Curr Neurol Neurosci Rep DOI 10.1007/s11910-012-0285-4

INVITED COMMENTARY

Phenotypic Differences in Dyt1 Between Ethnic Groups Woong-Woo Lee & Tae-Beom Ahn & Sun Ju Chung & Beom Seok Jeon

# Springer Science+Business Media, LLC 2012

Abstract A DYT1 mutation is the most common genetic cause of early-onset primary torsion dystonia. Herein we present the phenotypes of 25 Korean dystonia patients with DYT1 mutations. We further compare the clinical features of the Asian patients with those of the Western DYT 1 mutation patients. In Korean patients, upper extremity was the most common site of symptom onset while there were a few patients with axial-onset dystonia. Generalized dystonia was the most common subtype followed by segmental dystonia. A Woong-Woo Lee and Tae-Beom Ahn these authors equally contributed to this work. This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education, Science and Technology (2010-0021653). W.-W. Lee Movement Disorder Center, Seoul National University Hospital, 101 Daehak-ro Jongno-gu, Seoul 110-744, South Korea e-mail: [email protected] T.-B. Ahn Department of Neurology, College of Medicine, Kyung Hee University, 23 Kyungheedae-ro Dongdaemun-gu, Seoul 132-872, South Korea e-mail: [email protected] S. J. Chung Department of Neurology, College of Medicine, Ulsan University, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, South Korea e-mail: [email protected] B. S. Jeon (*) Department of Neurology and Movement Disorder Center, Seoul National University Hospital, 101 Daehak-ro Jongno-gu, Seoul 110-744, South Korea e-mail: [email protected]

few patients from the same families had their symptoms at the same age. The clinical features of Korean patients were similar to those of other Asian patients. The Asian patients were differentiated from Western patients by more frequent axial onset, no cranial involvement at onset, and more common segmental dystonia. The variable clinical manifestation in different ethnic groups may suggest that ethnicity is a significant modifier of DYT1 dystonia. Keywords Primary torsional dystonia . DYT1 . Phenotype . Korea . Asian . Ethnic differences

Introduction In 1911, Oppenheim [1] reported on patients with involuntary tonic muscle spasms. These patients with generalized dystonia were first referred to by him as “dystonia musculorum deformans.” The term “Oppenheim dystonia” was based on this historical report, but with the discovery of the DYT1 gene it has gone by the name “DYT1 dystonia.” Since the DYT1 mutation was discovered in the Ashkenazi Jewish population as a founder mutation, it has been established that DYT1 dystonia is the most common genetic cause of early-onset primary torsion dystonia and it has been observed in many ethnic groups [2–4]. It is inherited in an autosomal-dominant pattern with reduced penetrance, approximately 30 % [5]. Although early limb-onset dystonia with eventual generalization is the typical course of DYT1 dystonia, there were a few cases with atypical presentation such as stiff person syndrome, dystonia onset after injury or medication, and severe bulbar involvement [6, 7]. Other characteristics such as late-onset age were also reported as atypical [8]. In our previous study, we reported on several Korean patients with DYT1 dystonia and showed that some

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characteristics of Korean and Japanese patients with DYT1 mutation, such as higher frequency of axial involvement, were different from those of the Western patients [9]. Subsequently, new cases of DYT1 mutation in Chinese patients were also reported [10–13]. In this report we summarize the clinical features of Korean DYT1 dystonia patients. In addition, we will once again compare Asian DYT1 patients with the Western patients, this time including the newly discovered Chinese cohort and our own newly diagnosed cases.

Method Patients and Genetics Genetic testing for the GAG deletion on chromosome 9, which characterized the DYT1 mutation, was performed in all the patients with primary dystonia as a routine clinical practice. All the patients gave their informed consent for the genetic study. A few family members of the patients with DYT1 mutation participated in the genetic evaluation after informed consent. Polymerase chain reaction was performed to detect GAG deletion in the DYT1 gene by the same method used in the previous study [3, 9]. The patients with the DYT1 mutation were identified from the Seoul National University Hospital and the Asan Medical Center. Among the patients with DYT1 mutations, the clinical features of five patients were previously reported [9]. Medical records of all the patients with DYT1 dystonia were reviewed and analyzed. Institutional Review Boards of the hospitals approved our research protocol. Phenotypic Differences According to Ethnicity We searched all the clinical and genetic studies on DYT1 published on PubMed (http://www.ncbi.nlm.nih.gov/ pubmed) until February 2012. For a comparison study among the different ethnic patients the patients were classified into three groups: Ashkenazi Jewish group (AJ), nonJewish Western group (NJ), and Asian group (Asian) including Korean, Japanese, and Chinese patients [9]. We gathered the clinical information about ages at onset, time to generalization, dystonia onset sites, affected body parts, and clinical subtypes [9]. Affected sites were divided into cranial portion, cervical portion, truncal portion, arm and leg. Clinical subtypes were classified as focal, segmental, multifocal, and generalized form. Statistical Analysis The Windows SPSS package (version 18.0) was used for statistical analysis. Various statistical methods such as one-

way ANOVA, chi-square, and Fisher’s exact test were adopted according to data characteristics. As generalized dystonia is the worst subtype and closely related to the age at onset, we further analyzed the relationship between the age at onset and the time required to evolve into generalized dystonia by linear regression. The cutoff value of all the statistical analysis was set at P00.05. Results Clinical Characteristics of Korean Patients with DYT1 Mutation Twenty-five patients had the GAG deletion in the DYT1 gene. The mean onset age was 13.4 (±6.4) years, ranging from 7 to 30 years (Table 1). The ages at onset were the same in Family C (7 years old) and M (12 years old). Focal or segmental dystonia became generalized 8.4 (±9.5) years after the onset in 13 patients who ultimately developed generalized dystonia. Upper extremity was the most common onset site, exclusively in the right side. Among the patients with foot onset, the left side was predominant (71.5 %, 5 out of 7). Symptom onset side was significantly heterogeneous in lower extremity (P00.004). There were three patients with axial-onset dystonia (12 %; 2 cervical onset and 1 truncal onset), all were older than 17 at onset. Generalized dystonia was the most common subtype, followed by segmental dystonia and focal dystonia. There was no patient with multifocal dystonia. The arm was the most frequently involved, followed by the leg, trunk, neck, and face (Fig. 1). The clinical profile of Korean patients was similar to that of other Asian patients except there was more truncal involvement than cervical involvement (Fig. 1). There were four asymptomatic carriers among Family A, H, and L. Seven family members with DYT1 mutation from Family C and L had poorly described nondystonic tremor (Table 1). Comparison Among the Patients with Different Ethnicity There were 293 patients with DYT1 dystonia with detailed clinical data available for comparison study (89 patients in AJ, 148 patients in NJ, and 56 patients in Asian including 25 Koreans). In several studies, the data set was incomplete (Table 2) [2, 9–27]. Age at Onset The age at onset was available in 175 patients (AJ037, NJ083, Asian055) without significant difference among three ethnic groups (AJ 010.8 [±4.5], NJ 013.0 [±8.3], Asian 014.1 [±10.5]).

Curr Neurol Neurosci Rep Table 1 Clinical characteristics of the patients with DYT1 mutation in Korea Family Patient Onset Onset Clinical Involved name number age, y site subtype site

Family data

Time from onset to generalization, y

A

1a

7

H, Rt G

C, N, T, A, L Father: DYT1 (+), asymptomatic

2

B C

2 3b

7 7

A, Rt G H, Rt Foc

A, L A

1.5 –

4b

7

H, Rt Foc

A

D

5

7

H, Rt Foc

A

None

–

E F G H

6 7a 8 9

8 9

F, Rt F, Lt

T, A, L None C, N, T, A, L None

3 3

9 9

F, Lt G H, Rt Foc

T, A, L A

5 –

I J

10 11

10 10

H, Rt G F, Lt G

A, L A, L

K L

12 13a

10 12

F, Rt S H, Rt S

L A

M

N

14c 15c 16c 17

12 12 12 16

H, Rt H, Rt H, Rt H, Rt

S G G Foc

None – Mother: DYT1 (+), asymptomatic Uncle (maternal): DYT1 (+), – tremor A First sister: no genetic study, both hands dystonia (Rt>Lt) – C, N, T, A, L First sister: no genetic study, both hands dystonia (Rt>Lt) 3 A, L First sister: no genetic study, both hands dystonia (Rt>Lt) 3 A Daughter: no genetic study, tremor –

O P Q

18 19 20

R S

21a 22

T U

23a 24

17 17 18 19 22 20 27

H, Rt N H, Rt N H, Rt F, Lt F, Lt

S G S S G G G

N, A N, T, A A N, A T, A, L N, T, A, L N, T, A, L

None None Nephew: no genetic study, tremor None None None None

– 6 – – 23 30 20

V

25

30

T

S

N, T

None

–

Uncle (paternal): no genetic study, dystonia Grandfather: DYT1 (+), tremor Father: DYT1 (+), tremor Uncle (paternal): DYT1 (+), tremor Grandfather: DYT1 (+), tremor Father: DYT1 (+), tremor

–

Uncle (paternal): DYT1 (+), tremor G G

None Mother: DYT1 (+), asymptomatic; Sister: DYT1 (+), asymptomatic None None

7 2

Sorted by onset age. a

Data from our previous study [9].

b

Patient 3 and patient 4 are cousins who share the same grandfather.

c

Patient 14, patient 15, and patient 16 are sisters.

A arm; C cranial; DYT1 (+) positive for DYT1 mutation; Foc focal; F foot; G generalized; H hand; L leg; Lt left; N neck; Rt right; S segmental; T trunk.

Onset Site In Asians, the arm was most frequently affected at onset, followed by the leg and the axial muscles. Asian patients could be characterized by the absence of cranial-onset dystonia, lower frequency of leg-onset dystonia, and more common truncal involvement at onset (Fig. 1a). The majority of AJ were characterized by limb-onset dystonia, leaving only few patients with axial- and cranial-onset

dystonia. Although the limbs were the most common onset site in NJ, the leg was most frequently affected at onset than the arm, unlike other ethnic groups. The proportion of the axialand cranial-onset dystonia in NJ was higher than that of AJ (Fig. 1a). The patients with axial dystonia at onset were significantly older than those with limb-onset dystonia (axial-onset dystonia: n018, 22.2±14.6 years old; limb-onset dystonia: n0152, 11.9±6.8 years old; P<0.05) in all the patients with Asian and Western ethnicity.

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Sites Ever Involved Figure 1c shows several distinctive features of affected sites between ethnic groups. Although the most common site involved was upper extremity in all ethnic groups, the proportion of arm involvement was the least in Asian. The leg was more frequently involved in NJ than in Asian and AJ. The common involvement of the trunk and neck was remarkable in Asian (trunk involvement048.9 % and neck involvement052.1 %). In Asian and AJ, the frequency of facial involvement was about half of that of truncal and cervical involvement, which was not observed in NJ (Fig. 1c). Generalization of Dystonia In a separate analysis of all the patients regardless of the ethnicity, the frequency of generalization was 71.3 % (67 of 94) in the patients with onset age less than 10 years, 54.2 % (32 of 59) between 11 and 20 years, and 31.8 % (7 of 22) more than 21 years (P<0.01 by linear association). The time to generalization was between 8.3 (Korean patients in this study) and 22 years in Asian, whereas it was between 14 and 27 years in the Western patients [7]. Axial-onset dystonia became generalized less frequently than limb-onset dystonia in the Asian patients (P00.048); this difference in generalization between limb-versus axialonset dystonia was not found in other ethnic groups.

Conclusions

Fig. 1 Onset site (a), clinical subtypes (b), and affected sites (c) of the patients with DYT1 dystonia in different ethnic groups. AJ Ashkenazi Jewish patients; NJ non-Jewish Western group

Clinical Subtypes Generalized dystonia was the most common subtype in all ethnic groups, with the highest proportion in NJ. Segmental subtype dystonia was the more common form of dystonia in Asian patients than in other ethnic groups, whereas multifocal phenotype was rarely reported (Fig. 1b). Each subtype of nongeneralized dystonia appeared with similar frequency in AJ and NJ (Fig. 1b).

In this new analysis of our 25 Korean patients with a DYT1 mutation, there were more patients with arm-onset dystonia (40 % → 60 %), a new patient with truncal-onset dystonia, and new cases with focal dystonia (5, hand dystonia), compared to our previous study [9]. It was interesting that only the right side was first affected in all the patients with upper extremity–onset dystonia. In the cases of foot-onset dystonia, the onset was not confined in the right side. The discrepancy between handedness and first-affected side in the lower extremities was observed in the previous studies [16, 20]. Although we do not have detailed data on the relationship between the dominant side and the symptom onset side in our patients, intrinsic bipedal movement could be assumed to underlie the loose association between the handedness and dystonia onset side on the analogy of usage-dependent occurrence of task-specific dystonia such as embouchure dystonia [28]. Various genetic factors (eg, penetrance and genetic modifiers) and environmental factors (eg, critical injury or medication) could result in clinical heterogeneity (eg, onset age or symptom location) and severity from asymptomatic

1 1a 0

0 1c 0a 0

3 (49), 2 (49), 7 (56)b

0

Germany (5) 0 Germany (5) 0a Serbia (3) 0

0 0 0a 0

0 (56)

0

0 0 0

0 0 0

Italy (5) Italy (14) France (7) France (2)

Asian, non-Jews Japan (6)

Japan (11) China (3) China (1)

China (7) Taiwan (3) Korea (25)

0

0a 0 32 (56)

0

0 0a 0

0 0

L

7 2 1 2 1 15

4

3 7 6a 1 17 (56)

3 2a 2

3 0

16 16 3

31 2 1 14a 69 (145)

48 (87)

3 1 0 3 1 7

2

2 6 0a 1 29 (56)

1 0a 1

3 2

27 25 1

19 1 0 17a 102 (148)

37 (87)

Only appeared as axial without specific comments on cervical or truncal involvement.

Numbers of cases with neck, trunk, and total axial muscle involvement at onset.

Some data were uncertain. Tabulation was based on the authors’ decision.

6 1 1 4 1 13

3

4 13 5 1 2 (56)

2 4 1

2 3

30 32 5

25 2 1 21 16 (148)

49 (89)

2 0 0 0 0 0

0

0 0 1 0 16 (56)

1 0 2

2 1

4 3 2

6 0 0 7 15 (148)

13 (89)

Mul

3 2 0 3 1 7

0

1 1 0 1 9 (56)

1 1 0

2 0

4 4 0

8 1 0 5 15 (148)

14 (89)

Seg

C

0 0 0 0 1 5

3

0 0 1 0 10 (47)

1 0 0

0 0

7 6 0

13 0 0 0 22 (78)

2 0a 1 4 0a 3

NA

NA NA 2a 1 25 (48)

6 3 1 5a 1a 9

NA

NA NA 2a 1 22 (45)

3 3 1

1a NA

2a NA 1 3 2

11 NA 3

13 1 0 NA 25 (77)

5 NA 6

4 2 1 NA 25 (78)

T

A

L

7 0a NA 4a 1a 10

NA

NA NA 4a 2 45 (53)

1 2 1

0a NA

22 NA 3

14 1 0 NA 75 (79)

10 2a 1 4a 1a 23

4

NA NA 7 1 34 (54)

4 5 3

5a NA

43 NA 7

50 3 1 NA 60 (79)

9 1 1 4a 2a 13

4

NA NA 5 2

3 4 2

2a NA

35 NA 7

31 2 1 NA

14 (56) 15 (56) 54 (56) 34 (56)

N

Affected sites

13 (89) 7 (56)

Foc

A arm; C cranial; Foc focal; Gen generalized; L leg; Mul multifocal; N neck; NA not available; Seg segmental; T trunk.

c

b

a

The numbers in brackets refer to all available DYT1-dystonia cases in that category.

0 1

0 0

Germany (6) 0 Germany (4) 2

0 0 0

2c 1 2

2 1 1

0 3 2

0 0 0 0a 62 (145)

1 0 0

1 0 0 0a 6 (131), 0 (131), 7 (145)b

1 0 0 0a 7 (145)

0 (87)

0 0 0

1 (87)

A

Gen

T

C

N

Clinical subtype

Onset site

1 (87)

Ashkenazi Jews US (52) France (3) France (1) Israel (33) Western, non-Jews US (45) US (45) US (7)

Race/nation

Table 2 Racial differences in clinical phenotypes of DYT1 mutation

[20] [10] [11] [12] [13] [9] and this study

[18]

[17] [14] [24] [22]

[23] [2] [19]

[15] [25]

[21] [26] [27]

[21] [24] [22] [16]

Reference

Curr Neurol Neurosci Rep

Curr Neurol Neurosci Rep

carriers to florid generalization [7]. In our Korean cohort, there were two families with the patients of the same age at onset. Fixed age at onset of the affected members in the same family was only rarely reported (1 Japanese family and 1 NJ family) [19, 26]. The fixation of onset age seems to be more common in the Asians (3 families) than in the Westerns (1 family). It remains to be studied whether the fixed onset age might reflect stronger influence of DYT1. Age was also important in the generalization of dystonia. The patients with older age at onset showed decreased tendency toward generalization in the analysis of all the Asian and Western patients. The patients with axial-onset dystonia were significantly older with less chance to become generalized than those with limb-onset dystonia only in the Asian patients. As the clinical features of Korean patients were similar to those of other Asian populations, we performed a comparative analysis among the different ethnic groups, which showed unique features of Asian patients. The characteristics of Asian patients are more frequent axial-onset dystonia, absent cranial-onset dystonia, uneven frequencies among nongeneralized phenotypes, less patients with arm involvement, and more patients with axial (truncal + cervical) involvement. There were some features shared with AJ such as the predominance of arm-onset dystonia over leg-onset dystonia, a similar proportion of generalized dystonia, and more common involvement of trunk and neck than face compared to NJ. NJ showed unique features such as more common leg-onset dystonia than arm-onset dystonia, larger proportion of generalized dystonia, and more frequent leg involvement compared to Asian and AJ. Even frequencies of nongeneralized phenotypes were a common feature of AJ and NJ, differing from the predominance of segmental dystonia in Asian (Fig. 1b). As the clinical manifestation of Korean and other Asian patients harbored its own characteristics distinguishable from that of Jewish or non-Jewish Westerners, the ethnicity did play a significant role in clinical variability of DYT1 dystonia. Disclosure Conflicts of interest: W. Lee: none; T. Ahn: none; S.J. Chung: none; B.S. Jeon: has received grant support from SNUH; and has received travel/accommodations/meeting expenses unrelated to activities listed from Korean Neurological Association, Korean Movement Disorder Society.

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