NfL Shows Potential as CMT Biomarker, But More Work Needed

Blood plasma levels of the protein neurofilament light chain (NfL) are elevated in Charcot-Marie-Tooth disease (CMT) patients and correlate somewhat with disease severity, a recent study reports.

These findings suggest that the protein may serve as a clinical biomarker for identifying CMT and tracking disease progression, but more work in validating its use is necessary.

The study, “Plasma neurofilament light chain as a potential biomarker in Charcot‐Marie‐Tooth disease,” appeared in the European Journal of Neurology. 

CMT, a group of genetic disorders that result from mutations in more than 30 different genes, is characterized by damage to the peripheral nervous system, the network of nerves that supply movement and sensation to the arms and legs.

Its two most common forms are CMT type 1A (CMT1A), caused by duplication of the PMP22 gene, and CMT type X (CMTX1), caused by a GJB1 gene mutation in the sex-determining X chromosome.

Neurofilament is highly concentrated in nerve cell fibers and elevated in response to neuronal damage, making it a potential biomarker for diseases of the nervous system. However, whether neurofilament proteins can be used as markers of CMT remains largely unknown.

Researchers in Latvia assessed the levels of NfL — the smallest neurofilament subunit — in a group of 96 CMT patients, 52 of whom are from the same 19 families, and 60 healthy controls.

In the CMT group, 51 patients were female with a mean age of 38.6, and 41 were in the control group (mean age of 35.7). CMT patients were classified as CMT1A, CMTX1, and, for those without a known genetic mutation, as “other CMT.” 

Patients had significantly higher median NfL levels (12.5 picograms per milliliter, or pg/mL) compared to controls (5.2 pg/mL). NfL level was also found to be moderately associated with age, but not sex, in both groups.

Interestingly, median NfL levels were significantly higher in the CMTX1 group than in either the CMT1A or other CMT groups (16 vs. 12.5 and 11.8 pg/mL, respectively), even though these patients did not have more severe disease.

Although CMTX1 is caused by a mutation on the X chromosome and is typically more severe in males, patients did not show any sex-based difference in NfL levels or disease severity.

CMT severity was weakly but significantly associated with NfL levels, the research team found. CMT signs and symptoms, which almost exactly correlated with disease severity scores, also weakly correlated with NfL concentration.

While patient-reported duration of symptoms was moderately associated with age and weakly associated with the CMT severity, it did not associate with NfL levels.

Additional analysis revealed that NfL concentration could be used to distinguish CMT patients from healthy controls. An NFL concentration of 8.9 pg/mL predicted CMT with the highest accuracy, with 95% specificity (meaning only 5% false positives) and 74% sensitivity (26% false negatives).

“Our study shows that the NfL measurement is a promising biomarker in CMT,” the researchers wrote, adding that “more data are needed to establish whether the plasma level of NfL can genuinely be used to monitor disease progression.”

Potential use of NfL concentration as a clinical biomarker for CMT is limited by a number of factors, including a degree of the protein’s overlap between CMT patients and healthy controls, a lack of standardization as to an optimal NfL concentration threshold, its “modest correlation” with disease severity, and NfL’s “non-specificity as it is elevated in various neurological disorders,” the researchers wrote.

The team plans to conduct follow-up analyses with the study participants in two and five years to better assess the long-term potential of NfL as a CMT biomarker.