Deficiency of GlcNAc and HexNAc Linked to Progressive MS

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Study researchers investigated a marker of endogenous serum N-acetylglucosamine levels in patients with multiple sclerosis.

Reduction of N-acetylglucosamine (GlcNAc) and its stereoisomers, N-acetylhexosamine (HexNAc), may indicate progressive multiple sclerosis (PMS), according to study findings published in JAMA Neurology.

Study researchers conducted a cross-sectional study of 2 independent cohorts: a discovery cohort (healthy control patients, 66; patients with relapsing-remitting MS [RRMS], 33; patients with PMS, 21) and a confirmatory cohort (patients with RRMS, 125; patients with PMS, 55).

They measured retinal nerve fiber layer thickness (RNFL) with optical coherence tomography (OCT), measured thalamic volume and brain volume via magnetic resonance imaging (MRI), and assessed MS disability with the Expanded Disability Status Scale (EDSS) and MS functional composite (MSFC) of the Timed 25-Foot Walk Test, the 9-Hole Peg Test (9HPT), and the 3-second Paced Auditory Serial Additions Test.

They evaluated GlcNAc serum levels using liquid chromatography-tandem mass spectroscopy with ion pairing and found that the mean serum level of GlcNAc and HexNAc was 710 nM in the healthy control individuals, 682 nM in patients with RRMS, and 548 nM in patients with PMS.

A sensitivity analysis that removed patients aged 60 years and older confirmed the associations for patients with PMS vs healthy control individuals (B=-235.6 [standard error or SE=43.9]; P =9.7 × 10−7) or patients with RRMS (B=182.4 [SE=43.4]; P <.001) and patients with RRMS vs healthy control individuals (B=-76.8 [SE=37.0]; P =.04).

In the confirmatory cohort, mean HexNAc serum levels were much lower in patients with PMS (mean [SD] level, 405 nM) than among those with RRMS (mean [SD] level, 709 [193] nM; P =7.6 × 10−18; receiver operating characteristic area under the curve, 0.905).

Patients with primary progressive disease course from onset had HexNAc levels similar to those of patients with secondary-progressive MS (mean of 439, 381, respectively; P =.20).

HexNAc serum levels were inversely correlated with clinical disability, as measured by EDSS scores (P =4.73 × 10−12) and MSFC scores (P =8.2 × 10−5).

When study researchers corrected for age and sex, serum HexNAc levels were associated with scores on the Timed 25-Foot Walk Test (t=-4; P =5.8 × 10−5) and mean 9HPT scores (t=-2.6; P <.001).

Lower HexNAc serum levels were associated with normalized white matter volume (P =.03) and higher Multiple Sclerosis Severity Score (P =1.41 × 10−7). The serum levels were associated with both reduced thalamic volume (P =.04) and more severe retinal axonal degeneration as measured by peripapillary RNFL (B=0.012; P =.008), with age and sex as covariates.

Patients with low HexNAc levels at baseline showed a greater decrease in brain volume than those with high HexNAc levels at baseline, with age, sex, and baseline normalized brain volume as covariates (t=1.8; P =.04).

Limitations of the study included the fact that the cohorts were recruited from academic tertiary referral centers, the identification of HexNAc instead of GlcNAc in serum, the possible underpowered nature of the subgroup analyses and correlation analyses, the lack of investigation of HexNAc in association with advanced MRI parameters or macular OCT parameters, and the cross-sectional nature of the design.

Based on their findings, study researchers concluded that, “Combined, the data suggest that GlcNAc deficiency may be associated with progressive disease and neurodegeneration in patients with MS.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Brandt AU, Sy M, Bellmann-Strobl J, et al. Association of a marker of N-acetylglucosamine with progressive multiple sclerosis and neurodegeneration. JAMA Neurol. Published online May 10, 2021. doi:10.1001/jamaneurol.2021.1116