Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study

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.

Keywords: Charcot-Marie-Tooth Examination Score v2.0; Charcot-Marie-Tooth disease type 2A; genotype-phenotype correlations; mitofusin-2; standardized response mean.

Figure 1

The average age of onset of symptoms at each amino acid position for all the pathogenic and likely pathogenic variants with dominant inheritance and AR-CMT2A cases identified in this study. AR-CMT2A cases shown on the far right. For each amino acid position, the cumulative variant count irrespective of the amino acid substitution, is also listed (n; for example ‘p.Arg94–, n = 31’ contains all 31 cases of p.Arg94Trp, p.Arg94Gln, p.Arg94Gly and p.Arg94Leu). On the x-axis, the variants are equidistant from one another for graphical purposes; the distance between the variants displayed is not to scale. However, the primary structure of the MFN2 protein has been drawn below the graph in a skewed fashion to account for this and highlights which functional domains the variants reside in. The average age of onset of symptoms for each amino acid position is displayed with a horizontal red bar and the standard deviation bars, indicative of the spread in age of onset for each position, are also shown for all amino acid positions with variant counts of two or more.

Figure 2

Correlation of CMTESv2 and disease duration as surrogate evidence of disease progression. The disease duration was calculated by subtracting the age of onset from the age at assessment at the baseline visit. The dashed line represents the linear regression coefficient (R²). 148 patients with a dominant pathogenic or likely pathogenic MFN2 variant had CMTESv2 data at their baseline visit; the correlation between CMTESv2 and disease duration is statistically significant (two-tailed Spearman’s ρ 0.44, P < 0.001).

Figure 3

Correlation of CMTESv2 and disease duration in the three commonest missense variants causing CMT2A. The disease duration was calculated by subtracting the age of onset from the age at assessment at the baseline visit. The dashed line represents the linear regression coefficient (R²). (A) 24 patients with a heterozygous mutation at the p.Arg94– amino acid position had CMTESv2 data at their baseline visit. This subgroup includes patients with the variants p.Arg94Trp, p.Arg94Gln, p.Arg94Gly and p.Arg94Leu; the correlation between CMTESv2 and disease duration in this group is statistically significant (two-tailed Spearman’s ρ 0.65, P < 0.001). (B) Thirteen patients carrying the heterozygous variant p.Arg364Trp had CMTESv2 data at their baseline visit and the correlation between CMTESv2 and disease duration is statistically significant (two-tailed Spearman’s ρ 0.72, P = 0.0054). (C) Eighteen patients with a heterozygous variant at the p.Trp740– amino acid position had CMTESv2 data at their baseline visit and the correlation between CMTESv2 and disease duration is statistically significant (two-tailed Spearman’s ρ 0.58, P = 0.011).

Figure 4

Genotype-physical impact correlation in 29 patients with CMT2A due to pathogenic and likely pathogenic variants at the p.Arg94– amino acid position. Each horizontal set of data-points plotted over time (age in years) corresponds to one of the 29 patients (1–29 on the y-axis). Patients 1–16 carry the p.Arg94Trp variant, Patient 17 carries the p.Arg94Leu variant, Patients 18 and 19 carry the p.Arg94Gly variant, and Patients 20–29 carry the p.Arg94Gln variant. In each set of data-points, the red square represents the age at which the patient was first seen and enrolled in the study (baseline visit): the dashed line to its left represents retrospective information gathered by history and the solid line to its right represents prospective information gathered during the entirety of the study. The green diamond represents the last age with available clinical data. Most of the patients have only been seen once and hence the red square and green diamond coincide. The blue circle represents the age of onset of symptoms in the patient, the yellow triangle represents the age at which ankle-foot orthoses were needed and prescribed, the purple star represents the age at which walking aids (stick, walker) were required and the blue cross represents the age at which the patient reverted to the regular use of a wheelchair.