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Spinocerebellar Ataxia Type 1 in China
Molecular Analysis and Genotype-Phenotype Correlation in 5 Families
Yong-Xing Zhou, MD, PhD;
Wen-Hui Qiao, MD;
Wei-Hong Gu, MD;
Heng Xie, MD, PhD, MPH;
Bei-Sha Tang, MD;
Lian-Sheng Zhou, MD;
Bin-Xian Yang, MD;
Yoshihisa Takiyama, MD, PhD;
Shoji Tsuji, MD, PhD;
Hui-Yu He, MD;
Chu-Xia Deng, PhD;
Lev G. Goldfarb, MD, PhD;
Guo-Xiang Wang, MD, PhD
Arch Neurol. 2001;58:789-794.
ABSTRACT
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Background Twelve genetic types of autosomal dominant hereditary ataxia have been
recently identified and the genes responsible for most of them cloned. Molecular
identification of the type of ataxia is important to determine the disease
prevalence and its natural history in various populations.
Objectives To perform molecular analysis of 75 Chinese families affected with spinocerebellar
ataxia (SCA) and to evaluate the spectrum of mutations in these genes and
the correlation between genotypes and phenotypes in Chinese patients.
Setting Neurogenetics Unit, China-Japan Friendship Hospital, Beijing, China.
Methods One hundred nine patients from 75 kindreds diagnosed as having autosomal
dominant SCA, 16 patients with sporadic SCA or spastic paraplegia, 280 control
chromosomes of the Chinese population, and 120 control chromosomes of the
Sakha population were selected for this study. We conducted detailed mutational
analysis by direct sequencing of polymerase chain reaction products amplified
from genomic DNA.
Results Spinocerebellar ataxia type 1 (SCA1) was identified in 5 families with
12 studied patients. All affected family members were heterozygous for a CAG
repeat expansion in the SCA1 gene containing 51 to
64 trinucleotide repeats. Normal alleles had 26 to 35 repeats. Spinocerebellar
ataxia type 1 accounted for 7% of the studied Chinese families with ataxia.
In addition, we determined the frequency of a single vs double CAT interruption
in 120 control chromosomes of the Siberian Sakha population, which has the
highest known prevalence of SCA1, and compared this with 280 control chromosomes
from the Chinese populations. The results show that 64.7% of the Siberian
normal alleles contain a single CAT interruption, whereas 92% of the Chinese
had more than 1 interruption.
Conclusions Spinocerebellar ataxia type 1 is responsible for 7% of affected families
in the Chinese population. A correlation between the prevalence of SCA1 and
the number of CAT interruptions in the trinucleotide chain suggests that a
CAT-to-CAG substitution may have been the initial event contributing to the
generation of expanded alleles and influencing relative prevalence of SCA1.
INTRODUCTION
THE DOMINANTLY inherited spinocerebellar ataxias (SCAs) represent a
group of genetically diverse neurological conditions that are characterized
by progressive deterioration of balance due to degeneration of the cerebellum
and its afferent and efferent pathways.1, 2
Extracerebellar symptoms include nuclear or supranuclear ophthalmoparesis,
slow saccades, pyramidal and extrapyramidal signs, and axonal neuropathy.
Several genetically distinct types of autosomal dominant ataxia have been
mapped: SCA type 1 (SCA1) to chromosome 6p,3
SCA2 to 12q,4 SCA3/Machado-Joseph disease (MJD)
to 14q,5, 6 SCA4 to 16q,7 SCA5 to 11cen,8 SCA6
to 19p,9 SCA7 to 3p,10, 11, 12
SCA8 to 10q24,13 SCA10 to 22q13,14
SCA11 to 15q14-21.315 and SCA12 to 5q31-33.16 In 6 types, SCA1,17
SCA2,18, 19, 20 SCA3/MJD,21 SCA6,9 SCA7,22 and SCA12,16 the disease-causing
gene has been cloned and the mutation identified as an expansion of a CAG
trinucleotide repeat in the gene coding region. CAG repeat expansion is the
mutational mechanism in a large group of neurodegenerative diseases that includes,
in addition to ataxias, spinobulbar muscular atrophy,23
Huntington disease,24 and dentatorubral pallidoluysian
atrophy (DRPLA).25, 26
Spinocerebellar ataxia type 1 is an autosomal dominant neurodegenerative
disorder characterized by cerebellar ataxia, progressive motor deterioration,
and loss of cerebellar Purkinje cells and brainstem neurons. This type of
disease was first reported by Schut27 in a
large US family of Russian extraction. The SCA1 locus
was initially linked to the vicinity of the HLA locus on the short arm of
chromosome 6 in a small Japanese family,3 and
subsequently the SCA1 gene was mapped to the 6p22-p23
chromosomal region.28, 29, 30, 31, 32
The SCA1 gene was subsequently cloned and the mutation
identified as an unstable trinucleotide CAG repeat.17
This study was part of a larger effort to characterize 75 Chinese families
diagnosed as having autosomal dominant SCA. The results of molecular analysis
allowed the identification of SCA3/MJD in 26 of these families,33
SCA2 in 9,34 SCA6 in 2 (Y.-X.Z., et al, unpublished
data, 2000), and SCA7 in 2 (W.-H.G., et al, unpublished data, 2000), and we
provide herein the first documentation of molecularly confirmed SCA1 in Mainland
China.
PATIENTS AND METHODS
PATIENTS
One hundred nine individuals from 75 kindreds with autosomal dominant
SCA, 16 patients with sporadic SCA or spastic paraplegia, 280 control chromosomes
of the Chinese population, and 120 control chromosomes of the Sakha population
were selected for this study. The affected families originated in Beijing,
Shanghai, Shenyang, Hunan, Hubei, Jiangxi, Zhenjiang, Jiangsu, Hebei, and
Inner Mongolia, representing equally the southern and northern parts of China. Table 1 shows the distribution of patients
according to geographic origin. All subjects were examined by the same 3 neurologists
(G.-X.W., Y.-X.Z., and B.-S.T.). Studies of families with SCA2 and SCA3/MJD
have previously been reported.33, 34, 35, 36, 37, 38, 39, 40, 41, 42
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Table 1. Geographic Distribution and Frequency of Different Spinocerebellar
Ataxia Genotypes (Number of Families)*
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DNA SAMPLES
Blood samples were collected from 125 individuals affected with autosomal
dominant SCA and 16 patients with sporadic SCA or spastic paraplegia, 140
healthy Chinese controls, and 60 healthy Sakha controls after obtaining informed
consent. High-molecular-weight genomic DNA was extracted from either peripheral
leukocytes or lymphoblastoid cell lines transformed by Epstein-Barr virus
following standard procedures.43
IDENTIFICATION OF THE CAG REPEAT EXPANSION
The number of CAG repeat units in the SCA1
gene was determined by polyacrylamide gel electrophoresis of polymerase chain
reaction (PCR) fragments produced by amplification with primer pair Rep-1
and Rep-2 as outlined by Orr et al17 and Goldfarb
et al.44 SCA2 and SCA3/MJD1 alleles were amplified and analyzed on agarose
and acrylamide gels using previously described methods.18, 43 DRPLA alleles were amplified using primers and conditions
described by Koide et al.25 SCA6, SCA7, SCA8,
and SCA12 alleles were amplified using gene-specific
primers.9, 16, 22, 45
The antisense primer was fluorescently labeled. For PCR amplification, genomic
DNA was denatured at 95°C for 2 minutes and the reaction carried out for
32 cycles consisting of 1-minute denaturation at 95°C, 1-minute annealing
at 60°C, and 1-minute elongation at 72°C. This was followed by a final
elongation at 72°C for 7 minutes, in a total volume of 20 µL containing
200 ng of genomic DNA; 20 pmol/mL of each primer; 200 mmol/L each of deoxyadenosine
triphosphate, deoxyguanosine triphosphate, deoxythymidine triphosphate, and
deoxycytidine triphosphate; 50-mmol/L potassium chloride; 1.5-mmol/L magnesium
chloride; 10-mmol/L tromethamine, pH 8.8; and 5 U of Taq polymerase. The PCR
products were electrophoresed in a 5% denaturing polyacrylamide gel on an
automated ABI 373A sequencer, and analysis was performed by using the GeneScan
672 program (ABI-Perkin Elmer, Foster City, Calif).18, 44
With some samples, PCR was performed in a total volume of 20 µL containing
200 ng of genomic DNA; 20 pmol/mL of each primer; 200 mmol/L each of deoxyadenosine
triphosphate, deoxyguanosine triphosphate, and deoxythymidine triphosphate,
200 mmol/L for each; 30-µmol/L deoxycytidine triphosphate; 370 KBq of
[ -32P]–deoxycytidine triphosphate (370 MBq/mL); 50-mmol/L
potassium chloride; 1.5-µmol/L magnesium chloride; 10-µmol/L tromethamine,
pH 8.8; and 5 U of Taq polymerase.46 The PCR
products were electrophoresed in 5% denaturing polyacrylamide gel together
with PCR products from cloned templates of normal and expanded SCA1 alleles as size standards and subjected to autoradiography. A
molecular weight standard was included to accurately determine the number
of CAG repeats.
NUCLEOTIDE SEQUENCE ANALYSIS
The PCR products amplified from normal and SCA1
chromosomes were resolved by agarose gel electrophoresis and visualized by
ethidium bromide staining. DNA was recovered from agarose gel plugs using
the GeneClean kit (Bio101), subcloned into pGEM-T easy vector (Promega, Madison,
Wis), and transfected into DH5a-competent cells. Insert-containing clones
were sequenced using the Sequenase version 2.0 DNA sequencing kit. The numbers
of CAG repeats and CAT interruptions were determined from sequence analysis.
STATISTICAL ANALYSIS
Correlation of the age of disease onset with the number of CAG repeat
units was determined by Pearson correlation coefficient test. Other statistical
analyses were performed using the t test or  2 test.
RESULTS
SCA1 CHROMOSOMES AND GENOTYPE-PHENOTYPE CORRELATION
Most of our patients originated in the midnorthern, northeastern, mideastern,
and midsouthern regions of China, such as Beijing, Shanghai, Shenyang, Hunan,
Hubei, Jiangxi, Zhejiang, Jiangsu, Hebei, and Inner Mongolia. Table 1 shows the distribution of patients according to geographic
origin. The SCA1 mutation was detected in 5 (7%)
of 75 Chinese families with autosomal dominant SCA. All 12 patients with the
SCA1 phenotype were heterozygous for alleles with CAG repeat numbers within
a range of 51 to 64. The number of trinucleotide repeats in the normal alleles
of the Chinese control subjects ranged from 26 to 35. As in all other disorders
with CAG repeat expansion, we observed a statistically significant negative
correlation between the age of disease onset and the number of CAG repeat
units in the expanded alleles, with a Pearson correlation coefficient of r = -0.914.
Clinical features of the studied patients with SCA1 are summarized in Table 2. The mean ± SD age at last
examination was 37.3 ± 4.3 years. Patients with SCA1 in our series
shared classic clinical features of gait and limb ataxia, dysarthria, pyramidal
tract signs (spasticity, hyperreflexia, and extensor plantar responses), and
variable degree of oculomotor dysfunction, which includes 1 or more of the
following: nystagmus, slow saccades, and ophthalmoparesis. Saccades were slowed
in 50%. Gaze paralysis was most frequent in the vertical plane, usually upward
(33%). Nystagmus on lateral gaze was rare. Motor weakness, amyotrophy, and
mild sensory deficits manifested as proprioceptive loss were seen in some
patients. Dementia was evident in 4 (33%) of 12 patients with SCA1. Although
ataxia, dysarthria, and cranial nerve dysfunction were consistently present
in every SCA1-affected individual, considerable intrafamilial variability
was noted with regard to all of the other clinical features. Several of the
kindreds that did not have an expanded SCA1 CAG repeat displayed the same
clinical findings as were observed in SCA1 kindreds, reflecting the inherent
difficulty of clinical classification. The frequencies of specific clinical
signs were analyzed by the Mann-Whitney U test in
an effort to determine whether any correlation existed with the number of
CAG repeats, but none were found in our data set.
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Table 2. Clinical Characteristics of Patients With SCA1, SCA2, and
SCA3*
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COMPARISON OF THE CLINICAL PICTURE IN SCA1, SCA2, AND SCA3 AND RELATIVE
FREQUENCY OF SCA1 AMONG OTHER TYPES OF ATAXIA
The combined frequency of SCA1, SCA2, and SCA3/MJD in the Chinese population
was 53%. None of the 16 patients with sporadic SCA or spastic paraplegia tested
positive for SCA1, SCA2, SCA3, SCA6, or SCA7, nor did any of our patients
with inherited or sporadic ataxia test positive for SCA8, SCA12, or DRPLA,
including a large family with myoclonus epilepsy, tremor, and ataxia (data
not shown). Clinical finding in 12 patients from 5 SCA1 families were compared
with 16 patients from 9 SCA2 families and 72 patients from 26 SCA3/MJD families
in Table 2. Onset age was not
statistically different. Hyperactive reflexes and spasticity were more frequent
in SCA1, whereas hypoactive reflexes and slow saccades were more frequent
in SCA2; facial myokymia and horizontal nystagmus were seen more frequently
in SCA3/MJD. Of patients with SCA3/MJD, only 12 (46%) were correctly diagnosed
on clinical grounds. These patients manifested with typical adult-onset (type
II-III MJD) phenotype that included ophthalmoparesis with eyelid retraction,
facial myokymia, ataxia, spasticity, and amyotrophy. The remaining 54% of
the patients with SCA3/MJD had clinical features indistinguishable from patients
with other types of ataxia, such as SCA1 or SCA2. Of SCA2 families, only 5
(56%) and of SCA1 families only 2 (40%) were diagnosed on clinical grounds
alone. Molecular diagnosis was helpful in identifying or confirming the type
of SCA in each of these cases.
ASSOCIATION BETWEEN THE NUMBER OF CAT INTERRUPTIONS AND RELATIVE PREVALENCE
OF SCA1
The results of sequence analysis showed that 65% of the Siberian Sakha
and only 8% of Chinese normal alleles had a single CAT interruption. Based
on historic and ethnographic studies,47 the
Sakha (Ilakut) population, currently numbering 350 000, is a relatively
recent arrival in eastern Siberia. The prevalence of SCA1 is extremely high
in this small population,48 whereas the prevalence
of SCA1 in the Chinese population is significantly lower.
COMMENT
In 1992, at an MJD international workshop, families with a dominantly
inherited ataxia were discussed in detail, and several MJD families from China
were described as well as other SCA-type families.49
The discussion and agreement that dominantly inherited ataxias were present
in China led us to do a more detailed clinical-molecular analysis. Subsequently,
we have had the opportunity to evaluate members representing 75 Chinese kindreds
with dominantly inherited ataxia. The cloning of genes and identification
of the causative mutations in several types of SCA have provided a powerful
tool for establishing a definitive diagnosis by genetic testing. Our data
indicate that 5 (7%) of the studied families with hereditary ataxia originating
from various regions of China, including Beijing, Shanghai, Jiangsu, Zhejiang,
Hebei, Liaoning, Hunan, Hubei, Jiangxi, and Inner Mongolia, had SCA1. This
frequency is similar to the frequencies recently reported in other population
groups.50, 51, 52 The
prevalence of SCA2 and SCA3/MJD in China is also within the range observed
in other large populations.50, 51, 52, 53, 54, 55
The combined frequency of SCA1, SCA2, and SCA3/MJD among the Chinese families
with autosomal dominant ataxia is 53%. The prevalence of SCA6 and SCA7 is
4% and 3%, respectively (Y.-X.Z. and W.-H.G., unpublished data, 2000). None
of our patients had DRPLA, including a large family whose disease manifested
as myoclonus epilepsy, tremor, and ataxia, suggesting that DRPLA is rare in
non-Japanese populations. Analysis of 280 normal chromosomes from 140 individuals
demonstrated that the number of CAG repeats in the coding region ranges in
size from 26 to 35 repeats. The number of CAG repeats in normal and SCA1 Chinese
chromosomes is similar to those described in other reports.50, 51, 52
We found a strong inverse correlation between the age at disease onset and
the CAG repeat number in the expanded alleles, similar to features previously
described in Huntington disease and other studied SCAs.
We observed a wide spectrum of clinical features in patients with SCA1,
significantly overlapping with SCA2 and SCA3/MJD, but there was no statistically
significant correlation between the number of CAG repeat units in the SCA1 gene and clinical manifestations. Such correlations
were previously reported in patients with SCA3/MJD56
and SCA2. This discrepancy may be due to the small size of our data set. The
comparison of the clinical features of our patients with 3 reported series57, 58, 59 showed an overall
clinical similarity (Table 3).
Some statistical differences among series may be explained by differences
in evaluation criteria and examiners. Meanwhile, the fact that low occurrence
of slow saccades and sphincter disturbances and high occurrence of horizontal
nystagmus, lower limb weakness, lower limb amyotrophy, and knee reflexes occurred
in our patients with autosomal dominant cerebellar ataxia type 1 compared
with 3 other large groups60, 61, 62
could be explained by occurrence of different mutations in our population
(Table 4). The existence of different
clinical subtypes within autosomal dominant cerebellar ataxia type 1 has been
addressed.2
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Table 3. Comparison of Findings in Reported Series of Spinocerebellar
Ataxia Type 1
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Table 4. Comparison of Findings in Reported Series of Autosomal Dominant
Cerebellar Ataxia Type 1
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Of the patients with SCA1 whom we studied, only 2 could be reliably
diagnosed without genetic testing. A wide variety of phenotypes seen in SCA1
and a significant degree of clinical overlap with SCA2 and SCA3/MJD highlight
the difficulty of making the diagnosis on the basis of clinical information
alone. Of the patients with SCA2 we studied, only 5 (56%) and of the patients
with SCA3/MJD only 12 (46%) could be reliably diagnosed without genetic testing.
We found that SCA3/MJD, more often than other SCA types, manifests with specific
features such as ophthalmoparesis and characteristic eyelid retraction, facial
myokymia, ataxia, spasticity, and amyotrophy. Patients with SCA3/MJD who merely
have ataxia with slowed saccades were clinically indistinguishable from patients
with SCA1 or SCA2. The PCR-based testing makes it possible to diagnose the
type of ataxia with great certainty. This underscores the importance of genetic
testing for diagnostic accuracy in patients with autosomal dominant ataxia.
In the present study, we found a close association between the prevalence
of SCA1 in Chinese and Sakha populations and the frequency of CAT interruptions
in the SCA1 gene. A similar association between the
relative prevalence of SCA1 (15%)63 in the
North American population and the frequency of CAT interruptions (11%) was
reported.64 If a substitution of CAT for CAG
was the initial event contributing to generation of expanded alleles, the
Sakha population must have been predisposed to such a transition by simply
having more individuals carrying a single CAT interruption.
AUTHOR INFORMATION
Accepted for publication October 27, 2000.
We thank the families for their active involvement in this project.
We also thank Roger N. Rosenberg, MD, for his constructive and critical comments.
We thank S. G. Brodie, PhD, for valuable comments.
We gratefully acknowledge research support from the National Natural
Science Foundation of China and Research Foundation of the Ministry of Public
Health of China (Drs Y.-X. Zhou and Wang).
From the Neurogenetics Unit, Department of Neurology, China-Japan Friendship
Hospital, Hepingli, Beijing, China (Drs Y.-X. Zhou, Gu, Yang, He, and Wang);
Clinical Neurogenetics Unit, Medical Neurology Branch, National Institute
of Neurological Disorders and Stroke (Drs Y.-X. Zhou and Goldfarb) and Genetics
of Development and Disease Branch (Drs Y.-X. Zhou, Qiao, and Deng), and Division
of Cancer Epidemiology and Genetics, National Cancer Institute (Dr Xie), National
Institutes of Health, Bethesda, Md; Institute of Neurology, Hunan Medical
University, Changsha, China (Dr Tang); Department of Neurology, The First
People's Hospital of Xuzhou, Xuzhou, China (Dr L.-S. Zhou); Department of
Neurology, Jichi Medical School, Minamikawachi, Tochigi, Japan (Dr Takiyama);
and Department of Neurology, Brain Research Institute, Niigata University,
Niigata, Japan (Dr Tsuji).
Corresponding author and reprints: Yong-Xing Zhou, MD, PhD, Genetics
of Development and Disease Branch, Bldg 10/9N104, NIDDK, NIH, 10 Center Dr
Bethesda, MD 20892.
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