Reliability of Response Biomarker for CMT1A Validated in US Patients, Study Reports

The fat fraction of the calf muscle is a reliable biomarker for disease progression and treatment response in Charcot-Marie-Tooth disease type 1A (CMT1A), according to a recent study.

The study, “Validation of MRC Centre MRI calf muscle fat fraction protocol as an outcome measure in CMT1A,” was published in the journal Neurobiology.

CMT1A accounts for more than half of CMT patients. It is caused by a duplication of the PMP22 gene, leading to the impaired structure and function of the myelin sheath, the protective layer around nerve fibers.

The rising number of promising therapies in development for treating or halting CMT highlights the urgent need to identify reliable measures of patient function (response biomarkers).

Since early changes in the proportion of water in muscles followed by accumulation of fat within the muscles are common in neuromuscular disorders, magnetic resonance imaging (MRI) to quantify these changes has been widely studied as a response measure in these diseases.

A recent U.K. study in 18 CMT1A patients showed that the patients’ fat fraction in calf muscles — quantified through a fat-water separation MRI protocol that uses a method called three-point Dixon — was potentially the most responsive biomarker identified so far, with a significant increase over the 12 months of follow-up.

This increase in fat accumulation in the calf muscles was associated with reduced muscle strength, functional scores, and quality of life in these patients.

However, before the application of this potential biomarker in clinical trials, further validation was necessary in other groups of patients.

Researchers have now evaluated whether calf muscle fat fraction showed the same results in an American group of CMT1A patients and which initial values of fat fraction promoted better responsiveness results to be used in future clinical trials.

They enrolled 11 CMT1A patients, including six women and five men, who had a mean age of 41 years. The MRI protocol developed in the U.K. study was performed at the beginning of the study and after a year at the University of Iowa. Only 10 patients had data from both time points.

The responsiveness of a biomarker is measured based on its ability to change over a prespecified period of time and on its association with changes in validated measures of disease status.

Calf muscle fat fraction significantly increased after a year, and was strongly associated with age and disease severity — measured by the CMT Neuropathy Score, a reliable and valid measure of disease status and treatment response in CMT1A patients.

These results were similar to the ones previously found in the U.K. group of patients, validating them.

When the team analyzed the data from both groups, they found that the biomarker responsiveness was even stronger in patients showing more than 10% of fat fraction in calf muscle, which characterized older patients with more severe disease.

This suggested that calf muscle fat fraction has the potential to be a valuable response biomarker in clinical trials for adult patients, especially for those with higher initial values of fat fraction.

The researchers noted that the data confirmed the validity, reliability, and responsiveness of MRI calf muscle fat fraction protocol as a measure of disease progression and treatment response in an independent group of CMT1A patients.

“Further studies to examine responsiveness of FF [fat fraction] assessed in the distal calf or foot musculature are in process to identify a more responsive biomarker in this younger, more mildly affected subgroup,” they wrote.