ObjectiveTo gain insight into the natural history of arrested cerebral adrenoleukodystrophy (CALD) by quantifying the change in Neurologic Function Score (NFS) and Loes Score (LS) over time in patients whose cerebral lesions spontaneously stopped progressing.MethodsWe retrospectively reviewed a series of 22 patients with arrested CALD followed longitudinally over a median time of 2.4 years (0.7–17.0 years). Primary outcomes were change in radiographic disease burden (measured by LS) and clinical symptoms (measured by NFS) between patients who never developed a contrast-enhancing lesion (gadolinium enhancement (GdE)− subgroup) and those who did (GdE+ subgroup). Secondary analyses comparing patterns of neuroanatomic involvement and lesion number, and prevalence estimates, were performed.ResultsCerebral lesions were first detected at a median age of 23.3 years (8.0–67.6 years) with an initial LS of 4 (0.5–9). NFS was 0.5 (0–6). Overall change in NFS or LS per year did not differ between subgroups. No patients who remained GdE− converted to a progressive CALD phenotype. The presence of contrast enhancement was associated with disease progression (rs = 0.559, p < 0.001). Four patients (18.2%) underwent step-wise progression, followed by spontaneous resolution of contrast enhancement and rearrest of disease. Three patients (13.6%) converted to progressive CALD. Nineteen patients (86.4%) had arrested CALD at the most recent follow-up. The prevalence of arrested CALD is 12.4%.ConclusionArrested CALD lesions can begin in childhood, and patients are often asymptomatic early in disease. The majority of patients remain stable. However, clinical and MRI surveillance is recommended because a minority of patients undergo step-wise progression or conversion to progressive CALD.

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.

Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the ABCD1 gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in ABCD1. Fibroblasts from 36 male patients with confirmed ALD, 26 healthy control subjects and 17 individuals without a family history of ALD, all with an uncertain clinical diagnosis and a VUS identified in ABCD1, were included. We performed a combination of tests: (i) a test for very-long-chain fatty acids (VLCFA) levels, (ii) a D3-C22:0 loading test to study the VLCFA metabolism and (iii) immunoblotting for ALD protein. All ALD patient fibroblasts had elevated VLCFA levels and a reduced peroxisomal ß-oxidation capacity (as measured by the D3-C16:0/D3-C22:0 ratio in the D3-C22:0 loading test) compared to the control subjects. Of the VUS cases, the VLCFA metabolism was not significantly impaired (most test results were within the reference range) in 6/17, the VLCFA metabolism was significantly impaired (most test results were within/near the ALD range) in 9/17 and a definite conclusion could not be drawn in 2/17 of the cases. Biochemical studies in fibroblasts provided clearly defined reference and disease ranges for the VLCFA metabolism. In 15/17 (88%) VUS we were able to classify the variant as being likely benign or pathogenic. This is of great clinical importance as new variants will be detected.

Magnetic resonance imaging (MRI) is the gold standard for the detection of cerebral lesions in X-linked adrenoleukodystrophy (ALD). ALD is one of the most common peroxisomal disorders and is characterized by a defect in degradation of very long chain fatty acids (VLCFA), resulting in accumulation of VLCFA in plasma and tissues. The clinical spectrum of ALD is wide and includes adrenocortical insufficiency, a slowly progressive myelopathy in adulthood, and cerebral demyelination in a subset of male patients. Cerebral demyelination (cerebral ALD) can be treated with hematopoietic cell transplantation (HCT) but only in an early (pre- or early symptomatic) stage and therefore active MRI surveillance is recommended for male patients, both pediatric and adult. Although structural MRI of the brain can detect the presence and extent of cerebral lesions, it does not predict if and when cerebral demyelination will occur. There is a great need for imaging techniques that predict onset of cerebral ALD before lesions appear. Also, imaging markers for severity of myelopathy as surrogate outcome measure in clinical trials would facilitate drug development. New quantitative MRI techniques are promising in that respect. This review focuses on structural and quantitative imaging techniques—including magnetic resonance spectroscopy, diffusion tensor imaging, MR perfusion imaging, magnetization transfer (MT) imaging, neurite orientation dispersion and density imaging (NODDI), and myelin water fraction imaging—used in ALD and their role in clinical practice and research opportunities for the future.

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.

Objective To prospectively determine the value of optical coherence tomography (OCT) as a surrogate outcome measure for the progression of myelopathy in males with adrenoleukodystrophy. Methods Retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness were measured at baseline, 1‐ and 2‐year follow‐up in patients and age‐matched controls. We assessed the severity of myelopathy with clinical parameters: Expanded Disability Status Scale (EDSS), Severity Scoring system for Progressive Myelopathy (SSPROM), and timed up‐and‐go. Linear mixed model analysis was used to compare changes in retinal layer thickness of patients to controls. In addition, we correlated changes in retinal layer thickness with changes in clinical parameters. Results Longitudinal data were available for 28 patients and 29 controls. Peripapillary RNFL (pRNFL) thickness decreased significantly in patients compared to controls (−1.75µm, p = 0.001), whereas change in macular GCL and RNFL was not different between groups. Analysis of the symptomatic subgroup showed that, apart from a similar decrease in pRNFL thickness, GCL thickness decreased significantly (−0.55 µm, p = 0.014). There were moderately strong correlations between changes in retinal layer thickness and changes in clinical parameters of severity of myelopathy. Interpretation This prospective study demonstrates the potential of OCT‐measured retinal neurodegeneration as a surrogate outcome measure for the progression of myelopathy in adrenoleukodystrophy. As differences were small, our findings need to be confirmed with longer follow‐up and/or in a larger patient sample.

BACKGROUND AND PURPOSE: Cerebral adrenoleukodystrophy is a devastating neurological disorder caused by mutations in the ABCD1 gene. Our aim was to model and compare the growth of early cerebral lesions from longitudinal MRIs obtained in presymptomatic patients with progressive and arrested cerebral adrenoleukodystrophy using quantitative MR imaging-based lesion volumetry. MATERIALS AND METHODS:We retrospectively quantified and modeled the longitudinal growth of early cerebral lesions from 174 MRIs obtained from 36 presymptomatic male patients with cerebral adrenoleukodystrophy. Lesions were manually segmented using subject-specific lesion-intensity thresholding. Volumes were calculated and plotted across time. Lesion velocity and acceleration were calculated between sequentially paired and triplet MRIs, respectively. Linear mixed-effects models were used to assess differences in growth parameters between progressive and arrested phenotypes. RESULTS:The median patient age was 7.4 years (range, 3.9-37.0 years). Early-stage cerebral disease progression was inversely correlated with age (r ¼ À0.6631, P , .001), early lesions can grow while appearing radiographically stable, lesions undergo sustained acceleration in progressive cerebral adrenoleukodystrophy (b ¼ 0.10 mL/month 2 [95% CI, 0.05À0.14 mL/month 2 ], P , .001), and growth trajectories diverge between phenotypes in the presymptomatic time period. CONCLUSIONS:Measuring the volumetric changes in newly developing cerebral lesions across time can distinguish cerebral adrenoleukodystrophy phenotypes before symptom onset. When factored into the overall clinical presentation of a patient with a new brain lesion, quantitative MR imaging-based lesion volumetry may aid in the accurate prediction of patients eligible for therapy. ABBREVIATIONS: CALD ¼ cerebral adrenoleukodystrophy; HSCT ¼ hematopoietic stem cell transplantation; LS ¼ Loes score; t 0 ¼ time-zero X -linked adrenoleukodystrophy is a devastating neurologic disorder caused by mutations in the ABCD1 gene, which lead to an accumulation of very long chain fatty acids in plasma and tissue. 1 Multiple phenotypes emerge with no genotypephenotype relationship having been established. 2 Most patients will develop cerebral adrenoleukodystrophy (CALD), with the highest incidence occurring in childhood. 3 Lesions most often occur in the splenium (60%-80%) or genu (10%-15%) of the corpus callosum and spread confluently into the surrounding subcortical white matter. 4,5 More than 80% of children with CALD will experience inflammatory demyelination, "progressive CALD," followed by rapid neurodegeneration and death without treatment in 2-3 years. 6,7 Conversely, 15%-20% of children and most adults will undergo spontaneous arrest of disease, "arrested CALD" without evidence of brain inflammation and are ineligible for hematopoietic stem cell transplantation (HSCT). 8 HSCT is most successful when initiated in the window before the onset of neurologic symptoms. 7,[9][10][11] However, the presymptomatic window is narrow, 12,13...

Background: Myelopathy is the core clinical manifestation of adrenoleukodystrophy (ALD), which is the most common peroxisomal disorder. Development of therapies requires sensitive and clinically relevant outcome measures. Together with spastic paraparesis, balance disturbance is the main cause of disability from myelopathy in ALD. In this cross-sectional study, we evaluated whether postural body sway-a measure of balance-could serve as a surrogate outcome in clinical trials. Methods: Forty-eight male ALD patients and 49 age-matched healthy male controls were included in this study. We compared sway amplitude and sway path of ALD patients to controls. We then correlated the body sway parameters showing the largest between-group differences with clinical measures of severity of myelopathy. To correct for age, we performed multiple linear regression analysis with age and severity of myelopathy as independent variables. Results: All body sway parameters were significantly higher in patients than in controls, with medium to large effect sizes (r = 0.43-0.66, p < 0.001). In the subgroup of asymptomatic patients, body sway amplitude was also higher, but the difference with controls was smaller than for symptomatic patients (effect size r = 0.38-0.46). We found moderate to strong correlations between body sway amplitude and clinical severity of myelopathy (r = 0.40-0.79, p < 0.005). After correction for age, severity of myelopathy was a significant predictor of body sway amplitude in all regression models. Conclusions: These results indicate that postural body sway may serve as a surrogate outcome for myelopathy in ALD. Such outcomes are important to evaluate new therapies in clinical trials. Further longitudinal studies are needed and ongoing in this cohort.