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26-06-2023 | Diseases of the neuromuscular synapses and muscles | Original Communication

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

Authors: Mengli Wang, Honglan Yang, Zhiqiang Lin, Xiaobo Li, Lei Liu, Shunxiang Huang, Huadong Zhao, Xiying Zhu, Qiao Xiao, Ranhui Duan, Junling Wang, Stephan Zuchner, Beisha Tang, Ruxu Zhang

Published in: Journal of Neurology | Issue 10/2023

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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Title: The genetic and clinical spectrum in a cohort of 39 families with complex inherited peripheral neuropathies
Authors: Mengli Wang
Honglan Yang
Zhiqiang Lin
Xiaobo Li
Lei Liu
Shunxiang Huang
Huadong Zhao
Xiying Zhu
Qiao Xiao
Ranhui Duan
Junling Wang
Stephan Zuchner
Beisha Tang
Ruxu Zhang
Publication date: 26-06-2023
Publisher: Springer Berlin Heidelberg
Keywords: Diseases of the neuromuscular synapses and muscles
Myopathy
Published in: Journal of Neurology / Issue 10/2023
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-023-11821-z

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Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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