A Phase 1 Study of Oral Vitamin D3 in Boys and Young Men With X-Linked Adrenoleukodystrophy.

Background and Objectives: There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD. Methods: In this open-label, multicenter, phase 1 study, we recruited boys and young men with ALD without brain lesions to a 12-month study of daily oral vitamin D3 supplementation. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80 ng/mL) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in the brain, measured with magnetic resonance spectroscopy, and blood, measured via mass spectrometry. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. After a midstudy safety assessment, we modified the dosing regimen, so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily. Results: Between October 2016 and June 2019, we enrolled 21 participants (n = 12, fixed-dose regimen; n = 9, weight-stratified regimen) with a median age of 6.7 years (range: 1.9-22 years) and median weight of 20 kg (range: 11.7-85.5 kg). The number of participants achieving target vitamin D levels was similar in both groups at 6 months (fixed dose: 92%; weight stratified: 78%) and 12 months (fixed dose: 67%; weight stratified: 67%). Among the 12 participants in the fixed-dose regimen, half had asymptomatic elevations in either urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels in the brain, but not the blood, increased significantly between baseline and 12 months. Discussion: Our vitamin D dosing regimens were well tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels warrant further study as a biomarker for vitamin D and ALD. Classification of Evidence: This study provides Class IV evidence that fixed or weight-stratified vitamin D supplementation achieved target levels of 25-hydroxyvitamin D in boys and young men with X-ALD without brain lesions.

Vitamin D status and latitude predict brain lesions in adrenoleukodystrophy.

Objectives: Approximately 40% of boys with X-linked adrenoleukodystrophy (ALD) develop inflammatory demyelinating brain lesions (cerebral ALD, cALD) and are at risk for death or severe disability. Risk factors for cALD are poorly understood. Our objective was to evaluate whether vitamin D status, which influences immune function, is associated with risk for cALD. Methods: We used two independent cohorts to assess whether low vitamin D status is correlated with cALD. We used complementary proxies for vitamin D status: plasma 25-hydroxyvitamin D levels and latitude. In our first cohort, we measured 25-hydroxyvitamin D in biobanked plasma samples from ALD boys with initially normal brain MRIs followed at two expert centers. In a second cohort, we measured latitude (using home ZIP code) among ALD boys identified in a national administrative database (PHIS) covering 51 US pediatric hospitals. We used logistic regression models to estimate the odds of developing cALD in each cohort. Results: In the first cohort, we identified 20 ALD boys with a total of 53 plasma sample timepoints who met inclusion criteria; 50% (n = 10) subsequently developed cALD. Average 25-hydroxyvitamin D levels were lower among boys who developed cALD than those who did not (median 28.9 vs 36.6 ng/ml); p = 0.019. For each 10 ng/mL decrease in 25-hydroxyvitamin D, the odds ratio for developing cALD was 6.94; p = 0.044. In the second cohort, we identified 230 ALD boys across 28 states; 57% of boys (n = 132) developed cALD. Each 2° increase in latitude conferred an odds ratio of 1.17 (95% confidence interval, 1.01, 1.35); p = 0.036 for developing cALD. Conclusions: Using independent cohorts, we found that ALD boys with lower pre-morbid plasma levels of 25-hydroxyvitamin D, or more northerly latitude of residence, were more likely to develop cALD. These findings offer complementary lines of evidence that vitamin D and/or ultraviolet light exposure influence cALD risk.

Treatment of cerebral adrenoleukodystrophy: allogeneic transplantation and lentiviral gene therapy.

INTRODUCTION: Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with an incidence of 1 in 14-17,000 male births, caused by pathogenic variants within the ABCD1 gene. By adulthood, approximately 40% of the patients develop cerebral ALD, a severe, neuroinflammatory condition that is generally progressive and fatal without intervention. AREAS COVERED: Historically, only allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to halt progression of cerebral ALD, with superior outcomes obtained when HSCT is performed early in the disease process. More recently, a lentiviral-based gene therapy approach has been investigated as therapy for cerebral ALD as an alternative to allogeneic transplantation. A focused literature review was performed using the terms 'hematopoietic stem cell transplantation,' 'gene therapy' and 'adrenoleukodystrophy' to include relevant literature, especially comparing the experience with gene therapy and HSCT outcomes. We review the history and experience with HSCT in cerebral ALD and its limitations, as well as the information currently available in association with the gene therapy trials for cerebral ALD. EXPERT OPINION: The data regarding this lentiviral-based gene therapy approach and its relative risks and benefits is still being evaluated. This information is explored in the context of the experience with allogeneic HSCT for cerebral ALD.

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach.

Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 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 at 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 patients with ALD. 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. Hematopoietic 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 and presymptomatic individuals is increasing because of 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 emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.

Presymptomatic Lesion in Childhood Cerebral Adrenoleukodystrophy: Timing and Treatment.

BACKGROUND AND OBJECTIVES: We sought to characterize the natural history and standard of care practices between the radiologic appearance of brain lesions, the appearance of lesional enhancement, and treatment with hematopoietic stem cell transplant or gene therapy among boys diagnosed with presymptomatic childhood-onset cerebral adrenoleukodystrophy (CCALD). METHODS: We analyzed a multi-center, mixed retrospective/prospective cohort of patients diagnosed with presymptomatic CCALD (Neurologic Function Score [NFS] = 0, Loes Score [LS] = 0.5 - 9.0, Age < 13 years old). Two time-to-event survival analyses were conducted: (1) Time from CCALD lesion-onset-to-lesional enhancement, (2) Time from enhancement-to-treatment. The analysis was repeated in the subset of patients with (1) the earliest evidence of CCALD, defined as an MRI LS < 1, and (2) patients diagnosed between 2016 - 2021. RESULTS: Seventy-one boys were diagnosed with presymptomatic cerebral lesions at a median age of 6.4yo [2.4 - 12.1] with a LS of 1.5 [0.5 - 9.0]. Fifty percent of patients had lesional enhancement at diagnosis. In the remaining 50%, the median KM-estimate of time from diagnosis-to-lesional enhancement was 6.0 months [95%CI 3.6 - 17.8]. The median KM-estimate of time from enhancement-to-treatment is 3.8 months [95%CI 2.8 - 5.9]; two patients (4.2%) developed symptoms prior to treatment. Patients with a diagnostic LS < 1 were younger (5.8yo [2.4 - 11.5]), had a time-to-enhancement of 4.7mo [95%CI 2.7 - 9.30], and were treated in 3.8mo [95%CI 3.1 - 7.1]; no patients developed symptoms prior to treatment. Time from CCALD diagnosis-to-treatment decreased over the course of the study (ρ = -0.401, p = 0.003). CONCLUSION: Our findings offer a more refined understanding of the timing of lesion formation, enhancement, and treatment among boys with presymptomatic CCALD. These data offer benchmarks for standardizing clinical care and designing future clinical trials.

Nervonic Acid Attenuates Accumulation of Very Long-Chain Fatty Acids and is a Potential Therapy for Adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked inherited peroxisomal disorder due to mutations in the ALD protein and characterized by accumulation of very long-chain fatty acids (VLCFA), specifically hexacosanoic acid (C26:0). This can trigger other pathological processes such as mitochondrial dysfunction, oxidative stress, and inflammation, which if involves the brain tissues can result in a lethal form of the disease called childhood cerebral ALD. With the recent addition of ALD to the Recommended Uniform Screening Panel, there is an increase in the number of individuals who are identified with ALD. However, currently, there is no approved treatment for pre-symptomatic individuals that can arrest or delay symptom development. Here, we report our observations investigating nervonic acid, a monounsaturated fatty acid as a potential therapy for ALD. Using ALD patient-derived fibroblasts, we examined whether nervonic acid can reverse VLCFA accumulation similar to erucic acid, the active ingredient in Lorenzo's oil, a dietary intervention believed to alter disease course. We have shown that nervonic acid can reverse total lipid C26:0 accumulation in a concentration-dependent manner in ALD cell lines. Further, we show that nervonic acid can protect ALD fibroblasts from oxidative insults, presumably by increasing intracellular ATP production. Thus, nervonic acid can be a potential therapeutic for individuals with ALD, which can alter cellular biochemistry and improve its function.

Newborn Screening for X-Linked Adrenoleukodystrophy: Past, Present, and Future.

Newborn screening for X-linked adrenoleukodystrophy began in New York in 2013. Prior to this start, there was already significant information on the diagnosis and monitoring of asymptomatic individuals. Methods needed to be developed and validated for the use of dried blood spots. Following its institution in New York, its acceptance as a disorder on the Recommended Uniform Screening occurred. With it has come published recommendations on the surveillance and care of boys detected by newborn screening. There still remain challenges, but it is hoped that with periodic review, they may be overcome.

Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series.

Peroxisome biogenesis disorders-Zellweger spectrum disorders (PBD-ZSD)-are primarily autosomal recessive disorders caused by mutations in any of 13 PEX genes involved in peroxisome assembly. Compared to other PEX-related disorders, some PEX16 defects are associated with an atypical phenotype consisting of spasticity, cerebellar dysfunction, preserved cognition, and prolonged survival. In this case series, medical records and brain MRIs from 7 patients with this PEX16 presentation were reviewed to further characterize this phenotype. Classic PBD features such as sensory deficits and amelogenesis imperfecta were absent in all 7 patients, while all patients had hypertonia. Five patients were noted to have dystonia and received a treatment trial of levodopa/carbidopa. Four treated patients had partial but significant improvements in their dystonia and tremors, and 1 patient had only minimal response. Brain MRI studies commonly showed T2/FLAIR hyperintensities in the brainstem, superior and middle cerebellar peduncles, corticospinal tracts, and splenium of the corpus callosum. Genetic analysis revealed novel biallelic variants in 3 probands (c.683C > T/372delG; c.692A > G homozygous; c.865C > G/451C > T) and 1 novel variant (c.956_958delCGC) in another proband. We demonstrated residual PEX16 protein amounts by immunoblotting in fibroblasts available from 5 patients with this atypical PEX16 disease (3 from this series, 2 previously reported), in contrast to the absence of PEX16 protein in fibroblasts from a patient with the severe ZSD presentation. This study further characterizes the phenotype of PEX16 defects by highlighting novel and distinctive clinical, neuroradiological, and molecular features of the disease and proposes a potential treatment for the dystonia. ClinicalTrials.gov Identifier: NCT01668186. Date of registration: January 2012.

Sensorimotor outcomes in adrenomyeloneuropathy show significant disease progression.

Current outcomes used to evaluate adrenomyeloneuropathy are limited by rater bias, not sensitive to preclinical changes, and require years to decades to detect disease progression. Quantitative outcomes are needed that detect meaningful change in a short time period over a broad range of disability. The study aim was to track sensorimotor outcomes in adults with adrenomyeloneuropathy and evaluate differences in progression between men and women. This prospective observational cohort study analyzes data collected annually in the Phase III study of adults with adrenomyeloneuropathy. Outcomes include postural sway in four static standing conditions, great-toe vibration, hip strength, walking velocity, timed up-and-go, and 6-minute walk distance. Linear mixed model analysis was used to detect change in the outcomes in 2 years, correcting for age, sex, disability, symptom duration, and treatment across the cohort. Modeling was repeated for each sex to evaluate differences. Power computations were carried out by sex and for the full dataset. Sixty-one men and 87 women participated. Average age, 46 ± 12 years; Expanded Disability Status Scale, 3 (1-6.5); symptom duration, 10.8 ± 9.4 years. The cohort showed significant worsening in all standing conditions (P < .001), sensation (P = .0223) and strength (P = .001); but more stability in walking with only velocity (P < .0337) significantly declining. For each sex, postural sway declines significantly in all conditions (P < .01) except for eyes closed feet together for women. Strength declines significantly by sex for hip flexion (P < .03). Sex-specific significant decline is seen in walking (velocity P = .0276; distance P = .0072) for men only. Quantitative measures of postural sway, sensation strength, and walking are effective measures of adrenomyeloneuropathy progression in 2 years.

MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines.

BACKGROUND: Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy. METHODS: To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. RESULTS: One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI. CONCLUSION: Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.

Thiamine Deficiency With Mashed Potatoes: A Novel Case of Wernicke Encephalopathy Manifesting With Retinal Hemorrhages in a Pediatric Patient.

We present a case report of a 17-year-old obese female with one-week onset of progressive confusion and double vision, associated with 50-pound weight loss in five months. On fundus examination, retinal hemorrhages and abnormalities of eye movements were seen. MRI showed abnormalities that were consistent with diagnosis of Wernicke encephalopathy (WE). Thiamine replacement caused gradual improvement in patient's symptoms. Peripapillary hemorrhages on fundus examination, as seen in our patient, have been rarely seen in WE. Obesity with retinal hemorrhages, diplopia, etc. can be misleading due to idiopathic intracranial hypertension being the most common presentation in this subset. Thus, fundoscopy should be part of routine examination in WE-suspected patients.

Rare Spontaneous Attenuation of Childhood Inflammatory Cerebral Adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a neurodegenerative peroxisomal disorder with variable clinical phenotypes. Childhood cerebral ALD (CCALD) is at the most severe end of the disease spectrum. In CCALD, the clinical manifestations include increasing deficits in behavior, vision, hearing, coordination, and motor function, as well as seizures. Without treatment, CCALD often results in apparent vegetative state within 1 to 2 years of appearance of initial signs and symptoms. We present the case of a boy with classic inflammatory CCALD who exhibited spontaneous attenuation in disease progression. While extremely rare, spontaneous arrest of disease progression may occur in boys with inflammatory CCALD.

Volume of Gadolinium Enhancement and Successful Repair of the Blood-Brain Barrier in Cerebral Adrenoleukodystrophy.

Up to 40% of boys with adrenoleukodystrophy develop a severe central nervous system demyelinating form (cALD) characterized by white matter changes and gadolinium enhancement on magnetic resonance imaging (MRI). Hematopoietic cell transplant (HCT) is the only proven means to attenuate cALD progression. The elimination of active neuroinflammation is indicated radiographically by the resolution of gadolinium (Gd) enhancement and correlates to speed of donor neutrophil recovery. We analyzed 66 boys with cALD undergoing HCT for biomarkers correlating with early (30 days post-HCT) Gd signal resolution. We found that log Gd volume (cm3) on pre-HCT MRI strongly positively correlated to day 30 Gd resolution (P = .0003) with smaller volume correlating to higher proportion resolved, as was the baseline gadolinium intensity score (P = .04), plasma chitotriosidase activity (P = .04), and faster absolute neutrophil count recovery (P = .03). In multivariate analysis, log Gd volume remained superior in determining which patients would have Gd signal resolution by 30 days post-HCT (P = .016). A final analysis indicated that early Gd resolution also correlated with less neurologic progression from baseline to 1 year following HCT (P = .006). MRI Gd volume may serve as a contributing biomarker to better delineate outcomes and an important metric in comparing therapies in the treatment of cALD.

Failure of intrathecal allogeneic mesenchymal stem cells to halt progressive demyelination in two boys with cerebral adrenoleukodystrophy.

Cerebral adrenoleukodystrophy is an inflammatory demyelinating condition that is the result of a mutation in the X-linked ABCD1 gene, a peroxisomal very long chain fatty acid transporter. Although mutations in this gene result in adrenal insufficiency in the majority of affected individuals, 40% of those affected develop the demyelinating cerebral form, cerebral adrenoleukodystrophy (CALD). CALD is characterized by imaging findings of demyelination and contrast enhancement on magnetic resonance imaging (MRI). Although allogeneic hematopoietic cell transplantation can arrest progression of CALD early in its course, there is no accepted therapy for patients with advanced CALD. Mesenchymal stem cells (MSCs) have been used in a variety of clinical trials to capitalize on their anti-inflammatory properties as well as promote tissue repair. We delivered MSCs via intrathecal (IT) route to two boys with rapidly advancing CALD. The first boy received three doses 1 week apart, whereas the second boy received a single dose of IT MSCs. We note delivery of IT MSCs was feasible and without complication. Follow-up MRI scans after IT MSC delivery showed progressive demyelination in the first patient and no change in demyelination or contrast enhancement in the second patient. Although the infusion of IT MSCs was safe, it did not halt CALD progression in this setting, and future studies should focus on patient selection and dose optimization.

A report on state-wide implementation of newborn screening for X-linked Adrenoleukodystrophy.

Minnesota became the fourth state to begin newborn screening (NBS) for X-linked adrenoleukodystrophy (X-ALD) in 2017. As there is limited retrospective data available on NBS for X-ALD, we analyzed Minnesota's NBS results from the first year of screening. C26:0 lysophosphatidylcholine (C26:0-LPC) screening results of 67,836 infants and confirmatory testing (ABCD1 gene and serum VLCFA analysis) for screen positives were obtained. Fourteen infants (nine males, five females) screened positive for X-ALD and all were subsequently confirmed to have X-ALD, with zero false positives. The birth prevalence of X-ALD in screened infants was 1 in 4,845 and 1 in 3,878 males, more than five times previous reported incidences. Pedigrees of affected infants were analyzed, and 17 male (mean age of 17) and 24 female relatives were subsequently diagnosed with X-ALD. Phenotypes of these family members included self-reported mild neuropathy symptoms in two males and seven females, and childhood cerebral disease (ccALD) and adrenal insufficiency in one male. We observed fewer cases of ccALD and adrenal insufficiency than expected in male family members (5.9% of males for both) compared to previous observations. Together, these findings suggest that the spectrum of X-ALD may be broader than previously described and that milder cases may previously have been underrepresented. Other challenges included a high frequency of variants of uncertain significance in ABCD1 and an inability to predict phenotypic severity. We posit that thoughtful planning to address these novel challenges and coordination by dedicated specialists will be imperative for successful implementation of population-based screening for X-ALD.

Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study.

X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260.

Association between APOE4 and biomarkers in cerebral adrenoleukodystrophy.

Cerebral adrenoleukodystrophy (cALD) is an inflammatory neurodegenerative disease associated with mutation of the ABCD1 gene. Proteomic analysis of cerebral spinal fluid (CSF) from young males with active cALD revealed markers of inflammation including APOE4. APOE4 genotype has been associated with an inferior prognosis following acute and chronic neurologic injury. We assessed APOE4 inheritance among 83 consecutive young males with cALD prior to hematopoietic cell transplant and its association with markers of cerebral disease. The allele frequency of APOE4 was not significantly different from that of the general population at 17%. Young males with cALD that were APOE4 carriers had similar CSF protein and chitotriosidase activity to that of non-carriers. In contrast, APOE4 carriers had an increased burden of cerebral disease involvement as determined by MRI severity score (10.5 vs 7.0 points, p = 0.01), higher gadolinium intensity score (2.0 vs 1.3 points, p = 0.007), inferior neurologic function (neurologic function score 2.4 vs 1.0, p = 0.001), and elevated CSF MMP2 levels compared to that of non-carriers (13168 vs 9472 pg/mL, p = 0.01). These are the first data showing that APOE4 is associated with increased severity of cerebral disease in cALD and suggest it may be a modifier of disease.

Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation.

Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P = .01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE+) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE+ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE+ status is a strong predictor of disease progression in untreated patients. This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.