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. 2025 Feb 11;272(3):191.
doi: 10.1007/s00415-025-12925-4.

SOD1-related inherited peripheral neuropathies in a Japanese cohort: genetic variants and clinical insights

Masahiro Ando  1 , Yujiro Higuchi  2 , Jun-Hui Yuan  1 , Akiko Yoshimura  1 , Chikashi Yano  1 , Takahiro Hobara  1 , Fumikazu Kojima  1 , Yu Hiramatsu  1 , Satoshi Nozuma  1 , Tomonori Nakamura  1 , Yusuke Sakiyama  1 , Akihiro Hashiguchi  1 , Yuji Okamoto  1   3 , Takeshi Matsushige  4 , Jun Mitsui  5 , Shoji Tsuji  6   7 , Hiroshi Takashima  1
Affiliations

SOD1-related inherited peripheral neuropathies in a Japanese cohort: genetic variants and clinical insights

Masahiro Ando et al. J Neurol. .

Abstract

Background: Inherited peripheral neuropathies (IPNs) encompass a wide range of disorders affecting the peripheral nervous system, often with complex genetic causes and frequent underdiagnosis. The variants in the superoxide dismutase 1 (SOD1) gene, primarily linked to amyotrophic lateral sclerosis (ALS), have also been associated with peripheral neuropathy. The recent approval of Tofersen, targeting SOD1-related ALS, highlights the importance of precise genetic diagnosis. This study explores the clinical and genetic profiles of SOD1-related IPNs (SOD1-IPN) in a nationwide Japanese IPN cohort.

Methods: Clinical and genetic data were assessed from 1483 Japanese patients with IPN, with a focus on those harboring SOD1 pathogenic variants. The clinical evaluations included age of onset, gender, muscle weakness patterns, sensory disturbances, reflex responses, and electrophysiological findings.

Results: Seventeen patients with SOD1 pathogenic variants were identified, reinforcing SOD1's role in IPN. The average onset age was 47, with a slight male predominance. Distal muscle weakness was noted in 9 of 13 patients, and asymmetric muscle weakness and atrophy in 10 of 14 cases. Mild sensory disturbances were observed in eight patients, with some showing hyperreflexia and abnormal reflexes. Electrophysiology predominantly indicated a length-dependent, motor-dominant axonal neuropathy.

Conclusion: This study reveals the clinical variability and likely underdiagnosis of SOD1-IPN, supporting the integration of SOD1 screening in IPN genetic testing, especially for patients with asymmetric, length-dependent axonal neuropathy evident in clinical and electrophysiological assessments.

Keywords: Amyotrophic lateral sclerosis; Electrophysiology; Inherited peripheral neuropathy; SOD1.

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Conflict of interest statement

Declarations. Conflicts of interest: The authors report that there is no conflicts of interests.

Figures

Fig. 1
Fig. 1
Flowchart of SOD1 analyses in the Japanese IPN/CMT case series. Comprehensive genetic testing was conducted on 2519 Japanese patients with a clinical diagnosis of IPNs. The analysis included DNA microarrays, next-generation sequencing-based gene panel sequencing, and whole-exome sequencing (WES). An additional gene panel analysis covering 103 IPNs/CMT-related genes, including SOD1, was performed in 727 patients from 2022 onward. SOD1 mutations were identified in 17 patients
See this image and copyright information in PMC

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