Subréville Marie, Bonello-Palot Nathalie, Yahiaoui Douniazed, Beloribi-Djefaflia Sadia, Fernandes Sara, Stojkovic Tanya, Cassereau Julien, Péréon Yann, Echaniz-Laguna Andoni, Violleau Marie-Hélène, Soulages Antoine, Louis Sarah Léonard, Masingue Marion, Magot Armelle, Delmont Emilien, Sacconi Sabrina, Adams David, Labeyrie Céline, Genestet Steeve, Noury Jean-Baptiste, Chanson Jean-Baptiste, Lévy Nicolas, Juntas-Morales Raul, Tard Céline, Sole Guilhem, Attarian Shahram
Reference Center for Neuromuscular Disorders and ALS, APHM, CHU La Timone, Marseille, France.
Marseille Medical Genetics, Aix-Marseille University-Inserm UMR 1251, Marseille, France.
Eur J Neurol. 2021 Sep;28(9):2913-2921. doi: 10.1111/ene.14948. Epub 2021 Jun 29.
Preparations for clinical trials of unfolded protein response (UPR) inhibitors (such as Sephin1) that target the upregulated UPR in patients with Charcot-Marie-Tooth disease (CMT) carrying MPZ mutations are currently underway. The inclusion criteria for these trials are still being formulated. Our objective was to characterize the relation between genotypes and phenotypes in patients with CMT caused by MPZ mutations, and to refine the inclusion criteria for future trials.
Clinical and neurophysiological data of CMT patients with MPZ mutations were retrospectively collected at 11 French reference centers.
Forty-four mutations in MPZ were identified in 91 patients from 61 families. There was considerable heterogeneity. The same mutation was found to cause either axonal or demyelinating neuropathy. Three groups were identified according to the age at disease onset. CMT Examination Score (CMTES) tended to be higher in the early (≤22 years) and adult (23-47 years) onset groups (mean CMTESv2 = 10.4 and 10.0, respectively) than in the late onset group (>47 years, mean CMTESv2 = 8.6, p = 0.47). There was a significant positive correlation between CMTESv2 and the age of patients in Groups I (p = 0.027) and II (p = 0.023), indicating that clinical severity progressed with age in these patients.
To optimize the selection of CMT patients carrying MPZ mutations for the upcoming trials, inclusion criteria should take into account the pathophysiology of the disease (upregulated UPR). Recruited patients should have a mild to moderate disease severity and a disease onset at between 18 and 50 years, as these patients exhibit significant disease progression over time.
针对携带MPZ突变的夏科-马里-图斯病（CMT）患者中上调的未折叠蛋白反应（UPR）的抑制剂（如Sephin1）的临床试验准备工作正在进行中。这些试验的纳入标准仍在制定中。我们的目标是明确由MPZ突变引起的CMT患者的基因型与表型之间的关系，并完善未来试验的纳入标准。
在法国的11个参考中心回顾性收集了携带MPZ突变的CMT患者的临床和神经生理学数据。
在来自61个家庭的91例患者中鉴定出44种MPZ突变。存在相当大的异质性。发现相同的突变可导致轴索性或脱髓鞘性神经病变。根据发病年龄分为三组。早期（≤22岁）和成年期（23 - 47岁）发病组的CMT检查评分（CMTES）往往高于晚期发病组（>47岁，平均CMTESv2 = 8.6，p = 0.47），早期组平均CMTESv2 = 10.4，成年期组平均CMTESv2 = 10.0。在I组（p = 0.027）和II组（p = 0.023）中，CMTESv2与患者年龄之间存在显著正相关，表明这些患者的临床严重程度随年龄进展。
为了优化即将进行的试验中携带MPZ突变的CMT患者的选择，纳入标准应考虑疾病的病理生理学（UPR上调）。招募的患者应具有轻度至中度的疾病严重程度且发病年龄在18至50岁之间，因为这些患者随时间推移会出现明显的疾病进展。
