CMTES Could Measure Disease Progression in Clinical Trials: Study
The tool also might track the effectiveness of potential treatments for the disease
A standardized tool called the Charcot–Marie–Tooth Examination Score (CMTES) help track disease progression in people with Charcot-Marie-Tooth disease (CMT) caused by mutations in the myelin protein zero (MPZ) gene, a study reports.
It may also be useful for tracking the effectiveness of potential treatments in future clinical trials, researchers said.
“Our results suggest that the CMTES will serve as a valuable tool for clinical trials in axonal forms of MPZ neuropathy [nerve disease],” they wrote.
The study, “Disease Progression in CMT related to MPZ Mutations: A Longitudinal Study,” was published in the Annals of Neurology.
About 5% of CMT cases are caused by mutations in the MPZ gene, which needs to properly produce myelin, a fatty substance that wraps around nerve fibers and helps them send electrical signals. More than 200 different disease-causing mutations in MPZ have been documented.
There is substantial variability in how MPZ-mutant CMT presents, both in terms of clinical manifestations and biological changes in the nervous system. This variability can pose a challenge in clinical trials as it may be difficult to tell whether a therapy is effective amid the noise of naturally occurring, person-to-person differences.
Measuring CMT disease severity
An international team of scientists reported standardized disease severity scores for 136 people with CMT caused by MPZ mutations who were followed between 2009 and 2020.
To measure disease severity the researchers used two versions of the Charcot–Marie–Tooth Examination Score (CMTES), the original CMTES and the Rasch modified CMTES (CMTES-R). Higher scores on these measures reflect more severe disease.
The 136 patients ranged in age from 4 to 76 and just over half were identified as female (53%), being a sizable majority (88%) being white. Most (84.6%) were able to walk, with about a third (31%) relying on a mobility aid to do so.
Among those with available data, 54% had a demyelinating neuropathy, meaning they had a loss of myelin. The rest had axonal neuropathy, marked by damage to the long projections of nerve cells. At the start of the study, patients with axonal disease were significantly older (mean age 55 vs. 38), reported lower mean CMTES scores (9.6 vs. 11.8). and were less likely to require a wheelchair (6.8% vs. 20.6%). The average scores on the CMTES and CMTES-R at the start of the study (baseline) were 10.8 and 14.6 points, respectively.
This reflects “a moderate range of [disease] severity,” the researchers noted.
Patients with higher baseline CMTES and CMTES-R scores tended to be older, have more walking difficulties, and were more commonly identified as non-white.
Follow-up data for up to five years was available for some participants, with later time points generally having less patient data.
The available data show a strong, statistically significant association between worsening disease severity scores and time — after two years of follow-up, the average CMTES score increased by 0.87 points and average CMTES-R score increased by 0.96 points. Significant changes also were reported for later time points.
CMTES useful in clinical trials
“Our findings demonstrate progression in CMTES over time, with an estimated change of 0.87 points from baseline to 2-year follow-up, confirming that this clinical outcome assessment will be useful for future clinical trials,” the researchers wrote.
Despite these general trends, there was marked variability in how scores progressed, as has been previously reported. “Progression on the CMTES varied among participants with different MPZ variants [mutations], as well as between patients with the same variant and patients from the same family,” they wrote.
Also, the change in CMTES scores up to two years of follow-up was only significant in patients with scores classified as moderate disease at baseline, but not in those with mild or severe baseline CMTES scores.
“CMTES was only sensitive to change in participants with moderate neuropathy (as defined by the baseline CMTES), and did not reliably capture progression in patients on the phenotypic extremes,” the scientists wrote.
Results of statistical tests to look for factors associated with disease severity scores over time showed CMTES scores tended to worsen more quickly in axonal disease patients compared to those with demyelinating CMT. The team noted that the rate of CMTES progression tended to be slower as patients got older, though these results did not quite reach statistical significance.
“These data suggest that clinical trials in the adult population with MPZ neuropathy employing the CMTES may be most informative in participants with axonal neuropathy,” the researchers wrote, noting that a two-year, placebo-controlled clinical trial in type 2 MPZ-mutant CMT would need 62 patients in each treatment group to detect a significant effect on CMTES progression.
“Although this is still an ambitious number given the rarity of MPZ neuropathy, the recent rise in gene testing has led to a rapid identification of new MPZ cases,” they wrote.