Abstract
Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.
Highlights
Mitofusin-1 (MFN1) and mitofusin-2 (MFN2) are homologous mammalian proteins and members of the large mitochondrial transmembrane GTPase family, exhibiting ubiquitous expression in eukaryotic cells and playing a fundamental role in the dynamic mitochondrial remodelling process governed by mitochondrial fusion and fission (Chandhok et al, 2018)
The age distribution was considered as a single mode with an arbitrary cut-off at the age of 20 years, rather than bimodal, as there are no distinct paediatric and adult presentations in Charcot-MarieTooth disease type 2A (CMT2A)
We identified 179 patients from 133 families with dominant pathogenic (ACMG class 5) or likely pathogenic MFN2 variants (AD-CMT2A; Supplementary Table 3), and 17 patients from 13 families with AR-CMT2A (Supplementary Table 5); 13 of 17 patients with ARCMT2A harboured homozygous variants or compound heterozygous variants proven to be in trans phase
Summary
Mitofusin-1 (MFN1) and mitofusin-2 (MFN2) are homologous mammalian proteins and members of the large mitochondrial transmembrane GTPase family, exhibiting ubiquitous expression in eukaryotic cells and playing a fundamental role in the dynamic mitochondrial remodelling process governed by mitochondrial fusion and fission (Chandhok et al, 2018). These two highly coordinated biological processes, amongst other functions, are considered critical in mitigating mitochondrial stress, contributing to mitochondrial quality control and facilitating cellular apoptosis in cases of extreme cellular stress (Youle and van der Bliek, 2012). MFN2 mediates sites of endoplasmic reticulum-mitochondrial contact, which are important for calcium homeostasis (de Brito and Scorrano, 2008; Merkwirth and Langer, 2008; Filadi et al, 2015, 2017; Leal et al, 2016)
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