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Genetic and Clinical Profile of Chinese Patients with Autosomal Dominant Spastic Paraplegia

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Abstract

Background

Hereditary spastic paraplegia (HSP) refers to a group of neurodegenerative disorders characterized by bilateral weakness, spasticity, and hyperreflexia in the lower limbs. The autosomal dominant HSP (ADHSP) predominantly presents as the pure form, but the clinical profiles and causal genetic variants underlying ADHSP are complex, and many remain unknown.

Methods

A cohort of 15 Chinese HSP pedigrees (including 35 patients and their 22 relatives) were screened by multiplex ligation-dependent probe amplification (MLPA) or whole-exome sequencing (WES). Neurological assessments were also conducted.

Results

The main subtypes of HSP above detected in our cohort were SPG4, SPG3A, and SPG6. Fifteen HSP-inducing mutations were identified, among which six were novel mutations: SPAST c.1277T>C, c.1292G>C, c.1562T>C, and c.1693A>T, NIPA1 c.748A>C, and KIDINS220 c.4448C>G. As expected, the most common presentation of the ADHSP cases was the pure form, manifesting spasticity of lower limbs and hyperreflexia, as well as pyramidal signs. Differing substantially from previous reports for KIDINS220 variants, our study family exhibited autosomal dominant inheritance, and only presented with spastic paraplegia, with no signs of intellectual disability, nystagmus, or obesity.

Conclusion

Our work reveals a non-classical spastic paraplegia, intellectual disability, nystagmus, and obesity phenotype for a KIDINS220 mutation, which broadens both the clinical and genetic spectrum for ADHSP. Beyond underscoring the utility of using both MLPA and WES in studies of HSP, our work deepens the scientific understanding of phenotypes for ADHSP and defines new genetic variants to facilitate future diagnoses.

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Acknowledgements

We sincerely thank the patients and relatives for their participation in this study.

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Authors and Affiliations

Authors

Contributions

Conception and drafting of the work were performed by MZ, YJC, and XL. Data acquisition and data interpretation were performed by MWW, XHL, and ELD. Revision of the manuscript for intellectual content was conducted by XL, NW, and WJC. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Ning Wang or Xiang Lin.

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Funding

This work was supported by Grants 81801130, 81771230, and U1505222 from the National Natural Science Foundation of China, by the Natural Science Foundation of Fujian Province (2019J05076), by Grant 2017XQ1072 from the Startup Fund for Scientific Research of Fujian Medical University, by the Joint Funds for the Innovation of Science and Technology of Fujian Province (2017Y9094), by the National Key Clinical Specialty Discipline Construction Program and the Key Clinical Specialty Discipline Construction Program of Fujian.

Conflict of interest

The authors, Miao Zhao, Yi-Jun Chen, Meng-Wen Wang, Xiao-Hong Lin, En-Lin Dong, Wan-Jin Chen, Ning Wang, and Xiang Lin, declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (The First Affiliated Hospital of Fujian Medical University FYYY2006-01-19-01) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standard. This article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from all individual participants included in the study.

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Zhao, M., Chen, YJ., Wang, MW. et al. Genetic and Clinical Profile of Chinese Patients with Autosomal Dominant Spastic Paraplegia. Mol Diagn Ther 23, 781–789 (2019). https://doi.org/10.1007/s40291-019-00426-w

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