Blood Protein Test Predicts Seven Years of Nerve Damage in Rare Genetic Disease

A single blood measurement taken at a routine clinic visit may reveal how aggressively a devastating neurological disease will unfold over the next seven years. Researchers in the Netherlands report that neurofilament light chain, a protein released when nerve fibers break apart, powerfully predicts the course of spinal cord degeneration in men with X-linked adrenoleukodystrophy, one of the most common inherited neurometabolic disorders. The findings, published in Annals of Clinical and Translational Neurology, come from the longest prospective biochemical follow-up yet conducted in adults with this condition, and they arrive at a moment when new therapies are making accurate prognostic tools more urgent than ever.

X-linked adrenoleukodystrophy is caused by pathogenic variants in the ABCD1 gene, which cripple the cellular machinery that breaks down very long-chain fatty acids. These fatty acids accumulate throughout the body, and in the nervous system they drive progressive destruction of myelin and axons. Roughly 60 percent of male patients develop a leukodystrophy, an inflammatory destruction of brain white matter, while virtually all men and most women eventually develop a slowly progressive disease of the spinal cord that targets the dorsal columns and corticospinal tracts. This spinal cord form, often called myeloneuropathy, erodes the ability to walk over decades, yet its pace varies enormously between individuals and is notoriously difficult to quantify with existing clinical scales.

That variability is precisely the problem the Amsterdam team set out to solve. Traditional outcome measures such as the Expanded Disability Status Scale, or EDSS, and the six-minute walk test change slowly, meaning clinical trials must follow patients for years to detect meaningful differences. Large patient numbers are needed because progression rates differ so widely. A biomarker that could sort patients at baseline into fast and slow progressors would allow smaller, faster, and cheaper trials, and would give clinicians and families a rational basis for decisions about when to intervene.

The study drew on the ongoing Dutch X-ALD cohort, using data collected between 2015 and 2024 at Amsterdam University Medical Centers. The researchers selected 66 adult men with spinal cord disease, excluding those with active leukodystrophy, prior hematopoietic stem cell transplantation, gene therapy, or compassionate use of the drug leriglitazone, because these interventions independently alter disease trajectories. Blood samples were processed within two hours of collection, centrifuged, aliquoted, and frozen at minus 80 degrees Celsius in a biobank. Plasma concentrations of neurofilament light chain and glial fibrillary acidic protein, a marker of astrocyte injury, were measured using single-molecule array technology, an ultra-sensitive immunoassay capable of detecting proteins at femtomolar concentrations. Assays were run by certified technicians blinded to all clinical data, with intra-assay coefficients of variation of just 4.8 percent for NfL and 3.3 percent for GFAP.

The stratification strategy was deliberately simple. Because NfL levels rise with age even in healthy people, and because no disease-specific reference values exist for adrenoleukodystrophy, the team divided patients using cohort-based thresholds. Men whose baseline plasma NfL was at or above 15.7 picograms per milliliter, the upper quartile, were classified as high; the rest as low. The differences at baseline were striking. The high-NfL group was significantly older, averaging 58.4 years against 36.4 years, and scored far worse on every clinical measure: higher EDSS disability scores, lower scores on the Severity Scoring System for Myelopathy, and dramatically shorter six-minute walk distances, averaging 333 meters compared with 529 meters in the low group.

The longitudinal results were even more consequential. Over up to seven years of follow-up, the high-NfL group showed significant, measurable worsening on the EDSS as early as the first year of follow-up, with an estimated mean change of 0.24 points, and the deterioration continued relentlessly, accumulating to 1.70 points by year seven. The low-NfL group, by contrast, showed minimal and statistically insignificant change over the same period. The difference in progression slopes between the two groups was highly significant, with a beta coefficient of minus 0.27 and a p-value below 0.001. Walking capacity declined significantly only in the high-NfL group, while patient-reported myelopathy scores fell in both groups but did not separate statistically between them.

Because age is such a strong confounder, the researchers performed a sophisticated sensitivity analysis. They log-transformed baseline NfL values, regressed them on age within the cohort, and calculated standardized residuals that capture NfL elevations beyond what would be expected for a given age within the X-ALD population itself. Patients were then grouped into four categories spanning minus one to plus two standard deviations. The gradient was unmistakable: men in the very high residual group showed EDSS worsening of 0.137 points per visit and SSPROM decline of 1.276 points per visit, both highly significant, while the low residual group showed no significant progression on any outcome measure. Pairwise comparisons confirmed that the mean, high, and very high groups differed significantly from one another in their EDSS and SSPROM slopes even after correction for multiple testing. Crucially, the association between higher age-adjusted NfL and faster clinical progression persisted, supporting the interpretation that the protein reflects disease-related axonal injury rather than aging alone.

GFAP told a very different story. Although plasma GFAP levels rose significantly over the study period overall, baseline GFAP stratification showed no significant differences in EDSS, SSPROM, or walking test scores, and no significant differences in progression slopes between high and low groups. The authors conclude that GFAP, which marks astroglial activation rather than axonal loss, has limited prognostic value in this context and may serve better as a complementary marker than a standalone predictor. The contrast is biologically informative: adrenoleukodystrophy-related myelopathy is fundamentally a degeneration of axons and their myelin sheaths, so a cytoskeletal protein shed from damaged axons tracks the disease process more faithfully than a marker of astrocytic response.

The findings dovetail with a growing literature on NfL in other forms of the disease. Previous work by the same group had shown correlations between NfL concentrations and spinal cord disease severity, and pediatric studies have demonstrated that plasma NfL is a sensitive monitor of cerebral lesion development in childhood cerebral adrenoleukodystrophy, with increases of more than 50 percent from baseline serving as a robust indicator of active inflammation. Other researchers have reported NfL elevations in myeloneuropathy patients who later developed the cerebral form, reaching levels comparable to those seen in amyotrophic lateral sclerosis during active disease. The new results extend this framework to the slow, chronic degeneration of the adult spinal cord, showing that the same molecule captures both explosive inflammatory damage and grinding degenerative loss.

The authors acknowledge limitations, including the modest sample size, the use of cohort-derived rather than population-based thresholds, and the insensitivity of clinical scales to early change in a disease where axonal degeneration precedes measurable disability until a critical threshold is crossed. Even so, the effect sizes were substantial and the trajectories separated early. Given that this represents the longest biochemical prospective follow-up in adult men with X-ALD-related myeloneuropathy, the researchers argue that serum NfL should be integrated into clinical trial protocols both as a stratification tool, to balance fast and slow progressors across treatment arms, and as a candidate surrogate outcome measure. For patients living with an unpredictable disease, a number drawn from a routine blood draw may soon transform both research and care.

Subject of Research: Prognostic biomarkers for spinal cord disease progression in X-linked adrenoleukodystrophy

Article Title: Prognostic Value of Neurofilament Light Chain and Glial Fibrillary Acidic Protein in ALD‐Related Myelopathy

Article References: Kabak, E. G., Voermans, M. M. C., Heijst, H., Teunissen, C. E., & Engelen, M. (2026). Prognostic Value of Neurofilament Light Chain and Glial Fibrillary Acidic Protein in ALD‐Related Myelopathy. Annals of Clinical and Translational Neurology, 13(10), 2114-2123. https://doi.org/10.1002/acn3.70386

Image Credits: AI Generated

DOI: 10.1002/acn3.70386

Keywords: X-linked adrenoleukodystrophy, neurofilament light chain, GFAP, biomarkers, myelopathy, spinal cord disease, ABCD1, clinical trials, neurodegeneration, Simoa, prognosis, longitudinal study