NFL Biomarker May Be Unsuitable to Measure CMT1A Outcomes

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by Vanda Pinto PhD |

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Blood levels of the protein neurofilament light chain (NFL), a biomarker of several neurological disorders, may not be suitable to measure outcomes in patients with Charcot-Marie-Tooth disease type 1A (CMT1A), a recent study suggests.

The study, “A longitudinal and cross-sectional study of plasma neurofilament light chain concentration in Charcot-Marie-Tooth disease,” was published in the Journal of the Peripheral Nervous System.

CMT disease is a genetic disorder characterized by damage to peripheral nerves that supply movement and sensation to the arms and legs. There are several types and subtypes of CMT depending on various factors, including which genes are mutated, the way the disease is inherited, and the age of disease onset.

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Clinical trials for CMT need sensitive biomarkers to measure how well the tested treatments are working. In several neurological conditions, including CMT, the concentration of NFL — an indicator of nerve cell damage — is increased in the blood. However, for NFL to be used as a biomarker for CMT, it is necessary to evaluate how its concentration changes over time.

To find out more, a team of researchers based in the U.K. and U.S. determined variations in blood NFL levels over time in patients with CMT and in two mouse models of the disease.

In a previous study, the investigators had verified that NFL levels matched disease severity using blood samples from 75 CMT patients in the U.K. After six years, 27 of the 75 patients donated their blood again for the current study. Additionally, blood was collected from 49 patients examined at the Inherited Neuropathy Consortium clinic in the Department of Neurology at the University of Iowa.

The U.S. group comprised 18 patients with CMT1B, 18 with CMT1X, four with CMT2A, nine with CMT2E, and 25 controls. NFL levels were increased in patients with CMT1B, CMT1X, and CMT2A compared with controls, but not in CMT2E patients. Unlike in the earlier study, no association was found between the CMT subtypes and the two measures of disease severity, the CMT examination score (CMTES) and the CMT neuropathy score.

In the U.K. group, patients had CMT1A, CMT1X, CMT2A, CMT4C, CMT4B1, or hereditary sensory neuropathy type 1 (HSN1) — also a genetic disorder but predominantly affecting sensory nerves. Higher blood NFL concentrations were associated with a higher (more severe) CMTES in this patient group at the six-year follow-up. Blood NFL levels did not change significantly for CMT1A and HSN1 over six years, but were reduced in CMT1X.

Next, the team measured blood NFL levels at five, seven, nine, and 11 weeks in two mouse models of CMT2D. Compared with the control mice, NFL levels were significantly decreased in GARSC201R mice, a model of milder disease with normal life expectancy, at 11 weeks of age. However, in GARSP278KY mice — which have reduced life expectancy — blood NFL levels remained constant between seven and 11 weeks of age after being higher than in controls at five weeks, though not significantly.

“We have replicated our previous findings of increased concentrations in patients with CMT compared with controls, and we have shown that in mouse models of the disease, concentrations can vary over the lifetime of the animal and that in humans, the change in concentration may vary according to subtype,” the scientists wrote.

“We have also shown pilot data that NFL is unlikely to be suitable as a primary outcome measure in patients with CMT1A,” they added.

Currently, the team continues to investigate NFL and other biomarkers in CMT1A, CMT1B, CMT2A, and CMT1X.