Clinical and genetic features of CMT2T in Italian patients confirm the importance of MME pathogenic variants in idiopathic, late‐onset axonal neuropathies

IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Journal of the Peripheral Nervous System Pub Date : 2024-09-09 DOI:10.1111/jns.12657
Alessandro Geroldi, Andrea La Barbera, Alessia Mammi, Paola Origone, Andrea Gaudio, Clarissa Ponti, Francesca Sanguineri, Sabrina Matà, Martina Sperti, Ilaria Carboni, Emilia Bellone, Fabio Gotta, Chiara Gemelli, Sara Massucco, Guglielmino Valeria, Lucio Marinelli, Marina Grandis, Giulia Bisogni, Mario Sabatelli, Giuseppe Piscosquito, Gabriella Esposito, Angelo Schenone, Fiore Manganelli, Paola Mandich, Stefano Tozza, Marco Luigetti
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Abstract

Background and AimsSince 2016, biallelic mutations in the membrane metalloendopeptidase (MME) gene have been associated with late‐onset recessive CMT2 (CMT2T). More recently, heterozygous mutations have also been identified in familial and sporadic patients with late‐onset axonal neuropathy, ranging from subclinical to severe. This indicates that the heterozygous MME variants may not be fully penetrant, or alternatively, that they may be a potential risk factor for neuropathy. Here, we describe the clinical, neurophysiological, and genetic findings of 32 CM2T Italian patients.MethodsThe patients were recruited from four different Italian referral centers. Following a comprehensive battery of neurological, electrophysiological, and laboratory examinations, the patients' DNA was subjected to sequencing in order to identify any variants in the gene. Bioinformatic and modeling analyses were performed to evaluate the identified variants' effects.ResultsWe observe a relatively mild axonal sensory‐motor neuropathy with a greater impairment of the lower extremities. Biallelic and monoallelic patients exhibit comparable disease severity, with an earlier onset observed in those with biallelic variants. When considering a subgroup with more than 10 years of disease, it becomes evident that biallelic patients exhibit a more severe form of neuropathy. This suggests that they are more prone to quick progression.InterpretationCM2T has been definitively defined as a late‐onset neuropathy, with a typical onset in the fifth to sixth decades of life and a more rapidly progressing worsening for biallelic patients. CMT2T can be included in the neuropathies of the elderly, particularly if MME variants heterozygous patients are included.
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意大利 CMT2T 患者的临床和遗传特征证实了 MME 致病变体在特发性晚发性轴索神经病中的重要性
背景和目的自2016年以来,膜金属内肽酶(MME)基因的双重复突变一直与晚发性隐性CMT2(CMT2T)有关。最近,在晚发性轴索神经病(从亚临床到严重)的家族性和散发性患者中也发现了杂合突变。这表明,杂合子 MME 变异可能不具有完全的渗透性,或者说,它们可能是神经病变的潜在风险因素。在此,我们描述了 32 名 CM2T 意大利患者的临床、神经生理学和遗传学研究结果。在进行了全面的神经学、电生理学和实验室检查后,对患者的 DNA 进行了测序,以确定基因中的任何变异。结果我们观察到一种相对轻微的轴索感觉-运动神经病,下肢受损较重。双倍变体和单倍变体患者的疾病严重程度相当,双倍变体患者发病较早。如果考虑到发病时间超过 10 年的亚组,则可以明显看出双倍拷贝患者的神经病变更为严重。CM2T已被明确定义为一种晚发性神经病,典型的发病年龄为五六十岁,双倍拷贝患者的病情恶化速度更快。CMT2T 可归入老年神经病,特别是如果将 MME 变异杂合子患者包括在内的话。
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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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