RFC1 Repeat Expansions in Chronic Idiopathic Axonal Polyneuropathy: Prevalence, Phenotype, and Diagnostic Implications

IF 3 3区医学 Q1 CLINICAL NEUROLOGY

Journal of the Peripheral Nervous System Pub Date : 2026-08-12 DOI:10.1111/jns.70155

Vicente Gajate-García, María Fenollar-Cortés, Lucía Galán, Raluca Oancea-Ionescu, Antonio Guerrero-Solá, Alejandro Horga

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引用次数: 0

Abstract

Background and Aims

Chronic idiopathic axonal polyneuropathy (CIAP) accounts for approximately 20%–30% of adult-onset axonal polyneuropathies. Pathogenic RFC1 repeat expansions have emerged as a frequent cause of idiopathic sensory neuropathy, but their recognition in routine clinical practice may be challenging, particularly in the presence of potentially confounding comorbidities. We aimed to determine the prevalence of pathogenic RFC1 repeat expansions in a well-defined CIAP cohort, characterize the associated clinical and electrophysiological phenotype, and evaluate whether coexisting well-controlled diabetes mellitus (DM) or monoclonal gammopathy of undetermined significance (MGUS) may hinder recognition of RFC1-related neuropathy.

Methods

We performed a retrospective observational study of adult patients with CIAP followed at a tertiary neuromuscular unit. All patients underwent RFC1 genetic testing. Clinical and electrophysiological features were compared between RFC1+ and RFC1− patients in the full cohort and after exclusion of patients with DM or MGUS.

Results

Ninety patients met CIAP criteria and were analyzed. Twenty-four (27%) carried biallelic pathogenic AAGGG repeat expansions in RFC1, of whom 6 (25%) had coexisting DM or MGUS. Compared with RFC1− patients, RFC1+ individuals more frequently exhibited dysautonomic symptoms, unsteadiness, history of falls, need for walking support, chronic cough, impaired vibration sense in the upper limbs and up to the knees in the lower limbs, brisk upper-limb reflexes, mild cerebellar signs, an abnormal head-impulse test, and a positive Romberg's test. Most of these differences persisted after exclusion of DM or MGUS. Electrophysiological studies in RFC1+ patients showed widespread sensory nerve involvement, including the upper limbs, with relative motor sparing, whereas RFC1− patients exhibited a more typical length-dependent pattern.

Interpretation

Biallelic AAGGG repeat expansions in RFC1 were identified in 27% of patients with CIAP. Specific clinical and electrophysiological features may help distinguish RFC1-related disease from other forms of CIAP and identify candidates for genetic testing, even in the presence of potentially confounding comorbidities such as well-controlled DM or MGUS.

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慢性特发性轴突多发性神经病的RFC1重复扩增：患病率、表型和诊断意义

背景和目的：慢性特发性轴突多神经病变（CIAP）约占成人发病轴突多神经病变的20%-30%。致病性RFC1重复扩增已成为特发性感觉神经病变的常见原因，但在常规临床实践中对其的识别可能具有挑战性，特别是在存在潜在混淆合并症的情况下。我们的目的是在一个定义明确的CIAP队列中确定致病性RFC1重复扩增的患病率，表征相关的临床和电生理表型，并评估共存的控制良好的糖尿病（DM）或未确定意义的单克隆γ病（MGUS）是否会阻碍对RFC1相关神经病变的识别。方法：我们对成年CIAP患者进行了回顾性观察研究，随访于第三神经肌肉单位。所有患者均接受RFC1基因检测。比较全队列和排除DM或MGUS患者后RFC1+和RFC1-患者的临床和电生理特征。结果：90例患者符合CIAP标准。24例（27%）在RFC1中携带双等位致病性AAGGG重复扩增，其中6例（25%）共存DM或MGUS。与RFC1-患者相比，RFC1+患者更频繁地表现出自主神经异常症状、不稳定、跌倒史、需要行走支持、慢性咳嗽、上肢及下肢膝盖处振动感受损、上肢反射轻快、轻度小脑体征、头冲动试验异常和Romberg试验阳性。在排除DM或MGUS后，大多数差异仍然存在。RFC1+患者的电生理研究显示广泛的感觉神经受累，包括上肢，运动神经相对保留，而RFC1-患者表现出更典型的长度依赖模式。解释：27%的CIAP患者在RFC1中发现了双等位基因AAGGG重复扩增。特定的临床和电生理特征可能有助于将rfc1相关疾病与其他形式的CIAP区分开来，并确定基因检测的候选者，即使存在潜在的混杂合并症，如控制良好的糖尿病或MGUS。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of the Peripheral Nervous System 医学-临床神经学

CiteScore

6.10

自引率

7.90%

发文量

审稿时长

>12 weeks

期刊介绍： The Journal of the Peripheral Nervous System is the official journal of the Peripheral Nerve Society. Founded in 1996, it is the scientific journal of choice for clinicians, clinical scientists and basic neuroscientists interested in all aspects of biology and clinical research of peripheral nervous system disorders. The Journal of the Peripheral Nervous System is a peer-reviewed journal that publishes high quality articles on cell and molecular biology, genomics, neuropathic pain, clinical research, trials, and unique case reports on inherited and acquired peripheral neuropathies. Original articles are organized according to the topic in one of four specific areas: Mechanisms of Disease, Genetics, Clinical Research, and Clinical Trials. The journal also publishes regular review papers on hot topics and Special Issues on basic, clinical, or assembled research in the field of peripheral nervous system disorders. Authors interested in contributing a review-type article or a Special Issue should contact the Editorial Office to discuss the scope of the proposed article with the Editor-in-Chief.