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Genetic and clinical analyses of spinocerebellar ataxia type 8 in mainland China

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Abstract

Background

Spinocerebellar ataxia type 8 (SCA8) is a rare autosomal dominant neurodegenerative disease caused by CTA/CTG repeat expansion in the ATXN8/ATXN8OS gene.

Methods

To analyze the frequency and clinical characteristics of SCA8 patients in mainland China, we combined polymerase chain reaction (PCR) and triplet repeat-primed PCR (TRP-PCR) to detect the CTA/CTG expansion. We studied a cohort of 362 ataxia patients in which the other known causative genes had been previously excluded, from among 1294 index patients. Positive samples were validated by southern blotting.

Results

The CTA/CTG expansion was observed in six probands, accounting for approximately 0.46% (6/1294) in all patients, and 1.66% (6/362) in patients without definite molecular diagnosis. Clinically, aside from the typical SCA8 phenotype, some patients carrying the CTA/CTG expansion exhibited the cerebellar form of multisystem atrophy (MSA-C) and ataxia with paroxysmal kinesigenic dyskinesia (PKD).

Conclusion

For the first time, we described the PKD phenotype in association with CTA/CTG expansion, suggesting that CTA/CTG expansion might play a role in the pathogenesis of paroxysmal dyskinesia symptoms.

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Acknowledgements

We are grateful to the participating patients for their involvement. This work was supported by the National Key Research and Development Program of China (#2018YFC1312003, 2016YFC1306000); the Program of National Natural Science Foundation of China (#81671120, 81300981, 81430023, 81771231); the Clinical Scientific program of Xiangya Hospital, Central South University (#2015105); and Innovation Driven Program of Central South University (#506010108).

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Author notes

  1. Yao Zhou and Yanchun Yuan contributed equally.

Authors and Affiliations

  1. Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, Hunan, People’s Republic of China

    Yao Zhou, Yanchun Yuan, Zhen Liu, Sheng Zeng, Zhao Chen, Lu Shen, Hong Jiang, Beisha Tang & Junling Wang

  2. Laboratory of Medical Genetics, Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Lu Shen, Hong Jiang, Kun Xia, Beisha Tang & Junling Wang

  3. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Lu Shen, Hong Jiang, Beisha Tang & Junling Wang

  4. National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Lu Shen, Hong Jiang, Beisha Tang & Junling Wang

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  1. Yao Zhou
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Correspondence to Junling Wang.

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The authors declare that they have no competing interests.

Ethical approval

This study was approved by the Ethics Committee and the Expert Committee of Xiangya Hospital, Central South University (equivalent to an Institutional Review Board).

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Informed consent was obtained in writing from all participants.

Electronic supplementary material

Below is the link to the electronic supplementary material. Supplementary Table 3. List of variants identified by whole exome sequencing in the patient with PKD phenotype. The criteria for filtering: (1) dominant pattern: heterozygous variants (MAF ≤ 0.001). (2) recessive pattern: homozygous variants and compound heterozygous variants (MAF ≤ 0.01). In silico analysis: (1) stop gain/loss, frameshift and splice site mutations: falling within two base pairs of exon–intron junctions; (2) missense variants functionally predicted to be deleterious (REVE > 0.7). MAF minor allele frequency, REVE [38] combination of REVEL and VEST3.

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Zhou, Y., Yuan, Y., Liu, Z. et al. Genetic and clinical analyses of spinocerebellar ataxia type 8 in mainland China. J Neurol 266, 2979–2986 (2019). https://doi.org/10.1007/s00415-019-09519-2

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  • DOI: https://doi.org/10.1007/s00415-019-09519-2

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