Spinocerebellar ataxia type 7 (SCA7), a rare subtype of the spinocerebellar ataxias (SCAs), is an autosomal dominant inherited neurodegenerative syndrome characterized by progressive cerebellar ataxia and retinal degeneration. Initially, it was named as autosomal dominant cerebellar ataxias (ADCA) type II or olivopontocerebellar atrophy (OPCA) type III for the presence of pigmentary retinal dystrophy.1,2 Later on genetic study discovered its locus on chromosome 3p12-p21.1., and it was then known as SCA7 — one subtype of SCAs.3 The number of patients with genetically confirmed diagnoses of SCA7 increased rapidly because the widespread availability of direct gene testing had permitted the diagnosis of SCA7 in heterogeneous populations worldwide. However, SCA7 is a very rare subtype of SCA worldwide, with a prevalence of about 2% in SCA patients.4 Though SCA7 is found in different races, the current data available are mainly from white people. Thus, in this evidence-based study, we focus on the clinical and genetic aspects of SCA7 patients in East Asia population.
Data search and study selection
A search for the related publications was performed by using the “PubMed” database in July 2009, and published language was limited in English. The following search items were used, including “spinocerebellar ataxia type 7 OR SCA7 OR autosomal dominant cerebellar ataxias type II OR ADCA type II OR olivopontocerebellar atrophy type III OR OPCA type III OR chromosome 3p12-p21.1.”. Publications those discussed the prevalence or/and described the clinical and genetic features of patients with SCA7 were deemed relevant and were further reviewed and analyzed. Additional relevant articles were also searched from the citations in the publications identified by the initial search.
After reading the full texts, publications reporting patients from East Asia area were selected for further analysis. The prevalences of SCA7 in patients with SCA were extracted for different ethnic populations. Data of SCA7 families were all extracted from the publications, including the clinical and neuroimaging features, onset age, genetic features, and genotype-phenotype correlations.
Data were expressed as mean ± standard deviation (SD), the box plot, and the correlation of CAG repeat size with the onset age (bivariate correlation analysis) were all conducted by using the Statistical Package for Windows, version 16.0 (SPSS, Chicago, Illinois, USA). A two-sided P value less than 0.05 was considered statistically significant.
A total of 325 abstracts were retrieved from “PubMed” published from 1975 to July 1, 2009. Of them, 57 English entries were from East Asia, after excluding these not relevant to the topics, 21 articles were finally included for analysis, including 14 articles reporting prevalence of SCA7 and 7 reporting SCA7 families.
Prevalence of SCA7 in SCA patients
There were 14 studies reported the prevalence of SCA7 in patients with SCA (Table 1), including 5 from China,5–9 6 from Japan10–15 and 3 from Korea.16–18 Patients with SCA7 or other types of SCA were all detected by genetic approach in the articles. Despite the differences in the ethnic populations and study methods, the prevalences of SCA7 were similar, ranging from 0 to 7.7%. Half of the studies reported no SCA7 in their patients, 6 studies reported a prevalence of 0.8%-2.6%, and one study from South Korea reported the highest prevalence of 7.7%. Two studies reporting the prevalences of different types of SCA in the mainland of China were both from Xiangya Hospital, found the prevalences of SCA7 being 0 and 0.8%.5,6 One study from Hong Kong of China found no SCA7 in 16 SCA families. Studies from Japan were characterized by the clinical epidemiological methods, studying the prevalences of SCA subtypes in different regions.
Clinical and neuroimaging features of SCA7
A total of 7 articles described the details of SCA7 families, including 3 from China (4 families),19–21 1 from Japan (2 families),22 and 3 from South Korea (8 families).23–25 The 7 articles included 5 original articles and 2 case reports (Table 2).
The clinical features were described in 20 patients, and they all had gait ataxia and visual impairment. Dysarthria was reported to be invariably associated with gait ataxia in other reports;26 although dysarthria was not mentioned in most of our included articles, it was reported to be present in all the patients in one study from China and closely related to unsteady gait.20 Loss of normal foveal reflex, attenuated retinal arteries and somewhat pale of the optic disc can present in the early stage of retinal degeneration, while pigmentation and halolike macular lesions occur in the advanced stage. A case report from South Korea described that one SCA7 patient with no retinal degeneration had gait disturbance for 8 years.23 Other symptoms like dysphagia, slurred speech, slow eye movement, dysmetria, and nystagmus were all reported in the studies.
The most conspicuous feature of the neuroimaging was atrophy of the cerebellar region. However, Bang et al24 investigated the features of magnetic resonance imaging (MRI) findings in 9 patients with SCA7, and found that the primary pathology was the brainstem rather than the cerebellum; pontine atrophy could be present in all SCA7 patients regardless of cerebellar atrophy degrees or the severity or duration of illness, and cerebellar atrophy was not found in those with a short duration of illness or mild ataxia.
The onset age was reported in 26 symptomatic SCA7 patients. The clinical manifestations typically began in the 30’s of patients (median, 29 years; interquartile range (IQR), 19.5–36.5 years), and varied from 5 to over 52 years old (Figure 1). A small girl from the mainland of China was one of the youngest patients, who had progressive visual failure, unsteady gait and dysarthria since she was 5 years old; she was unable to stand at 9 years, and finally became blind before 14 years.20 Another younger patient was from Taiwan of China, with the disease onset at his 7 years old, and he died at the age of 12; he had a younger brother who had nystagmus from one month old, and died at the 17th month due to aspiration pneumonia; he was excluded due to absence of genetic data.21 The latest onset occurred on a Korean without retinal degeneration, who had gait disturbance at 52 years old.23
Onset age were also collected for 6 parent-offspring, and the results showed that the symptoms appeared 15 years ((15.17±4.215) years) earlier on average in the offspring of affected parents than in the parents themselves.
Genetics of SCA7
CAG repeats were described in 31 patients, including 14 Chinese, 5 Japanese, and 12 Korean. Mutant SCA7 alleles contained 40–100 repeats in these patients, with a median of 47 repeats (IQR, 44.5–50.0) (Figure 2). The patient with 40 CAG repeats had symptoms at 50 years,22 and the patient with 100 CAG repeats had symptoms at 7 years, and died at 12 years.20 CAG repeats numbers had also been collected for 8 parent-offspring, and the CAG repeats of the offspring was on average 13 repeats more than their parents (12.62±19.03).
There was a strong negative correlation between CAG repeat size and the onset age of patients(r=-0.739, P=0.000). The initial symptoms were described in 12 patients, including 6 with gait disturbance, 5 with visual impairment, and one with both. There was no difference in CAG repeat size between the patients with initial symptoms of visual impairment and gait disturbance (P=0.476).
SCA7 had been widely reported since the advanced molecular biological technique was used to identify the related genes. However, most of the clinical and genetic features available are those from the white people. Thus, it is of great importance to make a summary of the clinical and genetic features of the East Asia population. In our analysis, we found the prevalence of SCA7 in patients with SCA ranged from 0–7.7%, which was similar to that of the patients in West Europe and America, where most studies supported a prevalence of 0–4%.27–29 Two studies reporting the prevalence of SCA subtypes from patients in the mainland of China were both by Xiangya Hospital, and there was no advanced region-related epidemiological research.5,6
Although progressive visual impairment is the most conspicuous feature of SCA7, retinal degeneration is not found in each patient. Most researchers believe retinal degeneration aggravates with the progression of the disease. One case report from South Korea reported a patient had no retinal degeneration even in the presence of visual symptoms; the patients had a CAG repeat size of 42 and a progressive gait disturbance for 8 years.23 However, some authors insisted that optical coherence tomography could find discreet degenerations in these patients.30 Of the articles reporting SCA7 families, one from South Korea described the features of MRI imaging of the brain, and it was the only study investigated the imaging features from East Asia population.24
Reportedly, the onset of SCA7 was usually in the 30’s of its victims; our analysis obtained similar result.26 SCA7 patients had marked genetic anticipation, and we also found that the symptoms of SCA7 appeared 15 years earlier on average in the offspring compared with the parents. Patients with earlier onset often had severe disease, among the three patients who had symptoms younger than 10 years, one died; one was unable to stand before the end of that study.19–21 It was reported that the CAG repeats were 36–460 in SCA7 patients, and the range in normal subject is 4–35 repeats. The CAG repeats size of SCA7 was 40–100 in our analysis for East Asia population, while the normal range was 6–18. The increasing tendency of CAG repeat in the offspring had also been confirmed in our analysis, with a mean expansion of 13 repeats. Undoubtedly, the length of the SCA7 CAG repeat is inversely correlated with the onset age of patients (P=0.000). In addition, the length of the SCA7 CAG repeat was reportedly associated with the initial symptom of patients: patients with shorter repeats tend to have cerebellar ataxia rather than macular degeneration as their initial symptoms. However, we did not find any difference between patients with cerebellar ataxia and macular degeneration as their initial symptoms.
Skeletal muscle and liver biopsies had been performed in SCA7 patients, and the abnormal mitochondria have been discovered,31,32 but there have been no relevant reports on SCA7 families of East Asia population. We limited our search language in English in this study to guarantee the quality of the included studies; which, unfortunately, may exclude some excellent papers published in other languages, but we still thought those articles published in English could well demonstrated the research status of SCA7 in East Asia.
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