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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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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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