原著論文

Autosomal Dominant Cerebellar Ataxia among patients of
the Asahikawa Medical Center in Hokkaido
Yasuhiro Suzuki 1,2), Kento Sakashita 1), Hideaki Kishi1), Kenta Nomura1), Kosuke Yoshida1),
Yoko Aburakawa1), Kenji Kuroda1), Takashi Kimura1), Yoshiki Adachi3),
Chisato Murakami2), and Osamu Yahara1)
1)
2)
3)

Department of Neurology, Asahikawa Medical Center, National Hospital Organization, Asahikawa, Japan

Department of Clinical Research, Asahikawa Medical Center, National Hospital Organization, Asahikawa, Japan

Department of Neurology and Clinical Research, Matsue Medical Center, National Hospital Organization, Matsue, Japan

Abstract
Object The occurrence of autosomal dominant cerebellar ataxia (ADCA) differs widely by locationworldwide. The aim of this study was to assess the prevalence of ADCA subtypes among patients of
Asahikawa Medical Center in Hokkaido.
Patients and Methods This study was performed from July 2012 to June 2015. PCR and/or direct
sequencing were carried out for 50 participants who were each clinically diagnosed with spinocerebellar
ataxia (SCA).
Results Among the 50 participants, 25 had familial SCA, and 25 had sporadic SCA. SCA6 was the mostcommon type identified, found in 14 (43.8%) cases among 32 genetically confirmed cases. SCA6 wasfollowed by SCA1, SCA31, and dentatorubral-pallidoluysian atrophy (DRPLA), which each accountedfor four (12.5%) of the 32 cases. SCA7 and SCA17 were not detected in this study. Two SCA6 patientswere homozygous for a 21-CAG repeat allele, and each presented with early onset, pure cerebellar ataxia.
Among the 25 sporadic patients, 11cases (44%) was clarified one case with SCA1, six SCA6, one SCA8,
one SCA31, and two DRPLA. Notably, 18 participants could not be classified into an SCA type.
Conclusion This study reveals the prevalence of ADCA in Asahikawa Medical Center. It is important
to correctly diagnose the SCA subtype of each for effective counseling, management of therapy, andunderstanding of prognosis.
Key words: Asahikawa, autosomal dominant cerebellar ataxia, SCA6, homozygous, SCA31

Yasuhiro Suzuki, MD, PhD

Department of Neurology and Departmen of Clinical Research, Asahikawa Medical Center,
National Hospital Organization 7. Hanasaki-Chyo, Asahikawa, Hokkaido 070-8644, Japan
Tel: +81-166-51-3161; Fax: +81-166-53-9184
E mail: ysuzuki@asahikawa.hosp.go.jp―7―

SCA8, SCA17, or DRPLA were assessed by polymerase

Introduction

chain reaction (PCR) amplification with primer pairs, as

Autosomal dominant cerebellar ataxia (ADCA),

described by Mori et al. 3) Additionally, the PCR-RFLP

genetically defined as spinocerebellar ataxia (SCA), is(restriction fragment length polymorphism), method wascharacterized as progressive ataxia with variable degrees ofused to screen for mutations in the SCA31 gene 4).

extracerebellar symptoms. Harding proposed that ADCA
could be clinically divided into three categories, TypeResults

I, Type II, and Type III 1). However, we prefer a genetic

Blood samples were collected from each of the 50

classification based upon associated SCA loci. Notably,

participants who together represented a total of 46 families;

the number of newly identified SCA types is growing, and25 patients (6 males and 15 females from 19 different

SCA1 through SCA40 are currently recognized. Geneticfamilies and 10 males and 15 females from 21 differentabnormalities associated with this condition are variablefamilies) had familial SCA, and the other 25 patients (13and include repeat expansions in coding and noncoding

males and 12 females representing 25 different families)

regions of target genes, conventional mutations, and large

had sporadic SCA. The sex ratio, mean age at onset,gene rearrangements. Each genetic disorders can result

number of family members, and mean disease duration ofin neuronal cell death due to toxic gain-of-function or

the 50 participants from the 46 families are listed in Tableloss-of-function mechanisms. Several published studies

1. Mean age at onset and mean disease duration were 43.8

have reported that the frequency of ADCA varies among± 15.6 years and 16.0 ± 8.4 years, respectively, for thedifferent regions of Japan. To understand the etiology offamilial cases and 49.6 ± 14.4 years and 13.2 ± 8.1 years,

SCA, we investigated the prevalence of SCA at Asahikawa

respectively, for the sporadic cases. Table 2 summarizes theMedical Center, Asahikawa, Hokkaido.

results of the genetic analysis. Twenty one individuals from19 families had familial SCA (9 males and 12 females), andPatients and methods

11 individuals (6 males and 5 females) from 11 families hadPatientssporadic SCA. All patients were Japanese. SCA6, which

This study was performed from July 2012 to June 2015.

causes a polyglutamine disorder due to an expanded CAG

A total of 50 patients (23 males and 27 females) with ataxia

repeat in CACNA1A , was the most common, accounting

were enrolled in this study. The familial SCA patients arefor 14 (43.8%) of the 32 cases. Of 14 patients with SCA6

determined that there are progressors in family history. On(the 14 SCA6 patients), two were homozygous for athe other hand, the sporadic SCA patients are showed cases

21-repeat expansion; age at disease onset was 48 years oldthat unable to confirm proband. This study was approved byfor one patient and 58 years old for the other. The second

the Ethics Committee of Matsue Medical Center. Informed

most common were SCA1, SCA3, and DRPLA, accounting

consent was obtained from each participant prior to thefor four cases each. Of the 50 participants, four familial

study. Magnetic resonance imaging (MRI) was performed

SCA patients and 14 sporadic SCA patients could not beusing a 1.5 T MR scanner, and axial T1 weighted, T2 shortclassified into an SCA type.
Figure 1 shows the relationship between the age ofT inversion recovery (STIR), and ﬂuid-attenuated inversion

Table 1

recovery (FLAIR) images were generated for each patient.

Genetic analysis
Blood samples were obtained from each patient, andTable 1 Sex ratio, mean age at onset, and mean disease
duration among the present cases. Mean age of onset
and mean disease duration is showed by mean ± SD.

samples were used for molecular genetic analysis. Genomic
DNA was isolated from peripheral blood lymphocytes bya standard phenol/chloroform method. The presence ofmutations related to SCA1, SCA2, SCA3, SCA6, SCA7,

Number of families
Number of cases
Sex ratio (M/F)
Mean age at onset (Y)Mean disease duration (Y)―8―Familial cases

Sporadic cases

2125
10 / 1543.8 ± 15.6
16.0 ± 8.4252513 / 1249.6 ± 14.4
13.2 ± 8.1

Table 2
Table 2

Results of a genetic analysis examining 50 cases of spinocerebellar ataxia
The numbers in parenthesis shows percentage of each disorder among all diagnosed cases.
Familial

Disease namegure 1Sporadic

Family numbers

Cases (%)

Cases (%)

Total cases (%)

SCA1
SCA2
SCA3
SCA6
SCA7
SCA8
SCA17
SCA31DRPLA

312
70
20223
12
80
20
3
2

100
60
10
1
2

4 (12.5)
1 (3.0)2 (6.3)14 (43.8)0 (0)3 (9.4)0 (0)4 (12.5)
4 (12.5)

Number of diagnosed cases
Number of undiagnosed cases

221(84)4 (16)

11 (44)14 (56)32 (64)18 (36)

Total numbers

2125

2550

However, no family history of ataxia was reported for thelatter, and genetic analysis was not performed. Interestingly,
age of onset is wide range from 46-year-old to 72-year-old
in 22-repeat expansions in SCA6.
SCA8 expansions were detected in three individuals
from three different families. One patient was a 75-yearold female who developed the condition at 65 years ofage and had a 126-repeat expansion. Other SCA8 patients(a 79-year-old and a 50-year-old female) developed thecondition in their 20s. The two had comparable expansionsof 123 repeated units and 142 repeated units, respectively.
In addition, the 50-year-old female with SCA8 had a left
trigeminal schwannoma.
Figure 1 Relationship between age of onset and CAG repeat
length at expanded alleles in affected individuals(n=14, R2=0.55). The regression line is Y= -8.05X+
232.2 (where Y represents age of onset and X
represents repeat length). The cases involving
homozygous SCA alleles are indicated by an arrow.

Four individuals from three different families were eachfound to possess a SCA31 repeat expansion. One was a
79-year-old female (59 years old at disease onset) who had
an 4.0 kb insertion that contained a (TGGAA) n stretch.
Her brother and uncle each had ataxia, though neither
participated in the genetic analysis. Another two cases wereonset and the CAG-repeat length in the expanded allelesin affected individuals. An inverse correlation (n =14,R2=0.55) was noted between the length of CAG repeats andthe age of onset for individuals affected by SCA6. Of thetwo individuals with homozygous 21-repeat expansions inSCA6, one was a 68-year-old female who developed thecondition at 48 years of age, and the other was a 76-yearold female who developed the condition at 58 years of age.

a 79-year-old male and his 68-year-old brother who each
had an (TGGAA)n insertion; one was 3.4 kb long, and theother was 3.1 kb. The remaining case was a 65-year-oldmale with a sporadic case of ADCA.
Of the 11 sporadic SCA patients, six were due to SCA6,
two were due to DRPLA, and one case each was due toSCA1, SCA8, or SCA31. In this study, there were no cases
associated with SCA7 or SCA17.

―9―

in the CACNA1A gene, which codes for an α1A-voltage-Discussion

dependent calcium channel subunit, and belongs to a group

In the present study, we performed a genetic analysis

of CAG triplet repeat diseases that include SCA1, SCA2,of patients with SCA and investigated the prevalence ofMachado-Joseph disease (MJD)/SCA3, SCA7, SCA12, andADCA in the area around the Asahikawa Medical Center.

DRPLA 10). Normal CACNA1A alleles have 4 to 18 repeats,

The findings demonstrated that SCA6 was the mostwhereas expanded alleles in patients with SCA6 have 20 tocommon form of SCA. In addition, SCA1, SCA31, and29 repeats. Many published reports show that CAG-repeat

DRPLA were equally the second most common forms

length is loosely related to the age of onset. For example,of SCA. In the study, we demonstrated that there wereMariotti et al. described cases involving homozygous

cases which could be diagnosed with familial SCA even if

SCA6 alleles with intermediate-sized 19-repeat expansions

sporadic SCA patients. It is expected that precise genetic

11). In addition, Komeichi et al. described two sibs withdiagnose lead to appropriate genetic treatments in theSCA6 who were both homozygous for 20-repeat alleles

future.

12)

In Japan, the frequency of ADCA varies among several
3, 5, 6, 7); however, neither of the parents developed ataxia. We

examined two patients from different families who were. Recent reports from other districts of Japan

both homozygous for a 21-repeat expansion in SCA6 anddemonstrate that SCA3, SCA 6, and DRPLA are prevalent.

found that one patient had an earlier age of onset (48 years

In Japan, SCA31 is diagnosed based on disease-specificold). In 22-repat expansion in SCA6, we showed that there

insertions of penta-nucleotide (TGGAA) n repeats inis wide range of onset age from 47 to 72-year-old. Whether

SCA31-critical lesions upstream of PLEKHG4, and it haschanges in gene dosage caused gain-of-function or loss-of-areas4)

been defined as a fourth subtype of ADCA . Surprisingly,

function was unclear; nevertheless, our results suggested

SCA31 is the predominant subtype of ADCA in Nagano.

that the dosage of the CAG repeats expansion played someIn Nagano, approximately 42% of ADCA families haverole in phenotypic expression of SCA6.

8)SCA31 . Four out of the 32 participants identified withSCA8, classified as type I ADCA, is characterized

an SCA type (12.5%) were found to have with SCA31 in

by a slow progressive, predominantly cerebellar ataxia,

the current study. SCA6 and SCA31 are each subtypes ofcognitive dysfunction, pyramidal and sensory signs, and aADCA characterized by adult-onset and pure cerebellar

variable age at onset. Marked cerebellar atrophy is foundataxia; moreover, clinical features of these conditions areon MRI or CT scans 13, 14). Therefore, it can be difficult tovery similar. Consequently, it can be difficult to accurately

clinically discriminate SCA8 from the other SCAs, similar

diagnose these conditions. To address this, Sakakibara etto our three cases in the present study. First described inal. showed that SCA31 patients, unlike SCA6 patients, had1999 15), SCA8 is known to be associated with CTG/CAG

hearing loss and that MRI findings differed between SCA31

repeat expansion in the ataxin 8 gene on chromosomeand SCA6; specifically, cerebellar atrophy starts from

13q21. The pathogenesis of SCA8 is thought to result fromthe upper vermis in SCA31 patients, whereas the fourthRNA-mediated neurotoxicity that is similar to what causes

ventricle with middle cerebellar peduncle atrophy becomes

myotonic dystrophy type I 16).
In conclusion, we determined the prevalence of SCAenlarged in SCA6 patients, even at the early stage of disease9)

onset . The MRI findings of our study (data not shown)

subtypes among ADCA patients at Asahikawa Medical

were similar to those of Sakakibara et al. These differences

Center. This study verified the existence of geneticallybetween SCA6 and SCA31 in brain images might play aidentifiable SCA subtypes among patients with sporadic

key role in accurate diagnosis, although genetic analysis isADCA. It is important to correctly diagnose the SCA

also very important for distinguishing between SCA6 fromsubtype of each for effective counseling, management ofSCA31.

therapy, and understanding of prognosis.

SCA6 is caused by a small expansion of CAG repeats― 10 ―

type 31 is associated with “inserted” penta-nucleotide repeats

Conflict of Interest

containing (TGGAA)n. Am J Hum Genet. 2009; 85:544-557
14) Todd PK, Paulson HL. RNA-mediated neurodegeneration inThe authors state that they have no conﬂict of interest.

repeat expansion disorders. Ann Neurol. 2010; 67:291-300
15) Yamamoto-Watanabe Y, Watanabe M, Hikichi M, et al.

Acknowledgements

Prevalence of autosomal dominant cerebellar ataxia in Aomori,This study was supported in part by a grant-in-Aid forthe northernmost prefecture of Honshu, Japan. Intern Med. 2010;

Clinical Research from the National Hospital Organization.

49:2409-2414

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