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Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by three core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals, and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age of onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary.We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of ALD patients. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoeitic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses as well as presymptomatic individuals is increasing due to newborn screening and greater availability of next generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerges. This knowledge gap should direct future research and illustrates once again that international collaboration amongst physicians, researchers and patients is essential to improving care.

In this observational study, 159 patients with multiple sclerosis received personalized dosing of ocrelizumab incentivized by the COVID-19 pandemic. Re-dosing was scheduled when CD19 B-cell count was ⩾10 cells/µL (starting 24 weeks after the previous dose, repeated 4-weekly). Median interval until re-dosing or last B-cell count was 34 [30–38] weeks. No clinical relapses were reported and a minority of patients showed Expanded Disability Status Scale (EDSS) progression. Monthly serum neurofilament light levels remained stable during extended intervals. Two (1.9%) of 107 patients with a follow-up magnetic resonance imaging (MRI) scan showed radiological disease activity. Personalized dosing of ocrelizumab could significantly extend intervals with low short-term disease activity incidence, encouraging future research on long-term safety and efficacy.

Objective: To explore the potential of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) as biomarkers of spinal cord degeneration in adrenoleukodystrophy, as objective treatment-outcome parameters are needed. Methods: Plasma NfL and GFAP levels were measured in 45 male and 47 female ALD patients and compared to a reference cohort of 73 healthy controls. For male patients, cerebrospinal fluid (CSF) samples (n = 33) and 1-year (n = 39) and 2-year (n = 18) follow-up data were also collected. Severity of myelopathy was assessed with clinical parameters: Expanded Disability Status Scale (EDSS), Severity Scoring system for Progressive Myelopathy (SSPROM), and timed up-and-go. Results: NfL and GFAP levels were higher in male (P < 0.001, effect size (partial ƞ 2) NfL = 0.49, GFAP = 0.13) and female (P < 0.001, effect size NfL = 0.19, GFAP = 0.23) patients compared to controls; levels were higher in both symptomatic and asymptomatic patients. In male patients, NfL levels were associated with all three clinical parameters of severity of myelopathy (EDSS, SSPROM, and timed up-and go), while GFAP in male and NfL and GFAP in female patients were not. Changes in clinical parameters during follow-up did not correlate with (changes in) NfL or GFAP levels. Plasma and CSF NfL were strongly correlated (r = 0.60, P < 0.001), but plasma and CSF GFAP were not (r = 0.005, P = 0.98). Interpretation: Our study illustrates the potential of plasma NfL as biomarker of spinal cord degeneration in adrenoleukodystrophy, which was superior to plasma GFAP in our cohort.

ObjectiveTo prospectively determine the potential of diffusion MRI (dMRI) of the cervical spinal cord and the corticospinal tracts in brain as surrogate outcome measure for progression of myelopathy in men with adrenoleukodystrophy, as better outcome measures to quantify progression of myelopathy would enable clinical trials with fewer patients and shorter follow-up.MethodsClinical assessment of myelopathy included Expanded Disability Status Scale (EDSS), Severity Scoring System for Progressive Myelopathy (SSPROM), Timed Up-and-Go, and 6-Minute Walk Test. Applied dMRI metrics included fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity.ResultsData were available for 33 controls and 52 patients. First, cross-sectionally, differences between groups (controls vs patients; controls vs asymptomatic patients vs symptomatic patients) were statistically significant for fractional anisotropy, mean diffusivity, and radial diffusivity in spinal cord and brain corticospinal tracts (effect size 0.31–0.68). Correlations between dMRI metrics and clinical measures were moderate to strong (correlation coefficient 0.35–0.60). Second, longitudinally (n = 36), change on clinical measures was significant after 2-year follow-up for EDSS, SSPROM, and Timed Up-and-Go (p ≤ 0.021, effect size ≤0.14). Change on brain fractional anisotropy and radial diffusivity was slightly larger (p ≤ 0.002, effect sizes 0.16–0.28). In addition, a statistically significant change was detectable in asymptomatic patients using brain dMRI and not using the clinical measures. Change on clinical measures did not correlate to change on dMRI metrics.ConclusionAlthough effect sizes were small, our prospective data illustrate the potential of dMRI as surrogate outcome measure for progression of myelopathy in men with adrenoleukodystrophy.

Background Progressive myelopathy is the main cause of disability in adrenoleukodystrophy (ALD). Development of therapies is hampered by a lack of quantitative outcome measures. In this study, we investigated whether myelopathy in ALD is associated with retinal neurodegeneration on optical coherence tomography (OCT), which could serve as a surrogate outcome measure. Methods Sixty-two patients (29 men and 33 women) and 70 age-matched and sex-matched controls (33 men and 37 women) were included in this cross-sectional study. We compared retinal nerve fiber layer (RNFL), ganglion cell layer (GCL) and peripapillary retinal nerve fiber layer (pRNFL) thickness between ALD patients and controls. In addition, we correlated these OCT measurements with clinical parameters of severity of myelopathy. Results Patients had significantly thinner RNFL (male group, p < 0.05) and pRNFL superior and temporal quadrant [both male (p < 0.005) and female (p < 0.05) groups] compared to controls. Comparing three groups (symptomatic patients, asymptomatic patients and controls), there were significant differences in RNFL thickness (total grid and peripheral ring) in the male group (p ≤ 0.002) and in pRNFL thickness (superior and temporal quadrant) in both male (p ≤ 0.02) and the female (p ≤ 0.02) groups. Neuroretinal layer thickness correlated moderately with severity of myelopathy in men (correlation coefficients between 0.29-0.55, p < 0.02), but not in women. Conclusions These results suggest that neurodegeneration of the spinal cord in ALD is reflected in the retina of patients with ALD. Therefore, OCT could be valuable as an outcome measure for the myelopathy of ALD. Additional longitudinal studies are ongoing.

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All men and most women with X‐linked adrenoleukodystrophy (ALD) develop myelopathy in adulthood. As clinical trials with new potential disease‐modifying therapies are emerging, sensitive outcome measures for quantifying myelopathy are needed. This prospective cohort study evaluated spinal cord size (cross‐sectional area ‐ CSA) and shape (eccentricity) as potential new quantitative outcome measures for myelopathy in ALD. Seventy‐four baseline magnetic resonance imaging (MRI) scans, acquired in 42 male ALD patients and 32 age‐matched healthy controls, and 26 follow‐up scans of ALD patients were included in the study. We used routine T 1 ‐weighted MRI sequences to measure mean CSA, eccentricity, right‐left and anteroposterior diameters in the cervical spinal cord. We compared MRI measurements between groups and correlated CSA with clinical outcome measures of disease severity. Longitudinally, we compared MRI measurements between baseline and 1‐year follow‐up. CSA was significantly smaller in patients compared to controls on all measured spinal cord levels ( P < .001). The difference was completely explained by the effect of the symptomatic subgroup. Furthermore, the spinal cord showed flattening (higher eccentricity and smaller anteroposterior diameters) in patients. CSA correlated strongly with all clinical measures of severity of myelopathy. There was no detectable change in CSA after 1‐year follow‐up. The cervical spinal cord in symptomatic ALD patients is smaller and flattened compared to controls, possibly due to atrophy of the dorsal columns. CSA is a reliable marker of disease severity and can be a valuable outcome measure in long‐term follow‐up studies in ALD. Synopsis A prospective cohort study in 42 adrenoleukodystrophy (ALD) patients and 32 controls demonstrated that the spinal cord cross‐sectional area of patients is smaller compared to healthy controls and correlates with severity of myelopathy in patients, hence it could be valuable as a much needed surrogate outcome measure.