Clinical and genetic study of a Chinese family with spinocerebellar ataxia type 7
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.68674
Source of Support: None, Conflict of Interest: None
Spinocerebellar ataxia 7 (SCA7) is a rare disease, and only few SCA7 families have been reported, especially from East Asia. Clinical features of a genetically confirmed SCA7 Chinese family were evaluated. The onset of the disease varied from 4 years to 48 years, and the initial presenting feature was cerebellar ataxia or visual impairment, or both. There were abnormal findings on fundus photography, electroretinogram, flash visual evoked potential and oscillatory potentials. Abnormal mitochondria were also found in skeletal muscle or liver biopsies. The number of cytosine adenine guanine (CAG) repeats ranged from 50 to 97, and the length of CAG repeat was inversely correlated with the age of onset (r=-0.867, P=0.025). Conclusion: The clinical manifestations and SCA7 gene of SCA7 patients were homogeneous in this study. Larger CAG repeats had not only resulted in earlier onset, but also related to the rapid progression and severity of the disease. Abnormal mitochondria may be a common finding in biopsy studies of various organs in SCA7 patients.
Keywords: Biopsy, cytosine adenine guanine, onset, spinocerebellar ataxia 7
Spinocerebellar ataxia 7 (SCA7), a rare autosomal dominant neurodegenerative disease first described in 1937, accounts for 1%-11.7% of the autosomal dominant cerebellar ataxias. ,, The gene for SCA7 patients has been mapped to chromosome 3p12-13, with the pathologic alleles containing 36-460 CAG repeats. , The most prominent clinical presentations include progressive gait ataxia and visual impairment; other symptoms include saccade, dysphagia, opthalmoplegia, and pyramidal signs. ,
Here we report a large Chinese family with clinical phenotype and/or genetically diagnosed as SCA7. The CAG repeat size was identified in each member of the family, and detailed investigations on magnetic resonance imaging (MRI) of the brain, ophthalmology, and muscle/liver biopsies are also described. To the best of our knowledge, this is the first report on muscle/liver biopsy findings of East Asian SCA7 patients.
The family was a 5-generation Chinese (Han ethnic) family with a total of 34 members; the first generation was born in the early 20th century. The index case was highly suspected of SCA7 due to the conspicuous unsteady gait and visual failure when he first visited our hospital. Eight members were then clinically diagnosed as SCA7. All the 30 living family members received neurologic examinations followed by genetic testing. The peripheral blood was collected for DNA analysis of CAG trinucleotide expansion repeats. PCR primers used for CAG expansion were 5′-TAGGAGCGGAAAGAATGTCGGAG-3′ and 5′-CAGGAAGTTTGGAAGCCTCAACC-3′. 
Ophthalmologic examinations and MRI of the brain were also performed in some members. The ophthalmologic examinations included fundus photography, electroretinogram (ERG), flash visual-evoked potential (FVEP), and oscillatory potentials (OPs). Electron microscopy examinations of muscle biopsies of the right rectus femoris were performed in 3 patients (III 5, III9, III11). Moreover, liver biopsy was performed in 1 patient (III11) by using the standard methods. Informed consents were obtained from all the participants, and the study was approved by the Ethical Committee of Changhai Hospital, Second Military Medical University, Shanghai.
The correlation of the age of onset with the CAG repeat size was determined by using the Pearson correlation coefficient. Statistical analysis was performed by SPSS software for Windows, version 16.0 (SPSS Inc, Chicago, Illinois, USA).
The pedigree of the family is presented in [Figure 1] and the clinical data of the patients are summarized in [Table 1].
III 9. The male index case had a progressive visual loss and blue-yellow color blindness at the age of 22 years, and ataxia was present 4 years later.
When he was admitted to our hospital, moderate pigmentary changes in the macular region and granular pigmentation in the peripheral retinal region were found by funduscopic examination. Extinguished ERGs were observed during light adaptation and dark adaptation. The latency period was normal, but the amplitudes of the right eye and the left eye on FVEPs decreased by 80% and 70%, respectively. The amplitudes of OPs decreased by 88% for the right eye and by 83% for the left.
MRI of the brain showed marked atrophy of the cerebellum, pons, and midbrain, and enlarged cerebral ventricles [Figure 2], although the electroencephalogram (EEG) was normal.
Electron microscope examination of the skeletal muscle
There were neither inflammatory cells nor abnormal blood vessels around the muscle fibers. But many abnormal mitochondria were observed under the sarcolemma, with long, irregular, tubular, or absence of mitochondrial cristae [Figure 3].
III 1. She had suffered impaired visual acuity and unsteady gait for nearly 20 years, and died at the age of 67 years due to unknown cause.
III 1. The patient had decreased visual acuity of both eyes at the age of 41 years, and unstable gait with occasional clumsiness was developed 5 years later. She finally died of "pulmonary disease" at the age of 62 years.
III 3. She had visual impairment and unsteadiness of gait simultaneously at 43 years of age, and visited our hospital in a wheelchair at the age of 67 years. Funduscopic examination found pigmentary disturbance in the maculas and peripheral retinal regions, with pallor of the optic disc. MRI of the brain showed severe cerebellar atrophy and enlarged cerebral ventricle.
III 5. Progressive impairment of visual acuity started at the age of 34 years, and walking unsteadily was developed 1 year later. Although progression of the disease was slow, the patient had dysarthria and dysphagia at 44 years. Moderate macular pigmentary disturbance and salt and pepper retinal changes were found by funduscopic examination [Figure 4]. Extinguished amplitudes were found on ERG, and low amplitudes were found on FVEPs (a 60% decrease for the right eye and a 70% decrease for the left eye) with normal latencies. The amplitudes of OPs decreased by more than 85% for both eyes. Brain MRI showed a clear atrophy of the cerebellum and brain stem, and the EEG was normal. Abnormal aggregations of mitochondria, with different sizes and irregular mitochondrial cristae, were noticed in the muscle samples under electron microscope. Giant mitochondria, inclusion body, or crystal structure was not seen.
III 11. The disease started with gait disturbances and clumsiness when he was 26 years old. When he visited our hospital, mild pigmentary alteration was observed in the macular area. Brain MRI revealed atrophy of the cerebellum. No abnormal mitochondria or other marked pathologic changes were found in skeletal muscle biopsy; however, degeneration of the liver cells was noticed, with turgescent mitochondria or vacuoles in these cells, without any giant mitochondria, inclusion body, or crystal structure [Figure 5].
III 15. The patient presented with unsteadiness of the gait at the age of 27 years, and developed visual acuity impairment 6 years later. Funduscopic examination revealed disappeared foveal reflex, and brain MRI showed atrophy of the cerebellum and brain stem.
III 5. He had conspicuous decrease of visual acuity at 4 years of age, and then he was unable to distinguish the colors accurately. Unsteady gait, dysarthria, and dysphagia were all present when he was 5 years old. At the age of 7 years, he could not eat food independently and was fed through a nasal tube. Brain MRI showed atrophy of the cerebellum and brain stem. Finally, he died of pulmonary infection 6 month later.
There were no abnormal findings in other members of this family.
The results of CAG expansion of the patients are shown in [Table 1]. The total number of the CAG repeats was 472 in the 7 available patients (III 1 and III 1 were not available), with a mean of 67 repeats. Of the 30 living family members, III 8 was an asymptomatic genetically diagnosed patient, who was 8 years old and had 56 CAGs. CAG repeats of other members ranged 8-25. The length of CAG repeat was inversely correlated with the onset age of patients (r = −0.867, P = 0.025). The expansions of CAG repeats on alleles of offspring were 11.5 (Median), and the onset of SCA7 in younger generations was 16 years (Median) earlier than their parents.
SCA7 was infrequent or almost undetected in Japan; a study of 1,286 Japanese patients only found one family of SCA7.  Similar situations were also reported in Chinese and Koreans. , Our research makes a contribution to the data of SCA7 patients in East Asia.
The onsets of SCA7 varied from 4 to 48 year olds in our cohort, and as reported by others,  we also observed a marked anticipation in the 7 parental/filial generations with typical clinical manifestations. Patient III 15 had visual failure for 3 years, and funduscopic examination only showed disappearance of foveal reflex, without other abnormalities; however, pale optic disc, pigmented macular and peripheral retinal region were observed in patients III 5 and III 9, who had impaired visual acuity more than 10 years, indicating that the increased severity of visual failure is associated with earlier onset. Reportedly ERG, FVEP, and OPs were suitable for determination of the related retina impairment, especially for patients whose visual acuity was difficult to observe. ,
CAG repeats are 40-100 in SCA7 patients and 6-18 in normal people in East Asia. ,,, The CAG repeats were 50-97 in our research. Patient III 8 had no clinical manifestations and was considered as genetically diagnosed SCA7. We found a strong negative correlation between the size of the CAG repeats and onset age, larger repeats resulting in earlier onset. , Besides, larger CAG repeat size was also associated with the rapid progression and the severity of the disease. 
Forsgren et al. first reported the uneven distribution of mitochondria between the large fiber areas; a similar phenomenon was also observed in our patients.  Abnormal mitochondria and paracrystalline inclusions were discovered in the liver biopsy of SCA7 patients, including white and black people.  We are the first to perform biopsies of skeletal muscle and liver in Asians. SCA7 and mitochondrial cytopathy shared many common symptoms, such as ophthalmoplegia, pyramidal sign, extrapyramidal diseases, optic atrophy, and retinopathy. We are the first to identify the changes in mitochondrial distribution, morphology, and number in the skeletal muscle and liver cells of Chinese SCA7 patients, which indicates that SCA7 and mitochondrial cytopathy may share some common pathologic basis. It was also reported that the heart can be affected in some infantile SCA7 cases with very large repeat size,  indicating more organs can be involved in SCA7. In addition, degeneration of liver cells was found in patient III 11 without marked pathologic changes in the skeletal muscle biopsies, suggesting that liver damage may occur before skeletal muscle damage. However, the muscular and mitochondrial abnormalities in Chinese SCA7 patients and the relationship of SCA7 with mitochondrial cytopathy still need to be studied further.
In conclusion, the clinical presentations and SCA7 gene alteration of SCA7 patients are consistent in our cohort. Our findings provide valuable data for the diagnosis of SCA7 in Asians.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]