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

The therapeutic landscape has changed dramatically over the past several years. Treatment options now span substrate reduction and replacement, cofactor replacement, enzyme replacement, RNA-based therapies, cell therapy, gene therapy, and gene editing. The general trend, Whitehead notes, is a movement away from ongoing metabolic replacement strategies such as dietary modification, cofactor supplementation, and enzyme replacement therapy toward single-instance genetic interventions like gene therapy and, eventually, gene editing. To keep pace with this rapidly evolving field, clinicians can consult a dynamic, continuously updated resource known as the Metabolic Treatabolome, which catalogs treatable inherited metabolic disorders. For the practicing radiologist, however, the essential message is simpler: certain reproducible patterns on MRI and MR spectroscopy should trigger immediate consideration of a treatable neurogenetic condition, because these diseases arise from selective tissue vulnerability that produces identifiable and characteristic imaging signatures.

The first challenge is knowing when to suspect a metabolic disorder at all. The imaging characteristics of neurogenetic brain diseases often overlap with far more common entities, particularly hypoxic-ischemic injury and encephalitis. Profound hypoxic-ischemic injury in neonates typically affects the posterior putamen, the posterior limb of the internal capsule, and the ventrolateral thalamus simultaneously, because these regions have high energy demands. When patterns diverge from this expectation, metabolic disease should rise on the differential. Specific red flags include deep gray nuclear lesions that spare the thalami or basal ganglia, temporally disparate lesions, brainstem-predominant abnormalities, unexplained reduction in brain volume, malformations, and chronic lesions in a newborn, none of which fit the typical timeline or distribution of oxygen deprivation or infection.

Among the white matter-dominant disorders, X-linked adrenoleukodystrophy stands out as the single most important diagnosis to know. Caused by variants in the ABCD1 gene, a peroxisomal defect, it is the most common leukodystrophy, it is treatable, and it shows a moderately specific imaging pattern: in roughly 80 percent of cases, demyelination begins in the splenium of the corpus callosum, spreads to the forceps major, descends along projection fibers, and ultimately involves auditory and visual white matter tracts. Active inflammation is marked by reduced diffusivity and contrast enhancement. Alternative phenotypes include frontal onset, deep diffuse, and projectional patterns. With the addition of ABCD1 to the recommended uniform screening panel in the United States, 47 states and the District of Columbia now perform newborn screening, and MRI surveillance identifies the fewer than half of affected boys who develop the cerebral form. Treatment, most effective early when few brain lesions exist, is allogeneic hematopoietic stem cell transplantation, with autologous gene-modified stem cell transplant as a second-line option. Patients with typical lesions and a Loes score below 10 may qualify for therapy, and post-treatment stability is defined as a Loes score below 10 or an increase of less than 6 points from baseline.

Two other leukodystrophies, Krabbe disease and metachromatic leukodystrophy, illustrate how clinical context and subtle imaging distinctions guide diagnosis. Juvenile-onset Krabbe disease can closely mimic X-linked adrenoleukodystrophy with poorly marginated splenial and forceps major abnormality, while the infantile form looks different, featuring lesions in the dentate nuclear hilus, deep cerebral hyperattenuation on CT from galactosylceramide deposition, thalamic T2 shortening, optic chiasm thickening, and enhancement of cranial nerves and the cauda equina. A striated, tigroid pattern in the corona radiata from perivascular myelin sparing is typical but not specific. Hematopoietic stem cell transplant works best before symptoms appear, ideally in the first month of life, which makes newborn screening for GALC enzyme activity, now implemented in 18 states, critically important. Metachromatic leukodystrophy shares several features with infantile Krabbe disease but usually spares the chiasm and hindbrain, may involve the genu earlier, and lacks the deep cerebral hyperattenuation. Markedly elevated myoinositol on spectroscopy and gallbladder disease, even in pre-symptomatic patients, provide additional clues. The preferred treatment is gene therapy using lentivirally modified ARSA, available for children under seven who are pre-symptomatic or only mildly symptomatic, and six states have added MLD to newborn screening panels since its endorsement.

Maple syrup urine disease demonstrates how imaging can track treatment response in real time. This aminoacidopathy typically presents at the end of the first neonatal week with encephalopathy and striking white matter edema, with symmetric, markedly reduced diffusivity and swelling in myelinating and myelinated tracts of the cerebrum, cerebellum, and brainstem. Spectroscopy reveals elevated branched-chain amino acids and ketoacids as a broad doublet near 0.9 to 1 ppm, though detecting these peaks reliably at 3 tesla requires careful echo time selection due to anomalous J-coupling. While protein restriction is necessary and leucine, isoleucine, and valine cannot be eliminated entirely from the diet, liver transplantation is considered a definitive treatment that permits a more relaxed diet. A favorable post-transplant scan shows resolution of the diffusion abnormalities and intramyelinic edema, resolution of lactate, normalization of NAA, and reduction of the branched-chain amino acid peaks, findings documented in a patient imaged seven years after curative transplantation. The mucopolysaccharidoses, a group of multi-system lysosomal storage disorders, offer another treatable example: enlarged perivascular spaces combined with skeletal changes such as a J-shaped sella, frontal bossing, and odontoid hypoplasia suggest the diagnosis, and weekly enzyme replacement therapy has been shown to resolve white matter signal abnormality and stabilize neurological symptoms in eligible patients.

Menkes disease, an X-linked copper transport disorder caused by ATP7A variants, produces one of the most visually distinctive findings in pediatric neuroradiology: diffuse marked elongation and tortuosity of the intracranial arteries, present almost always, even in neonates, because copper is essential for vessel wall integrity. Supporting findings include delayed myelination, transient tumefactive temporal lobe vasogenic edema between one and ten months of life, basal ganglia lesions with reduced diffusion, and skeletal changes such as Wormian bones and fractures. Early daily subcutaneous copper histidinate injections, which bypass the defective copper transporter, are essential for preventing severe neurodegeneration, reducing seizures, and prolonging life. On the gray matter side, Wilson disease from ATP7B variants shows basal ganglia, thalamic, midbrain, and pontine lesions with a characteristic mixed increased-and-decreased signal, where T2 signal correlates with neurological dysfunction and T1 signal with hepatic dysfunction, and the famous face of the giant panda in the midbrain may appear. Copper reduction through diet, zinc supplementation, and chelation, or curative liver transplantation, addresses the underlying metabolic derangement.

Several other gray matter disorders reward pattern recognition. Biotin-thiamine-responsive basal ganglia disease, from SLC19A3 variants, causes thalamic and cortical edema with prominent putaminal involvement, and responds, as its name promises, to lifelong biotin and thiamine supplementation. Glutaric aciduria type 1 announces itself structurally before the basal ganglia lesions appear, with underopercularization and enlarged temporopolar subarachnoid spaces, and early l-carnitine with an arginine-restricted, lysine-free diet is highly effective at preventing permanent striatal injury. Urea cycle defects produce hyperammonemic brain injury with peri-insular and deep cortical lesions that spare the thalami, a pattern unusual in hypoxic-ischemic injury, alongside elevated glutamine and glutamate with reduced myoinositol on spectroscopy; dietary management and, in neonatal-onset ornithine transcarbamylase deficiency, curative liver transplantation are the mainstays. Molybdenum cofactor deficiency type A responds to substrate replacement with cyclic pyranopterin monophosphate, and neuronal ceroid lipofuscinosis CLN2, the most common childhood neurodegenerative disease group, can be slowed by bi-weekly intraventricular cerliponase alfa, identifiable on imaging by cerebellar-predominant atrophy, thalamic T2 shortening, and subinsular signal change.

Finally, MR spectroscopy deserves special emphasis because it can be diagnostic even when the MRI appears entirely normal. Fatty acid metabolism disorders such as CPT1 deficiency produce elevated lipid peaks at 0.9 and 1.3 ppm on a normal-appearing scan, and respond to dietary modification with frequent high-carbohydrate meals and medium-chain fatty acid supplementation. Galactosemia yields a large doublet at 3.7 ppm from toxic galactitol accumulation, which inverts at intermediate echo times and normalizes with dietary change. Cerebral creatine deficiency syndromes show markedly reduced creatine peaks at 3 and 3.95 ppm, and creatine supplementation can normalize the spectrum in AGAT and GAMT deficiency. The review recommends a low threshold for adding short-echo single-voxel spectroscopy to any suspected neurometabolic case, with the voxel placed in the deep gray nuclei for poliodystrophies and parietal white matter for suspected leukodystrophies. The overarching conclusion is unambiguous: symmetric gray or white matter lesions in patterns atypical for hypoxic-ischemic injury and infection, or a characteristic spectroscopic signature, should prompt consideration of these not-to-be-missed disorders, because failure to recognize them promptly delays lifesaving and morbidity-reducing treatment.

Subject of Research: Neuroimaging patterns of treatable neurogenetic and inherited metabolic brain diseases in children

Article Title: Don’t miss this treatable neurogenetic disease!

Article References: Whitehead, M. T. (2026). Don’t miss this treatable neurogenetic disease!. Pediatric Radiology. https://doi.org/10.1007/s00247-026-06796-8

Image Credits: AI Generated

DOI: 10.1007/s00247-026-06796-8

Keywords: neurogenetic diseases, leukodystrophy, MRI, MR spectroscopy, X-linked adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy, maple syrup urine disease, Wilson disease, newborn screening, gene therapy, pediatric neuroradiology