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The genetic and clinical spectrum in a cohort of 39 families with complex inherited peripheral neuropathies

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Abstract

With complicated conditions and a large number of potentially causative genes, the diagnosis of a patient with complex inherited peripheral neuropathies (IPNs) is challenging. To provide an overview of the genetic and clinical features of 39 families with complex IPNs from central south China and to optimize the molecular diagnosis approach to this group of heterogeneous diseases, a total of 39 index patients from unrelated families were enrolled, and detailed clinical data were collected. TTR Sanger sequencing, hereditary spastic paraplegia (HSP) gene panel, and dynamic mutation detection in spinocerebellar ataxia (SCAs) were performed according to the respective additional clinical features. Whole-exome sequencing (WES) was used in patients with negative or unclear results. Dynamic mutation detection in NOTCH2NLC and RCF1 was applied as a supplement to WES. As a result, an overall molecular diagnosis rate of 89.7% was achieved. All 21 patients with predominant autonomic dysfunction and multiple organ system involvement carried pathogenic variants in TTR, among which nine had c.349G > T (p.A97S) hotspot variants. Five out of 7 patients (71.4%) with muscle involvement harbored biallelic pathogenic variants in GNE. Five out of 6 patients (83.3%) with spasticity reached definite genetic causes in SACS, KIF5A, BSCL2, and KIAA0196, respectively. NOTCH2NLC GGC repeat expansions were identified in all three cases accompanied by chronic coughing and in one patient accompanied by cognitive impairment. The pathogenic variants, p.F284S and p.G111R in GNE, and p.K4326E in SACS, were first reported. In conclusion, transthyretin amyloidosis with polyneuropathy (ATTR-PN), GNE myopathy, and neuronal intranuclear inclusion disease (NIID) were the most common genotypes in this cohort of complex IPNs. NOTCH2NLC dynamic mutation testing should be added to the molecular diagnostic workflow. We expanded the genetic and related clinical spectrum of GNE myopathy and ARSACS by reporting novel variants.

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The original contributions presented in the study are included in the article, and further inquiries can be directed to the corresponding authors.

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Acknowledgements

The authors would like to thank the patients and their family members for their participation in this study.

Funding

This study was supported by the National Natural Science Foundation of China (8177366 and 82001338), the China International Medical Foundation (CIMF-Z-2016-20-1801), the Hunan Provincial Natural Science Foundation (2021JJ40934), and Changsha Municipal Natural Science Foundation (kq2014260).

Author information

Author notes

  1. Mengli Wang and Honglan Yang have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China

    Mengli Wang, Honglan Yang, Zhiqiang Lin, Xiaobo Li, Lei Liu, Shunxiang Huang, Huadong Zhao, Xiying Zhu & Ruxu Zhang

  2. Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

    Junling Wang & Beisha Tang

  3. Dr John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA

    Stephan Zuchner

  4. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China

    Qiao Xiao & Ranhui Duan

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  1. Mengli Wang
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Contributions

RZ was responsible for the concept, design, and manuscript editing; MW and HY performed the data analysis and the original draft preparation; ZL, XL, LL, SH, HZ, XZ, QX performed the data acquisition and analysis; JW, SZ, and BT supervised the study and reviewed the manuscript. The version to be published has been read and approved by all the authors, and each author believes the manuscript represents honest work.

Corresponding author

Correspondence to Ruxu Zhang.

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None declared.

Ethical approval

This study conformed with the World Medical Association Declaration of Helsinki and was approved by the ethics committee of the Third Xiangya Hospital (No. 2020-S035). Written informed consent was obtained from all participants or their first-grade relatives.

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Wang, M., Yang, H., Lin, Z. et al. The genetic and clinical spectrum in a cohort of 39 families with complex inherited peripheral neuropathies. J Neurol 270, 4959–4967 (2023). https://doi.org/10.1007/s00415-023-11821-z

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  • DOI: https://doi.org/10.1007/s00415-023-11821-z

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