Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study
Authors: Pipis Menelaos , Feely Shawna M E , Polke James M , Skorupinska Mariola , Perez Laura , Shy Rosemary R , Laura Matilde , Morrow Jasper M , Moroni Isabella , Pisciotta Chiara , Taroni Franco , Vujovic Dragan , Lloyd Thomas E , Acsadi Gyula , Yum Sabrina W , Lewis Richard A , Finkel Richard S , Herrmann David N , Day John W , Li Jun , Saporta Mario , Sadjadi Reza , Walk David , Burns Joshua , Muntoni Francesco , Ramchandren Sindhu , Horvath Rita , Johnson Nicholas E , Züchner Stephan , Pareyson Davide , Scherer Steven S , Rossor Alexander M , Shy Michael E , Reilly Mary M ,   for the Inherited Neuropathies Consortium - Rare Disease Clinical Research Network (INC-RDCRN), Baratta Silvia , Bray Paula , Calabrese Daniela , Cornett Kayla , Donlevy Gabrielle , Eichinger Katy , Foscan Maria , Genitrini Silvia , Grant Natalie Rose , Jones Tara , Lee Diana , McCray Brett A , Magri Stefania , Menezes Manoj , Mullen Krista , Nanji Tina , Nuzzo Sara , Pagliano Emanuela , Poh Roy , Park Eun , Sadaf Saba , Saveri Paola , Siskind Carly , Sowden Janet E , Sumner Charlotte J , Thomas Simone 
Published: October 2020

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.