Phenotype variation correlates with CAG repeat length in SCA2 - A study of 28 Japanese patients1

Journal of the Neurological Sciences 159 (1998) 202–208

Phenotype variation correlates with CAG repeat length in SCA2 - A study of 28 Japanese patients 1 a, b d d d Hidenao Sasaki *, Akemi Wakisaka , Kazuhiro Sanpei , Hiroki Takano , Shuichi Igarashi , Takeshi Ikeuchi d , Kiyoshi Iwabuchi e , Toshiyuki Fukazawa c , Takeshi Hamada c , Tatsuhiko Yuasa f , Shoji Tsuji d , Kunio Tashiro a a

Department of Neurology, Hokkaido University, School of Medicine, N-15 W-7, Kita-ku, Sapporo, Japan Department of Pathology, Hokkaido University, School of Medicine, N-15 W-7, Kita-ku, Sapporo, Japan c Hokuyukai Neurological Hospital, Sapporo, Japan d Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan e Department of Neurology and Psychiatry, Kanagawa Rehabilitation Center, Atsugi, Japan f Department of Neurology, Kohnodai Hospital, National Center of Neurology and Psychiatry, Ichikawa, Japan b

Received 12 February 1998; received in revised form 23 April 1998; accepted 28 April 1998

Abstract Spinocerebellar ataxia-2 (SCA2) is an autosomal dominant ataxia caused by an abnormal CAG repeat expansion in a novel gene on chromosome 12q24.1. The size of the mutant allele is unstable during transmission, and correlates inversely with age at onset. We studied eight Japanese SCA2 families, including 28 patients, to assess the effect of repeat length on the phenotype features of SCA2. Frequencies of slow eye movements (SEM), reflex activity, dementia, choreiform movements, and axial tremor correlated significantly with CAG repeat size. Parkinsonism was seen in a man homozygote for SCA2 mutation. The clinical variety of SCA2 is apparently influenced by the size of the mutant allele, as is the case in other CAG repeat disorders.  1998 Elsevier Science B.V. All rights reserved. Keywords: Spinocerebellar ataxia-2; Hereditary spinocerebellar ataxia; Triplet repeat; Slow eye movement; Choreiform movements; Hyporeflexia

1. Introduction Dominantly inherited spinocerebellar ataxia (SCA) is a cluster of heterogeneous disorders. Among these disorders, SCA2 was first mapped to chromosome 12q23–q24.1, based on a linkage study of a Cuban cohort of subjects [10]. Mutation of the SCA2 gene has recently been identified, independently by three different groups, including our group [13,31,33]: the number of CAG repeat units in mutant SCA2 alleles inversely correlates with age at *Corresponding author. Tel.: 181 11 7161161; fax: 181 11 7005356; e-mail: [email protected] 1 Presented in part at the 122nd annual meeting of the American Neurological Association, San Diego, Cal, Sep–Oct, 1997. 0022-510X / 98 / $19.00  1998 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 98 )00166-X

onset, and is unstable during transmission regardless of gender of the affected parent; the SCA2 gene is expressed ubiquitously. A similar mutation was already found in the open reading frame of each gene causing spinal and bulbar muscular atrophy (SBMA) [20] and Huntington’s disease (HD) [39], SCA1 [29], Machado–Joseph disease (MJD) [16], dentatorubral–pallidoluysian atrophy (DRPLA) [18,26], and SCA7 [5]. Neuropathologically, SCA2 affects a multi-systemic structure throughout the nervous system. Olivopontocerebellar atrophy (OPCA) with severe nigral degeneration was the common finding in seven autopsied patients from Cuba [27]. Clinically, the majority of patients had tremor, slow eye movement (SEM) and hyporeflexia, in addition to ataxia [27,28]. After the first description of

H. Sasaki et al. / Journal of the Neurological Sciences 159 (1998) 202 – 208

Cuban subjects, a number of SCA2 families from different ethnic background have been reported [2,3,6,7,12,22,30]. Their clinical features are quite similar to those of Cuban subjects. On the other hand, marked phenotype variation was noted in the six families studied by Geschwind et al. [9]. Recent studies reported that the frequency of several clinical signs, such as myoclonus, dystonia and myokymia, increased with the number of CAG repeats [4,23,36]. Our previous study on a large pedigree disclosed that clinical features varied depending on age at onset [34]. Knowledge of unstable CAG expansions in SCA2 has made it feasible to analyze the phenotypic variations of SCA2 based on size of the expanded CAG repeat of the mutant SCA2 gene. In the present work, we asked whether CAG repeat size of the mutant allele correlates with the phenotypic variation in SCA2.

203

generation was the main finding, such being consistent with findings in Cuban families [27] and from the French West Indies [6]. Clinical features of the largest family (P2) and the linkage analysis to SCA2 locus has been published [34]. In addition to these eight families, two other patients were probands of other families recently identified in Hokkaido and were included in this study. As shown (Table 1), a total of 84 individuals were examined and 35 individuals were found to be affected. Of 35 affected individuals, 28 gave information for age at onset Mean age at onset was 33.1612.9 (S.D.) years, the range being 13–56 years.

2.2. SCA2 allele genotyping These eight families and two additional probands were all enrolled in the previous study for SCA2 mutation, and were subsequently found to carry an abnormally elongated CAG repeat expansion in SCA2 gene [33]. In these subjects, 41 individuals, 35 affected and six at-risk, carried a mutant allele showing abnormal expansion of the CAG repeat. Forty were heterozygotes for the SCA2 allele, having one normal sized allele and one abnormally expanded allele. There was one affected man homozygous for SCA2 mutation. In those 41 individuals carrying the mutant SCA2 allele, CAG repeat size was 18–22 in normal alleles (95% had 22 repeats, n540 alleles), and 35–55 repeats with the mean 41.664.5 (SD, n542 mutant alleles). In the 27 heterozygous patients informative for age at onset, there was a significant inverse correlation between age at onset and number of CAG repeats (Pearson’s correlation coefficient520.81, P,0.001).

2. Materials and methods

2.1. SCA2 families and their background Based on the linkage study, we identified two Japanese families with SCA2 (P2 and P35) in Hokkaido island [12]. Since that report, we identified six other unrelated families (Table 1). Seven of the eight families were originally found on Hokkaido island, and one other family (P65) was identified in Tokyo. Ancestors of the families in Hokkaido came from various areas of the Islands of Japan, and there was no segregation in any particular area. All families were found to be linked with the microsatellites on the SCA2 candidate interval, and only the largest family (P2) had a significant led score with D125105 (Zmax 53.05 at Q 50.00) [34]. Neuropathological examination was made on four autopsied patients from three families, and findings in patients from two families were reported, respectively [1,14] ‘OPCA’ pathology accompanied with severe nigral de-

2.3. Patients for clinical evaluation Twenty-eight patients, 15 men and 13 women, were evaluated by the neurologists among the present authors and were examined using X-ray CT or MR brain imaging.

Table 1 SCA2 family and patients Family

Individuals examined a

Family profiles Collected from

Total

Number of patients

27

11

9

9

P12 P14 P29 P32 P35 P36 P65

Hokkaido, Niigata, Tokyo Hokkaido Hokkaido Hokkaido Hokkaido Hokkaido Hokkaido Tokyo

6 11 5 6 14 5 8

2 3 3 2 6 2 4

2 2 3 1 3 2 4

2 2 3 2 3 2 3

Probands

Hokkaido

2

2

2

2

Total

(8 families)

84

35

28

28

P2

a

Informative for age at onset

Neurologically evaluated

All the subjects were analysed for SCA2 mutation in the Japanese, and the genotyping data are in the original report by Sanpei et al. [33].

204

H. Sasaki et al. / Journal of the Neurological Sciences 159 (1998) 202 – 208

Severely disabled patients were examined in their homes or in institutes where they had been admitted. Of these 28 patients, 27 gave reliable information for age at onset, whereas one man, aged 79, had a history of more than ten years of symptoms but his exact age at onset could not be determined unequivocally. Mean age at onset was 33.5613.1 (S.D.) years, the range being 13–56 years (n527). Mean duration was 13.566.0 years, the range being 2–25 years (n527).

2.4. Statistical analyses Two group differences were examined by two sample t test with Welch’s correction. Correlation for clinical parameters to CAG repeat size, as well as to age at onset and duration of the disorder, were examined by non-parametric Mann–Whitney U test. To examine the difference among three groups, x 2 -method was used to determine frequencies of neurological signs and ANOVA was used in case of clinical duration. A P,0.05 value was considered to be statistically significant.

3. Results

3.1. Clinical features of SCA2 patients In 27 patients heterozygous for SCA2 alleles, ataxia occurred first and was the dominant feature from onset. However, in one man homozygous for SCA2 mutation, symptoms were first like those for parkinsonism, and

parkinsonism concomitant with ataxia and slow eye movement (SEM) was the prominent feature at the time of the present study. Neurological findings of the 28 patients are summarized in Table 2, according to the duration of illness. As shown, ataxia–SEM–hyporeflexia syndrome was the most frequent manifestation. Other frequently accompanying signs and symptoms were extensor plantar response (15 / 28, 54% of all), reduction of vibratory sensation (15 / 28, 54%), and pseudobulbar type dysphagia (14 / 28, 50%). Mild limitation of upward gaze (5 / 28, 18%) or lateral gaze (5 / 28, 18%) was observed in some, but the frequency was not increased with the clinical duration. Gaze nystagmus was infrequent and observed only in three older patients with the onset at ages 38–52 years. With the advance of the disorder, staring eye, facial twitching, or muscle atrophy were evident in some patients. Fasciculation was not observed in limb muscles. Limb reflexes were frequently reduced (20 / 28, 71%), limb reflex was absent in three younger patients with onset ranging from ages 13 to 30 years, whereas it was retained in six older patients when the onset ranged from ages 38 to 52 years. None had limb spasticity. Axial tremor was observed in eight patients, and was particularly severe and disabled the activity in patients in an advanced stage of the disorder. At this stage, loss of interest, emotional lability, inability to concentrate, or disorientation were seen. Such ‘dementia’ was manifested in seven patients (25% of all). Choreiform movements were infrequent (3 / 28, 11%) but were seen in the young patients, for whom onset ranged from ages 13 to 19 years. Parkinsonian rigidity was present in two patients: a bed-ridden patient with 21 years’

Table 2 Neurological features of 28 SCA2 patients Clinical parameters Duration (No of patients) Dementia Dysarthria Staring eye Gaze limitation: upward lateral Slow eye movement Gaze nystagmus Facial twitching Dysphagia Limb atrophy Limb and truncal ataxia Limb reflex: hyperactive Normal Reduced Absent Extensor plantar response Limb hypotonia Parkinsonian rigidity Reduction of vibratory sense Axial tremor Choreiform movements

Frequency of neurological signs (%) 1–10 years (6)

$11 years (22)

Overall (28)

0 100 0 17 33 50 0 17 33 0 100 0 0 83 17 33 50 0 33 33 0

32 100 9 18 14 77 14 18 55 27 100 9 14 68 9 59 55 5 59 27 14

25 100 7 18 18 71 11 18 50 21 100 7 11 71 11 54 54 7 54 29 11

H. Sasaki et al. / Journal of the Neurological Sciences 159 (1998) 202 – 208

205

duration, and a patient homozygous for SCA2 mutation (described later). Myoclonus, as noted in Cuban subjects [28], was not seen in our subjects. In those 27 patients, two patients showed ataxia with few associate signs: one man aged 50 with the duration of 11 years, and the other man aged 52 with the duration of six years. Limb reflex was normal in the former, and reduced in the latter.

3.2. Correlation of neurological signs to the clinical duration, age at onset, and CAG repeats We first searched for a possible correlation between the frequency of various neurological signs and the duration of the disorder. From 27 informative patients, a significant rank correlation (Mann–Whitney U test, P,0.05) was seen for staring eye, SEM, and dysphasia (data not shown). Next, we examined the correlation to the age at onset in these 27 patients. A significant correlation was noted for the frequencies of dementia, SEM, reflex activity, and choreiform movements (data not shown). Dementia, SEM, hyporeflexia, including those with absent limb reflex, and choreiform movements were significantly frequent in patients with onset at a younger age, whereas retained limb reflex was significantly frequent in the later-onset patients. Other neurological signs showed no significant difference for either age at onset or clinical duration. Then, we examined correlation of the frequencies of these clinical features with CAG repeat length of the expanded alleles. For the analysis, a homozygote patient was not included. In the 27 heterozygote patients, mean CAG repeat size of mutant SCA2 allele was 42.964.6 (S.D.), the range being 35–55. A significantly positive correlation was found for dementia, SEM, hyporeflexia, axial tremor, and choreiform movements; dementia, SEM, choreiform movements gave a highly significant P value #0.01. These neurological signs were the same as seen in the correlation study for age at onset. Based on these results, patients heterozygous for SCA2 mutation and informative for onset age (n526) were grouped into three according to the CAG repeat length: the range being 35–40 (group A, n58), 41–45 (group B, n510), and 46–55 repeats (group C, n58). Then, the frequencies of signs correlated with CAG repeat length were compared with findings with the x 2 -method (Fig. 1). Again, significant differences were observed for dementia (P,0.002), choreiform movement (P,0.010), and SEM (P,0.017). To examine whether these differences were influenced by the clinical course, the duration after onset of each groups was compared with ANOVA: mean clinical duration was 13.066.7 years (S.D.) in group A, 14.266.8 in group B, and 13.064.7 in group C. There were no significant differences among the three groups. We conclude that, in SCA2, the variety of clinical presentations is influenced by length of mutant allele.

Fig. 1. Frequencies of neurological signs according to the CAG repeat length of the mutant SCA2 gene.

3.3. Clinical features of a patient homozygote for SCA2 mutation A man from the largest family (P2) was homozygous for the SCA2 allele, with 39 / 39 repeats. His parents were first cousins, both died in the eighth decade of life, and only the father was thought to be affected. In this man, ‘unstable gait’ was the initial symptom, and it appeared at age 38. At age 42, he felt some difficulty in speaking. At age 48, gait disturbance worsened and ‘tremor’ developed in the right hand. At that time, he was diagnosed as having ‘Parkinson’s disease’. Administration of levodopa partially alleviated his symptoms. When he was first examined at age 52 by one of us, he was unable to walk alone. He showed expressionless face, scanning speech, and obvious cogwheel rigidity concomitant with limb and gait ataxia. Parkinsonian type resting tremor was not observed. Limb reflexes were absent, with normal plantar response. Rapid pursuit eye movement was saccadic. Neither gaze limitation, nystagmus, nor SEM was observed at that time. Sensory perception was not disturbed. Brain X-ray CT detected atrophic changes in the cerebellum and brain stem. At the last examination at age 64, he became bed-ridden

206

H. Sasaki et al. / Journal of the Neurological Sciences 159 (1998) 202 – 208

state with marked rigidity, bradykinesia, upward gaze limitation, SEM, and psudobulbar type dysphasia.

4. Discussion Ataxia associated with SEM and hyporeflexia is commonly described in previous studies [2,3,6–8,27,28], indicating that it is the most frequent phenotype in SCA2. However, the phenotype can vary within or between families [3,6,9,34]. Our results indicate that such clinical variation in SCA2 is influenced by the CAG repeat length of mutant allele. Dementia, SEM, hyporeflexia, axial tremor, or choreiform movements significantly correlate with CAG repeat size or age at onset. Among them, dementia, SEM, and choreiform movements gave a highly significant P value (P#0.01) for both age at onset and CAG repeat length. Such neurological manifestations are prone to develop early in the younger-onset patients with a larger CAG repeat expansion than in the later-onset patients with a moderate repeat expansion. On the other hand, limb reflex activity is often preserved in the lateronset patients. SEM correlated with CAG repeat size, as well as age at onset, and also with duration of the illness. This means that SEM is frequent in younger-onset patients and that it becomes evident with the advance of the disorder. These observations are reasonable since there is a strong inverse correlation between age at onset and CAG repeat length in mutant SCA2 gene. The results of the present study almost coincide with those of recent reports [4,23,36]. However, in contrast to their study, either dystonia or myoclonus were not observed in our patients. In DRPLA and MJD, age at onset and phenotypes are known to correlate with the length of mutant allele. In DRPLA, patients with a larger expansion have myoclonus epilepsy, whereas patients with a smaller expansion have a choreoathetosis with ataxia [18]. Also in MJD, patients with a larger expansion manifest bradykinesia–dystonia– spasticity syndrome, whereas patients with a smaller expansion have ataxia with neuropathy [24,38]. Although such variation is not so apparent in SCA1, clinical severity and rate of progression is accelerated in younger-onset patients [15]. The present study showed that such phenotype variation is also seen in SCA2, thereby confirming our previous observations [34], as well as the report from French West Indies [6], that the variety correlates with the age at onset. In other dominant SCA, parkinsonism is a rare manifestation in MJD and is classified as type IV phenotype [32]. However, it is exceedingly rare in the clinical studies of SCA2 [2,3,6,8,27,28]. Recently, only a patient with onset at age 12 was reported to show bradykinesia and marked rigidity [36]. Our patient with parkinsonism means that the clinical spectrum of SCA2 is wider than heretofore considered. Dosage effect of the mutant gene on clinical expression

is not consistent in CAG triplet disorders. In HD, homozygotes do not differ in phenotype, age at onset, or course from typical heterozygotes [25,40]. Such differences are also not apparent in homozygotes for SCA1 mutation; age at onset of homozygotes was reported to correlate with size of a larger, not a smaller mutant allele [11]. On the other hand, acceleration of age at onset and enhanced severity are seen in the homozygotes for MJD mutations [17,21,37,38] and DRPLA [35]: in DRPLA, atypical phenotype presenting spastic paraplegia is reported [19]. In the present study, there was a man homozygote for the SCA2 mutation. Age at onset of the homozygote patient (age 38 years), does not clearly differ from that in four heterozygote patients with 39 repeat units (range: 38–51 years). His illness became manifest with parkinsonism which dominated throughout the entire clinical course. Although the clinical presentation of our homozygous patient is distinct from that of heterozygous patients, its implication needs to be determined in the study of other homozygous patients. From these observations, SCA2 shares common clinical findings as is the case in other CAG triplet repeat disorders, such as SBMA, HD, SCAl, MJD/ SCA3, and DRPLA. In all these disorders, an unstable CAG repeat inversely correlates with age at onset, can produce anticipation phenomenon and phenotype variation. These similarities support the thesis that a common mechanism is likely to underlie in the molecular pathology of such disorders. However, it is uncertain how the polyglutamine repeat, the transcript of CAG repeats, impair cellular metabolism, and subsequently slowly progressive neuronal cell death with selective anatomical involvement occurs.

Acknowledgements We thank members of the families for participation in this study. This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas and a Grant-in-Aid for Scientific Research hA(2) and B(2)j, Ministry of Education, Science, Sports and Culture, Japan, and a grant from Research on Ataxic Diseases, the Ministry of Health and Welfare, Japan.

References [1] Ando M, Takahashi T, Fujii M. An autopsy case of olivopontocerebellar atrophy (hereditary type). Asahikawa Nisseki Ishi (in Japanese) 1991;5:182–197. [2] Belal S, Cancel G, Stevanin G, Hentati F, Khati C, Ben Hamida C, Auburger G, Agid Y, Ben Hamida M, Brice A. Clinical and genetic analysis of a Tunisian family with autosomal dominant cerebellar ataxia type one linked to the SCA2 locus. Neurology 1994;44:1423– 6. ¨ [3] Burke K, Abele M, Fetter M, Dichgans J, Skalej M, Laccone F, Didierjean O, Brice A, Klockgether T. Autosomal dominant cerebel-

H. Sasaki et al. / Journal of the Neurological Sciences 159 (1998) 202 – 208

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

lar ataxia type I. Clinical features and MRI in families with SCA1, SCA2, and SCA3. Brain 1996;119:1497–505. ¨ A, Didierjean O, Imbert G, Burk K, Lezin A, Belal Cancel G, Durr ˜ J, Chneiweiss S, Benomar A, Abada-Bendib M, Vial C, Guimaraes H, Stevanin G, Yvert G, Abbas N, Saudou F, Lebre A-S, Yahyaoui M, Hentati F, Veniant J-C, Klockgether T, Mandel J-L, Agid Y, Brice A. Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families. Hum Mol Genet 1997;6:709–15. ¨ A, Yvert G, Cancel G, Weber David G, Abbas N, Stevanin G, Durr C, Imbert G, Saudou E, Drabkin H, Gemmill R, Giunti P, Benomar A, Wood N, Ruberg M, Agid Y, Mandel J-L, Brice A. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 1997;17:65–70. ¨ A, Smadja D, Cancel G, Lezin A, Stevanin G, Mikol J, Durr Bellance R, Buisson G-G, Chneiweiss H, Dellanave J, Agid Y, Brice A, Vemant J-C. Autosomal dominant ataxia type I in Martinique (French West Indies): clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families. Brain 1995;118:1573– 81. Filla A, De Michele G, Banfi S, Santoro L, Perretti A, Cavalcanti F, Pianese L, Castaldo I, Barbieri F, Campanella G, Cocozza S. Has spinocerebellar ataxia type two a distinct phenotype? Genetic and clinical study of an Italian family. Neurology 1995;45:793–6. Filla A, De Michele G, Campanella G, Perretti A, Santoro L, Serlenga L, Ragno M, Calabrese O, Castaldo I, De Joanna G, Cocozza S. Autosomal dominant cerebellar ataxia type I. Clinical and molecular study in 36 Italian families including a comparison between SCA1 and SCA2 phenotypes. J Neurol Sci 1996;142:140– 7. Geschwind DH, Perlman S, Figueroa CP, Treiman LJ, Pulst SM. The prevalence and wide clinical spectrum of the spinocerebellar ataxia type two trinucleotide repeat in patients with autosomal dominant cerebellar ataxia. Am J Hum Genet 1997;60:842–50. Gispert S, Twells R, Orozco G, Brice A, Weber J, Heredero L, Scheufler K, Riley B, Allotey R, Nothers C, Hillermann R, Lunkes A, Khati C, Stevanin G, Hernandez A, Magariflo C, Klockgether T, ¨ A, Chneiweiss H, Enczmann J, Farrall M, Beckmann J, Mullan Durr M, Wemet P, Agid Y, Freund H-J, Williamson R, Auburger G, Chamberlain S. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23–24.1. Nat Genet 1993;4:295–9. Goldfarb LG, Vasconcelos O, Platonov FA, Lunkes A, Kipnis V, Kononova S, Chabrashvili T, Vladimirtsev VA, Alexeev VP, Gajdusek DC. Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1. Ann Neurol 1996;39:500–6. Ihara T, Sasaki H, Wakisaka A, Takada A, Yoshiki T, Matsuura T, Hamada T, Suzuki Y, Tashiro K. Genetic heterogeneity of dominantly inherited olivopontocerebellar atrophy (OPCA) in the Japanese: linkage study of two pedigrees and evidence for the disease locus on chromosome 12q (SCA2). Jpn J Hum Genet 1994;39:305– 13. Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Gamier J-M, ¨ A, Didierjean O, Weber C, Mandel J-L, Cancel G, Abbas N, Durr Stevanin G, Agid Y, Brice A. Cloning of the gene for spinocerebellar ataxia-2 reveals a locus with high sensitivity to expanded CAG / glutamine repeats. Nat Genet 1996;14:285–91. Iwabuchi K, Nagatomo H, Tanabe T, Oda T, Itoh H, Hanihara T, Yagishita S. A family with Menzel’s disease showing dementia and various extrapyramidal symptoms. Brain and Nerve (in Japanese) 1993;45:841–9. Jodice C, Malaspina P, Persichetti F, Novelletto A, Spadaro M, Giunti P, Morocutti C, Terrenato L, Harding AE, Frontali M. Effect of trinucleotide repeat length and parental sex on phenotypic variation in spinocerebellar ataxia one. Am J Hum Genet 1994;54:959–65. Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I,

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30] [31]

[32]

207

Kimura J, Narumiya S, Kakizuka A. CAG expansions in a novel gene for Machado–Joseph disease at chromosome 14q32.1. Nat Genet 1994;8:221–7. Kawakami H, Maruyama H, Nakamura S, Kawaguchi Y, Kakizuka A, Doyu M, Sobue G. Unique features of the CAG repeats in Machado–Joseph disease. Nat Genet 1995;9:341–5. Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T, Saito M, Tomoda A, Miike T, Naito H, Ikuta F, Tsuji S. Unstable expansion of CAG repeat in hereditary dentatorubral–pallidoluysian atrophy (DRPLA). Nat Genet 1994;6:9–13. Kurohara K, Kuroda Y, Maruyama H, Kawakami H, Yukitake M, Matsui M, Nakamura S. Homozygosity for an allele carrying intermediate CAG repeats in dentatorubral–pallidoluysian atrophy (DRPLA) gene results in spastic paraplegia. Neurology 1997;48:1087–90. LaSpada AR, Wilson EM, Lubhn DB, Harding AE, Fishbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77–9. Lang AE, Rogaeva EA, Tsuda T, Hutterer J, St George-Hyslop P. Homozygous inheritance of the Machado–Joseph disease gene. Ann Neurol 1994;36:443–7. Lopes-Cendes I, Andermann E, Attig E, Cendes F, Bosch S, Wagner M, Gerstenbrand F, Andermann F, Rouleau GA. Confirmation of the SCA-2 locus as an alternative locus for dominantly inherited spinocerebellar ataxias and refinement of the candidate region. Am J Hum Genet 1994;54:774–81. Lorenzetti D, Bohlega S, Zoghbi HY. The expansion of the CAG repeat in ataxin-2 is a frequent cause of autosomal dominant spinocerebellar ataxia. Neurology 1997;49:1009–13. Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, Dawson DM, Sudarsky L, Guimaraes J, Loureiro JEL, Nezarati MM, Corwin LI, Lopes-Cendes I, Rooke K, Rosenberg R, MacLeod P, Farrer LA, Sequeiros J, Rouleau GA. Correlation between CAG repeat length and clinical features in Machado–Joseph disease. Am J Hum Genet 1995;57:54–61. Myers RH, Leavitt J, Farrer LA, Jagadeesh J, McFarlane H, Mastromauro CA, Mark RJ, Gusella JF. Homozygote for Huntington disease. Am J Hum Genet 1989;45:615–8. Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, Takeda T, Tadokoro K, Kondo I, Murayama N, Tanaka Y, Kikushima H, Umino K, Kurosawa H, Furukawa T, Nihei K, Inoue T, Sao A, Komure O, Takahashi M, Yoshizawa T, Kanazawa I, Yamada M. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet 1994;6:14–8. ˜ J, Fernandez R, GonzalezOrozco G, Estrada R, Perry TL, Arana Quevedo A, Galarraga J, Hansen S. Dominantly inherited olivopontocerebellar atrophy from eastern Cuba; clinical, neuropathological, and biochemical findings. J Neurol Sci 1989;93:37–50. ´ Sagaz R, Auburger Orozco Diaz G, Nodarse Fleites A, Cordovese G. Autosomal dominant cerebellar ataxia: clinical analysis of 263 ´ Cuba Neurolopatients from a homogeneous population in Holguın. gy 1990;40:1369–75. Orr HT, Chung M-Y, Banfi S, Kwiatokowski Jr. TJ, Servadio A, Beaudet AL, McCall AE, Duvick LA, Ranum LPW, Zoghbi HY. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1993;4:221–6. Pulst S-M, Nechiporuk A, Starkman S. Anticipation in spinocerebellar ataxia type 2. Nat Genet 1993;5:8–10. Pulst S-M, Nechiporuk A, Nechiporuk T, Gispert S, Chen X-N, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, DeJong P, Rouleau GA, Auburger G, Korenberg JR, Figueroa C, Sahba S. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 1996;14:269–76. Rosenberg RN. Machado–Joseph disease: an autosomal dominant motor system degeneration. Mov Disord 1992;7:193–203.

208

H. Sasaki et al. / Journal of the Neurological Sciences 159 (1998) 202 – 208

[33] Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, Wakisaka A, Tashiro K, Ishida Y, Ikeuchi T, Koide R, Saito M, Sato A, Tanaka H, Hanyu S, Takiyama Y, Nishizawa M, Shimizu N, Nomura Y, Segawa M, Iwabuchi K, Eguchi I, Tanaka H, Takahashi H, Tsuji S. Identification of the gene for spinocerebellar ataxia type two (SCA2) using a direct identification of repeat expansion and cloning technique (DIRECT). Nat Genet 1996;14:277–84. [34] Sasaki H, Fukazawa T, Wakisaka A, Hamada K, Hamada T, Koyama T, Tsuji S, Tashiro K. Central phenotype and related varieties of spinocerebellar ataxia-2 (SCA2) - a clinical and genetic study with a pedigree in the Japanese. J Neurol Sci 1996;144:176– 81. [35] Sato K, Kashihara K, Okada S, Ikeuchi T, Tsuji S, Shomori T, Shomori T, Morimoto K, Hayabara T. Does homozygosity advance the onset of dentatorubral–pallidoluysian atrophy? Neurology 1995;45:1934–6. [36] Shols L, Gispert S, Vorgerd M, Vieira-Saecker AMM, Blanke P, Auburger G, Amoiridis G, Meves S, Epplen JT, Przuntek H, Pulst S-M, Riess O. Spinocerebellar ataxia type 2. Genotype and phenotype in German kindreds. Arch Neurol 1997;54:1073–80. [37] Sobue G, Doyu M, Nakao N, Shimada N, Mitsuma T, Maruyama H,

Kawakami H, Nakamura S. Homozygosity for Machado–Joseph disease gene enhances phenotypic severity. J Neurol Neurosurg Psychiatry 1996;60:354–7. [38] Takiyama Y, Igarashi Y, Rogaeva EA, Endo K, Rogaev EI, Tanaka H, Sherrington R, Sanpei K, Liang Y, Saito M, Tsuda T, Tanano H, Ikeda M, Lin C, Chi H, Kennedy JL, Lang AE, Wherrett JR, Segawa M, Nomura Y, Yuasa T, Weissenbach J, Yoshida M, Nishizawa M, Kidd KK, Tsuji S, St George-Hyslop PH. Evidence for intergenerational instability in the CAG repeat on the MJD1 gene and conserved haplotypes at flanking markers amongst Japanese and caucasian subjects with Machado–Joseph disease. Hum Mol Genet 1995;4:1137–46. [39] The Huntington’s disease collaborative research group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993;72:971–83. [40] Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney JB, Snodgrass SR, Shoulson I, Gomez F, Arroyo MAR, Penchaszadeh GK, Moreno H, Gibbons K, Faryniarz A, Hobbs W, Anderson MA, Bonilla E, Conneally PM, Gusella JF. Homozygotes for Huntington’s disease mutation. Nature 1987;326:194–7.