onset dystonia spreading down to the limbs, or limb onset spreading up to the cranial muscles. The patients' written consent was obtained according to the declaration of Helsinki, and the ethical committee of the Groupe Hospitalier Pitié-Salpêtrière approved the study. Molecular analysis Blood samples were taken, with informed consent, from patients and some of their relatives for extraction of genomic DNA. Mutational analysis was performed by digestion with BseRI of PCR (polymerase chain reaction) fragments generated from genomic DNA (Ozelius et al., 1997a). PCR analysis of the polymorphic markers D9S2160, D9S2161, D9S63 and D9S2162, which span a region of ~320 kb of genomic DNA containing the DYT1 gene, was carried out with the oligonucleotide primers reported previously (Kwiatkowski et al., 1992; Ozelius et al., 1997b). PCR conditions and analysis of the amplified products were as described previously (Ozelius et al., 1992). Comparison of the common haplotype in Ashkenazi Jews with the haplotype of French Canadian DYT1 families was carried out using the data of L. Ozelius (personal communication) on the latter families. Results There were eight index cases with typical, 13 with atypical and nine with uncertain phenotype. The phenotype was concordant among patients in 14 of the 22 families. The 946delGAG mutation in the DYT1 gene was found in four of the typical families (SAL-405, SAL-416, SAL-417 and SAL-420), two of the uncertain families (SAL-449 and SAL-451) and none of the atypical families. The mutation occurred in 10 patients, three unaffected parents aged 71 (SAL-405–2), 42 (SAL-451–7) and 39 (SAL-420–8) years, and one unaffected sibling (SAL-417–15) (Fig. 1). In family SAL-420, the grandfather was reported by the family to have suffered from writers' cramp. Only two families (SAL-416 and SAL-449) were Ashkenazi Jews. The mutation was not detected in families with non-alcohol-responsive myoclonic dystonia. The clinical characteristics of the 10 patients from the six DYT1 families are described in Table 1. All patients had their first dystonic posture at or before the age of 20. The mean age at onset was 9 ± 4 years (range 5–20 years) and patients were examined after a mean disease duration of 22 ± 17 years (range 3–45 years). The site of onset was an upper limb in all but one patient, who had onset in the foot. This is an unusual finding and is perhaps due to the small number of patients. At the time of examination, dystonia was generalized in seven patients. In three patients with disease durations ranging from 3 to 30 years, dystonia remained focal or segmental. Six patients had tremor, which was evident in four of them when writing. The two apparently sporadic cases (in families SAL-449 and SAL-451) were classified as uncertain because of the cranial involvement with facial and oromandibular dystonia in one and blepharospasm in the other. The mean age of onset of dystonia in patients without the DYT1 mutation was significantly later (31 ± 23 years; range 3–74 years, n = 34) than in those with the deletion (P < 0.01). In families with generalized or mixed phenotypes, however, the mean age at onset was similar in DYT1 carriers (10 ± 5 years, n = 7) and in the non-carriers (8 ± 8 years, n = 12). The sites of onset were significantly different in DYT1 carriers and non-carriers: arm (90% versus 32%); leg (10% versus 12%); neck (0% versus 32%); cranial (0% versus 24%) (P < 0.05). No common haplotype that segregated with the disease in the six DYT1 families was detected by haplotype reconstruction with four microsatellite markers (D9S2160, D9S2161, D9S63 and D9S2162), which span 320 kb of DNA, covering the DYT1 locus. An isolated Ashkenazi Jew (SAL-449–16) carried the alleles associated with the common Ashkenazi Jew haplotype at the four loci, but parental information was not available and therefore the phase of the haplotype was unknown. Interestingly, the Ashkenazi Jew family SAL-416 had another haplotype, indicating the existence of at least two independent mutations in the Ashkenazi Jew population. Four other haplotypes were observed in the four non-Ashkenazi Jew families, none of which were similar to those found in two French Canadian families described previously (Kramer et al., 1994; L. Ozelius, personal communication). Discussion We report the screening of 30 families or isolated cases with idiopathic torsion dystonia for the DYT1 mutation, a GAG deletion at position 946. Six out of our 30 families carried the mutation. This indicates that the mutation frequency varies according to the population studied, since the majority of cases with typical early-onset dystonia in both Ashkenazi Jewish and non-Jewish patients carried the mutation studied previously (Ozelius et al., 1997a). In addition, the 946delGAG mutation was excluded in two families with autosomal dominant non-alcohol-responsive myoclonic dystonia. As predicted from previous reports, the DYT1 mutation was associated with early onset. The symptoms at onset differed, however, in patients who were reported in the literature before the DYT1 gene had been identified, but who were identified as haplotype carriers in family studies using linkage analysis with respect to the DYT1 locus on chromosome 9 (Bressman et al., 1994). In that study, 42 out of 90 (47%) patients had onset in the leg and 43 out of 90 (48%) in the arm compared with one out of nine and eight out of nine, respectively, in the present study. The difference observed for the onset of dystonia in the arm may be due to the fact that in the study of Bressman et al. the relatives were not systematically examined and mild arm onset dystonia could have been missed. In addition, our sample of patients with the DYT1 mutation is relatively small. The distribution of dystonia was different between the two Ashkenazi Jewish families, remaining focal in one patient of family SAL-416 without the common Ashkenazi Jew haplotype but generalized in the patient from family SAL-449, which shared alleles of the common Ashkenazi Jew haplotype. Incomplete penetrance of ITD, estimated at 30–40% (Bressman et al., 1989), was confirmed by this study, since four individuals who carried the mutation were still unaffected at ages ranging from 7 to 71, later than the latest onset in three other carriers. However, onset up to 44 years of age was reported in the haplotype carrier study of Bressman et al. (1994). Expression of the disease was also incomplete in several other cases, since the disease did not become generalized in all patients, even after disease durations ranging up to 30 years. This suggests that there are other factors modulating the penetrance and phenotypic expression of the disease in addition to the DYTl gene mutation. For clinical practice, it is important to consider the possibility that the DYT1 mutation is present in patients with focal dystonia. A common founder effect is excluded in the French DYT1 families, which probably all derive from independent founder mutations. Furthermore, one Ashkenazi Jew patient carried the common Ashkenazi Jew haplotype, but it was absent in the other Ashkenazi Jew family, indicating at least another ancestral mutation among the Ashkenazi Jew population. At least six independent ancestral mutations can therefore be suspected in the French population. Genetic counselling for ITD is difficult because of the low penetrance and variable clinical expression in DYT1 gene carriers, as well as the existence of further genetic heterogeneity demonstrated by linkage analysis in large pedigrees. Most of our families with early-onset generalized ITD did not have the 946delGAG mutation, and two new loci have recently been identified on chromosomes 8 (Almasy et al., 1997) and 18p (Leube et al., 1997), which are associated with different dystonic phenotypes. Clinical characteristics of 10 DYT1 patients . Positive family history . Sex . Age at onset (years) . Disease duration (years) . Site of onset . Distribution . Tremor . Other . SAL-405-003 Siblings F 10 40 Hand Arm, both legs Writing SAL-405-004 Siblings M 11 37 Unknown Neck, arms, legs, trunk Writing SAL-405-005 Siblings M Childhood 38 Arm Generalized No Bilateral thalamotomy SAL-416-009 Daughter F 20 22 Hand Foot, arm Writing, head Dysarthria SAL-416-014 Mother F 9 3 Hand Both arms No SAL-417-009 Son M 7 30 Hand Writer's cramp No SAL-417-014 Father M 7 3 Hand Larynx, both arms, trunk Postural SAL-420-011 Grandfather F 6 3 Hand trunk Both arms, leg Postural SAL-449-016 No M 9 45 Foot Cranial, neck, arms, legs, trunk Dysarthria SAL-451-011 No M 5 13 Hand Cranial, neck, legs, arms, trunk Postural, writing Nystagmus, decreased reflexes . Positive family history . Sex . Age at onset (years) . Disease duration (years) . Site of onset . Distribution . Tremor . Other . SAL-405-003 Siblings F 10 40 Hand Arm, both legs Writing SAL-405-004 Siblings M 11 37 Unknown Neck, arms, legs, trunk Writing SAL-405-005 Siblings M Childhood 38 Arm Generalized No Bilateral thalamotomy SAL-416-009 Daughter F 20 22 Hand Foot, arm Writing, head Dysarthria SAL-416-014 Mother F 9 3 Hand Both arms No SAL-417-009 Son M 7 30 Hand Writer's cramp No SAL-417-014 Father M 7 3 Hand Larynx, both arms, trunk Postural SAL-420-011 Grandfather F 6 3 Hand trunk Both arms, leg Postural SAL-449-016 No M 9 45 Foot Cranial, neck, arms, legs, trunk Dysarthria SAL-451-011 No M 5 13 Hand Cranial, neck, legs, arms, trunk Postural, writing Nystagmus, decreased reflexes Open in new tab Clinical characteristics of 10 DYT1 patients . Positive family history . Sex . Age at onset (years) . Disease duration (years) . Site of onset . Distribution . Tremor . Other . SAL-405-003 Siblings F 10 40 Hand Arm, both legs Writing SAL-405-004 Siblings M 11 37 Unknown Neck, arms, legs, trunk Writing SAL-405-005 Siblings M Childhood 38 Arm Generalized No Bilateral thalamotomy SAL-416-009 Daughter F 20 22 Hand Foot, arm Writing, head Dysarthria SAL-416-014 Mother F 9 3 Hand Both arms No SAL-417-009 Son M 7 30 Hand Writer's cramp No SAL-417-014 Father M 7 3 Hand Larynx, both arms, trunk Postural SAL-420-011 Grandfather F 6 3 Hand trunk Both arms, leg Postural SAL-449-016 No M 9 45 Foot Cranial, neck, arms, legs, trunk Dysarthria SAL-451-011 No M 5 13 Hand Cranial, neck, legs, arms, trunk Postural, writing Nystagmus, decreased reflexes . Positive family history . Sex . Age at onset (years) . Disease duration (years) . Site of onset . Distribution . Tremor . Other . SAL-405-003 Siblings F 10 40 Hand Arm, both legs Writing SAL-405-004 Siblings M 11 37 Unknown Neck, arms, legs, trunk Writing SAL-405-005 Siblings M Childhood 38 Arm Generalized No Bilateral thalamotomy SAL-416-009 Daughter F 20 22 Hand Foot, arm Writing, head Dysarthria SAL-416-014 Mother F 9 3 Hand Both arms No SAL-417-009 Son M 7 30 Hand Writer's cramp No SAL-417-014 Father M 7 3 Hand Larynx, both arms, trunk Postural SAL-420-011 Grandfather F 6 3 Hand trunk Both arms, leg Postural SAL-449-016 No M 9 45 Foot Cranial, neck, arms, legs, trunk Dysarthria SAL-451-011 No M 5 13 Hand Cranial, neck, legs, arms, trunk Postural, writing Nystagmus, decreased reflexes Open in new tab Fig. 1 Open in new tabDownload slide Partial pedigrees of six DYT1 families. Black squares and circles represent affected men and women, respectively. Asymptomatic gene carriers are represented by a black dot. Asterisks indicate individuals who were sampled and analysed. Haplotypes segregating with the disease are boxed. Distances between markers are indicated according to Ozelius et al. (1997b). Fig. 1 Open in new tabDownload slide Partial pedigrees of six DYT1 families. Black squares and circles represent affected men and women, respectively. Asymptomatic gene carriers are represented by a black dot. Asterisks indicate individuals who were sampled and analysed. Haplotypes segregating with the disease are boxed. Distances between markers are indicated according to Ozelius et al. (1997b). We wish to thank Professor L. Ozelius for giving us the haplotype for the French Canadian DYT1 families, Dr M. Ruberg for critical reading of this manuscript, Drs M. Abada, S. Belal, H. Chneiweiss, A. Nivelon-Chevallier, P. Pollak, O. Rascol, F. Tison and J.-C. Vernant for referring patients, J. Bou for technical assistance and A. Camuzat, C. Penet and Y. Pothin for their contributions to this study. 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Construction of a GT polymorphism map of human 9q. Genomics 1992 ; 12 : 229 –40. Leube B, Hendgen T, Kessler KR, Knapp M, Benecke R, Auburger G. Sporadic focal dystonia in northwest Germany: molecular basis on chromosome 18p. Ann Neurol 1997 ; 42 : 111 –4. Ozelius L, Kramer PL, Moskowitz CB, Kwiatkowski DJ, Brin MF, Bressman SB, et al. Human gene for torsion dystonia located on chromosome 9q32–q34. Neuron 1989 ; 2 : 1427 –34. Ozelius LJ, Kramer PL, de Leon D, Risch N, Bressman SB, Schuback DE, et al. Strong allelic association between the torsion dystonia gene (DYT1) and loci on chromosome 9q34 in Ashkenazi Jews. Am J Hum Genet 1992 ; 50 : 619 –28. Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer PL, Shalish C, et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet 1997 ; 17 : 40 –8. Ozelius LJ, Hewett J, Kramer P, Bressman SB, Shalish C, de Leon D, et al. Fine localization of the torsion dystonia gene (DYT1) on human chromosome 9q34: YAC map and linkage disequilibrium. Genome Res 1997 ; 7 : 483 –94. © Oxford University Press 1999

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Brain – Oxford University Press

Published: Jan 1, 1999

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