NCAM1: A Potential Biomarker for Charcot-Marie-Tooth Disease Progression

Diagnosis Charcot-Marie-Tooth disease and tablets on a wooden table.
Diagnosis Charcot-Marie-Tooth disease and tablets on a wooden table. Medicine concept.
Researchers sought to identify biomarkers across different types of Charcot-Marie-Tooth disease by analyzing blood samples from both mouse models and patients.

Both neural cell adhesion molecule 1 (NCAM1) and growth differentiation factor 15 (GDF15) proteins have been identified as potential biomarkers of Charcot-Marie-Tooth (CMT) disease progression in mouse models and patients with CMT in a multitargeted proteomics study published in the journal Brain.

CMT is the most common hereditary neuromuscular disorder, with a prevalence of about 1 in 2500 people. A key hurdle in developing therapies for CMT is that no biomarkers have been established to assess disease progression which are needed to evaluate drug efficacy.

The objective of the current study was to assess CMT biomarkers by analyzing blood samples from mouse models with different CMT types and blood samples from CMT patients.

The researchers used data from a cohort of 41 patients with CMT recruited at the Newcastle upon Tyne Hospitals in the United Kingdom. Unaffected family members and age-matched volunteers (n=12) were recruited as a control cohort and a disease control cohort (n=11) comprised of patients with bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) myopathy and distal muscle wasting or Becker or Duchene Muscular Dystrophy.

A total of 4 mouse models of different types of CMT was used to analyze blood and a healthy group of mice served as controls.

Human and mouse model serum samples underwent a comparative proteomic quantification and muscle samples were assessed via immuno-labelling.

The CMT cohort had a mixture of etiologies. There were patients with CMT1 (n=23) with pathogenic mutations in one of three genes and CMT2 (n=18) with pathogenic variants in one of eight genes.

Sera from CMT1 patients had six elevated proteins and CMT2 had four elevated proteins compared with control individuals.

Peptide levels of neural cell adhesion molecule 1 (NCAM1) were observed to be 22.2% increased in the CMT cohort compared with control individuals (P =.0004). NCAM1 levels were also elevated in mouse models.

Stratified by CMT subtype, NCAM1 peptides were 36.1% increased among patients with a causal mutations in the peripheral myelin protein 22 (PMP22) gene (P =.0028) and 11.6% increased in the patients with glycyl-tRNA 37 synthetase (GARS) or aminoacyl-tRNA synthetase (AARS) causal mutations (P =.0318).

A threshold of 44.35 ng/ml NCAM1 distinguished between patients and control individuals with a sensitivity of 78% and specificity of 70%. NCAM1 was able to identify patients with PMP22-associateddisease with a receiver operating characteristic (ROC) area under the curve (AUC) of 0.797 (95% CI, 0.661-0.9324) and GARS/AARS-associateddisease an AUC of 0.7467 (95% CI, 0.578-0.914).

The level of NCAM1 was higher among patients with severe neuropathy compared with mild neuropathy (mean, 61.3 vs 47.6 ng/ml; P =.016) and correlated with the CMT Examination Score (r, 0.33; P =.026). NCAM1 levels were also associated with symptom severity in mice.

Compared with the disease control cohort, no difference was observed between control individuals and the muscular dystrophy cohort. The GNE myopathy cohort had a small increase in NCAM1 but had levels significantly lower than that CMT cohort (P =.032).

Skeletal muscle biopsies indicated that complement components of NCAM1 were increased among the CMT cohort compared with control individuals, supporting the association between NCAM1 and neuromuscular pathology of the disease.

“We propose that NCAM1 may be a biomarker of CMT with potential capacity to monitor disease-progression, as demonstrated in patients and in several mouse models,” the researchers stated.

In the study, the protein GDF15 was also found to be elevated in patients with CMT and in mouse models compared with the control groups. The researchers noted GDF15 levels could identify CMT vs non-CMT with a sensitivity of 94% and a specificity of 93%. This protein also correlated with disease severity among patients who were mildly affected.

This study was limited by its small sample size and lack of longitudinal data. It remains unclear how NCAM1 peptide levels change over time.

“Our data indicates that serum GDF15 is a very strong diagnostic biomarker of CMT (AUC of 0.972, 95% CI; 0.936-1), while NCAM1 (AUC 0.748, 7 95% CI; 0.6268-0.869) is a more suitable serum biomarker of neuropathy progression,” the researchers concluded.

Disclosure: An author declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Jennings MJ, Kagiava A, Vendredy L et al. NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice. Brain. Published online February 10, 2022. doi:10.1093/brain/awac055