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Genotype–phenotype correlation in French patients with myelin protein zero gene‐related inherited neuropathy
Author(s) -
Subréville Marie,
BonelloPalot Nathalie,
Yahiaoui Douniazed,
BeloribiDjefaflia Sadia,
Fernandes Sara,
Stojkovic Tanya,
Cassereau Julien,
Péréon Yann,
EchanizLaguna Andoni,
Violleau MarieHélène,
Soulages Antoine,
Louis Sarah Léonard,
Masingue Marion,
Magot Armelle,
Delmont Emilien,
Sacconi Sabrina,
Adams David,
Labeyrie Céline,
Genestet Steeve,
Noury JeanBaptiste,
Chanson JeanBaptiste,
Lévy Nicolas,
JuntasMorales Raul,
Tard Céline,
Sole Guilhem,
Attarian Shahram
Publication year - 2021
Publication title -
european journal of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 124
eISSN - 1468-1331
pISSN - 1351-5101
DOI - 10.1111/ene.14948
Subject(s) - medicine , disease , clinical trial , age of onset , genotype , pathophysiology , gene mutation , mutation , phenotype , pediatrics , gastroenterology , gene , genetics , biology
Background and purpose 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. Methods Clinical and neurophysiological data of CMT patients with MPZ mutations were retrospectively collected at 11 French reference centers. Results 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. Conclusions 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.