A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot–Marie–Tooth neuropathy 1A

IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Journal of the Peripheral Nervous System Pub Date : 2024-04-05 DOI:10.1111/jns.12621
Isaac R. L. Xu, Matt C. Danzi, Ariel Ruiz, Jacquelyn Raposo, Yeisha Arcia De Jesus, Mary M. Reilly, Andrea Cortese, Michael E. Shy, Steven S. Scherer, David N. Herrmann, Vera Fridman, Jonathan Baets, Mario Saporta, Reza Seyedsadjadi, Tanya Stojkovic, Kristl G. Claeys, Pooja Patel, Shawna Feely, Adriana P. Rebelo, Inherited Neuropathy Consortium, Maike F. Dohrn, Stephan Züchner
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引用次数: 0

Abstract

Background

Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot–Marie–Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets. In this study, we present a comprehensive analysis of clinical examination results from 1564 CMT1A patients sourced from a prospective natural history study conducted by the RDCRN-INC (Inherited Neuropathy Consortium). Our primary objective is to delineate extreme phenotype profiles (mild and severe) within this patient cohort, thereby enhancing our ability to detect genetic modifiers with large effects.

Methods

We have conducted large-scale statistical analyses of the RDCRN-INC database to characterize CMT1A severity across multiple metrics.

Results

We defined patients below the 10th (mild) and above the 90th (severe) percentiles of age-normalized disease severity based on the CMT Examination Score V2 and foot dorsiflexion strength (MRC scale). Based on extreme phenotype categories, we defined a statistically justified recruitment strategy, which we propose to use in future modifier studies.

Interpretation

Leveraging whole genome sequencing with base pair resolution, a future genetic modifier evaluation will include single nucleotide association, gene burden tests, and structural variant analysis. The present work not only provides insight into the severity and course of CMT1A, but also elucidates the statistical foundation and practical considerations for a cost-efficient and straightforward patient enrollment strategy that we intend to conduct on additional patients recruited globally.

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针对 Charcot-Marie-Tooth 神经病 1A 基因改变因子研究的快速临床注册研究理念
夏科-玛丽-图斯病 1A 型(CMT1A)是由编码外周髓鞘蛋白 22(PMP22)的基因重复引起的,是最常见的遗传性神经病。尽管具有共同的遗传起源,但临床严重程度却有相当大的差异。据推测,遗传修饰因子是造成这种异质性的原因之一,识别这些修饰因子可能会发现新的治疗靶点。在本研究中,我们对来自 RDCRN-INC(遗传性神经病联盟)前瞻性自然史研究的 1564 名 CMT1A 患者的临床检查结果进行了全面分析。我们的主要目标是在该患者群中划分出极端表型特征(轻度和重度),从而提高我们检测具有巨大效应的遗传修饰因子的能力。
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来源期刊
CiteScore
6.10
自引率
7.90%
发文量
45
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.
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