A large multicenter study on the natural history of Charcot-Marie-Tooth disease type 2A (CMT2A) correlates different genetic profiles and disease-causing mutations to their effect on disease severity and progression.
The findings will help inform prognosis and provide data to support clinical trial design, researchers said.
The study, “Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study,” was published in the journal Brain.
CMT2A is caused by mutations (variants) in the MFN2 gene, which provides instructions for making mitofusin 2, a protein involved in the fusion and proper function of mitochondria, which are energy-producing structures within cells.
More than 100 MFN2 gene variants have been identified that underlie CMT2A. The disorder usually leads to severe symptoms before age 10, including motor disability and vocal cord problems.
Different variants cause varying degrees of disease severity, potentially leading to vision defects and learning difficulties.
Studies have examined the connection between specific variants (genotypes) and disease characteristics (phenotypes) at a particular point in time. Still, research investigating the natural history of CMT2A over time (longitudinal) are lacking.
To fill in this knowledge gap, researchers based at the University College London in the U.K., with collaborators at various sites worldwide, conducted a longitudinal study of the largest group of CMT2A patients reported to date. They sought to establish correlations between specific variants and disease characteristics that would inform prognosis and provide data to help clinical trial design.
Participants in this study were enrolled in the CMT natural history protocol (NCT01193075), a long-term observational study in people with different CMT types to identify genotype-phenotype correlations.
A total of 225 patients (average age 31.3 years, 100 males and 125 females) with MFN2 variants were recruited at sites in the U.S., U.K., Italy and Australia. Eighty-seven patients were younger than 20.
The team identified 179 patients from 133 families with dominant disease-causing (or likely disease-causing) MFN2 variants (AD-CMT2A), which means that one faulty gene inherited from one parent is enough to cause disease. Seventeen participants from 13 families had recessive variants (AR-CMT2A), characterized by two defective genes, one inherited from each parent. The remaining patients had mutations of uncertain significance.
Participants with AD-CMT2A or AR-CMT2A had a similar mean age of symptom onset (11.61 vs. 8.06 years), and showed no significant difference in disease duration at the beginning of the study (baseline) — 19.98 vs. 25.35 years.
In contrast, a significantly higher proportion of patients with AD-CMT2A had foot deformities compared to AR-CMT2A (79% vs. 53%), but there was a significantly higher proportion of AR-CMT2A patients who used ankle-foot braces (93% vs. 63%) and had undergone foot surgery (53% vs. 25%).
Overall, patients with AR-CMT2A had significantly higher mean CMT Examination scores (CMTESv2) at baseline (14.57 vs. 10.75) — meaning greater disability. There were no significant differences between the two groups in walking aids or wheelchair use, dexterity difficulties, optic nerve atrophy (shrinkage), hearing loss, or scoliosis, which is a sideways curvature of the spine.
Disease duration between childhood and adult-onset AD-CMT2A cases at baseline was similar. However, there was a significantly higher percentage of patients with childhood-onset AD-CMT2A using ankle-foot braces (68% vs. 40%), wheelchair-dependent (31% vs. 4%) and with impaired dexterity, defined as difficulties with cutlery and/or buttons (70% vs. 46%).
In addition, childhood-onset AD-CMT2A had significantly higher mean CMTESv2 scores (12.06 vs. 6.50), but no significant difference was seen relative to the adult-onset form in the prevalence of foot deformities, the use of walking aids, the prevalence of previous foot surgery, hearing loss, or scoliosis.
In an analysis of AD-CMT2A cases with variants residing within a critical portion of the mitofusin 2 protein (dynamin-GTPase domain) compared to mutations outside this region, the team found no significant differences in age at symptom onset and baseline mean CMT severity scores.
However, a higher proportion of patients with dynamin-GTPase domain variants used ankle-foot orthoses (70% vs. 53%), complained of dexterity difficulties (70% vs. 55%), and developed scoliosis (16% vs. 6%). The team also found no differences in age of onset, disease duration, or severity scores comparing those who carried variants that increased to patients whose mutations decreased mitochondrial fusion.
Data from those with AD-CMT2A showed a significant association between disease duration and CMTESv2 scores, indicating a greater severity as the disease progresses.
Patients with variants in the amino acid position arginine 94 (Arg94, a building block of mitofusin 2 protein) showed such significant association between baseline CMTESv2 and disease duration. Almost all of these 29 patients required ankle-foot braces in the first two decades of life.
Patients carrying an amino acid change at position 364 also showed the same correlation, but they had more severe disease early on and throughout the entirety of the disease compared to those with the Arg94 mutation. The opposite finding, meaning milder disease, was seen in patients with variants in position 740.
Of the 179 patients with AD-CMT2A, 38 had one-year follow-up data and 34 had two-year follow-up data, while six participants with AR-CMT2A had one-year follow-up, four had a two-year follow-up, and five had four-year follow-up data.
In those with AD-CMT2A, the CMTESv2 increased (worsened) significantly over one and two years. Analysis of the pediatric AD-CMT2A and AR-CMT2A cases grouped together found significant CMTESv2 increases over the same periods. There was no significant change in CMTESv2 in the AR-CMT2A group, “likely to be due to the small sample size of patients with available follow-up data from baseline,” the team wrote.
“Large CMT2A [group] studies such as ours are valuable to help investigators curate variants,” the investigators wrote. “Moreover, with genetic therapies in development and clinical trials on the horizon, we need to have responsive clinical outcome measures in order to be trial-ready.”
“This study provides evidence that CMTESv2 is a responsive outcome measure for a 2-year clinical trial that, together with the concurrent development of responsive biomarkers, means we are in a good position to perform clinical trials as candidate therapies become available for CMT2A,” they added.
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