RARE DISEASE
X-linked adrenoleukodystrophy
X-linked adrenoleukodystrophy
X-linked adrenoleukodystrophy
Synonyms: ALD, X-ALD, X-linked ALD
Synonyms: ALD, X-ALD, X-linked ALD
Synonyms: ALD, X-ALD, X-linked ALD
Drug discovery
20
drugs
With orphan designations
Overview
X-linked adrenoleukodystrophy (X-ALD) is an X-linked recessive disorder caused by ABCD1 mutations, leading to impaired peroxisomal breakdown of very-long-chain fatty acids (VLCFAs). This results in progressive neurodegeneration (demyelination, myelopathy) and adrenal insufficiency. Phenotypes include childhood cerebral ALD (rapidly fatal without intervention), adrenomyeloneuropathy (AMN), and isolated adrenal dysfunction [1][2][6]. Early diagnosis via VLCFA testing and MRI monitoring is critical for timely intervention [6][8].
Structured Overview
Burden
Mortality: Untreated cerebral ALD leads to death within 2–5 years of symptom onset [1][12].
Morbidity: Progressive paraparesis, incontinence, and neuropsychiatric decline in AMN; fractures, falls, and reduced QoL in females [4][14].
Healthcare challenges: Delayed diagnosis (>40% of females initially misdiagnosed), limited disease-modifying treatments for AMN [4][14].
Therapies
Hematopoietic stem cell transplant (HSCT): Curative for early-stage cerebral ALD (Loes score <9) [8][11].
Adrenal replacement: Lifelong glucocorticoid/mineralocorticoid therapy for adrenal insufficiency [6][8].
Emerging therapies: Gene therapy (lentiviral ABCD1 correction) and pharmacological agents (e.g., HDAC inhibitors) under investigation [3][13].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism, rare infertility disorders, rare neurological diseases, rare transplant-related disorders
Research Papers
572 drug discovery papers about X-linked adrenoleukodystrophy, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
572 drug discovery papers about X-linked adrenoleukodystrophy, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-04-16 | Pediatric X-linked adrenoleukodystrophy: phenotypes, variants, and HSCT outcomes.
X-linked adrenoleukodystrophy (ALD) presents variable neurologic and adrenal manifestations. Early diagnosis is critical for effective hematopoietic stem cell transplantation (HSCT). This study aims to characterize clinical phenotypes, expand the ABCD1 mutational spectrum, and evaluate HSCT outcomes in a Chinese pediatric cohort. We retrospectively reviewed 31 male children diagnosed with ALD from 2015 to 2023. Clinical features, adrenal function, brain MRI findings, and ABCD1 mutations were analyzed. Loes scores were determined for cerebral ALD (cALD). Overall survival was compared between early-stage cALD patients who underwent allogeneic HSCT and those who did not. Twenty-four patients had cALD, and seven presented with adrenal-only disease. Neurologic symptoms in cALD included visual/hearing impairment (37.5%), seizures (29.2%), and cognitive decline (16.7%). Adrenal insufficiency occurred in 62.5% of cALD patients. Genetic analysis identified 29 ABCD1 variants, including three novel pathogenic variants (c.77C > G, c.1119_1120insTC, c.1291C > T). While statistical significance was limited by sample size (P = 0.24), early-stage cALD patients receiving HSCT showed a clinically meaningful trend toward improved 5-year OS (78%) compared to non-transplanted patients (29%). A pre-transplant Loes score < 9 was a critical determinant of superior outcomes. We expanded the ABCD1 spectrum with three novel variants. Our findings confirm that early-stage HSCT (Loes < 9) offers a distinct survival advantage. The diagnostic delays observed in our cohort underscore the urgent need for implementing newborn screening to capture patients within the optimal therapeutic window. • X-linked adrenoleukodystrophy (ALD) shows marked clinical heterogeneity; cerebral ALD progresses rapidly, and early HSCT offers the best outcomes. • The Loes score is a key imaging biomarker guiding transplant timing, with lower scores predicting superior prognosis. • We report a Chinese pediatric cohort expanding the ABCD1 mutation spectrum with three novel pathogenic variants. • Survival analyses reinforce that HSCT at Loes < 9 confers a clinically meaningful advantage, highlighting diagnostic delays and the need for newborn screening.
2026-03-28 | Allogeneic Stem Cell Transplant for Cerebral Adrenoleukodystrophy: The Changing Role of Alternative Donors.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a key therapy for stabilizing neurological function and improving survival in cerebral adrenoleukodystrophy (CALD). Identifying a suitable matched related donor (MRD) or unrelated donor remains challenging, especially in countries with limited donor registry representation. These barriers have increased the use of alternative donors, such as haploidentical or umbilical cord blood grafts. Early transplantation is associated with better outcomes. We describe outcomes of seven consecutive children with rapidly progressive CALD who underwent allo-HSCT between January 2015 and December 2023 at a single institution in Colombia, including matched related donor and alternative donors (haploidentical related and umbilical cord blood). Clinical data, imaging, and transplant characteristics were collected retrospectively. Seven children underwent allo-HSCT at a median age of 8 years. The median (range) age at CALD diagnosis was 8 years (4-11), and the median interval from CALD diagnosis to allo-HSCT was 14 months (range, 6-36). Alternative donors were used in six of seven cases (86%). Neutrophil engraftment occurred in six patients (85%) at a median of 15 days (12-29), and platelet engraftment in all evaluable patients at a median of 18 days (12-27). The median follow-up duration after transplant was 24 months. Two patients experienced stable or preserved neurological function, while others showed progression or died from transplant or disease-related complications. This study highlights real-world outcomes of allo-HSCT for CALD in a resource-limited setting. The findings underscore the importance of early diagnosis and expedited donor access to optimize neurological outcomes.
2025-10-26 | Adrenoleukodystrophy: Current understanding of disease mechanisms, diagnosis, and therapeutic advances-a recent review.
Adrenoleukodystrophy (ALD) is a complex and devastating X-linked neurodegenerative disorder classified as rare brain disease with profound effects on patients and their families. It can manifest in various clinical forms, ranging from adult-onset adrenomyeloneuropathy (AMN) to rapidly developing childhood cerebral adrenoleukodystrophy (CCALD), each presenting unique diagnostic and treatment challenges. At the molecular level, ALD results from mutations in the ATP-binding cassette subfamily D member 1 (ABCD1) gene, which disrupts peroxisomal β-oxidation, leading to the accumulation of very long-chain fatty acids (VLCFAs) and subsequent neurological damage. Understanding these pathogenic mechanisms has led to significant improvements in diagnosis and treatment strategies. Advances such as newborn screening and molecular profiling have facilitated early detection and intervention, contributing to improved clinical outcomes. Therapeutic innovations, including gene therapy and hematopoietic stem cell transplantation (HSCT), hold promise for modifying disease progression and enhancing quality of life. Despite these developments, major challenges remain, including the identification of disease modifiers, discovery of new therapeutic targets, and establishing the personalized treatment strategies. This review summarizes the current understanding of ALD, including its clinical spectrum, molecular basis, diagnostic approaches, and emerging therapies. Ongoing research and interdisciplinary collaboration are crucial for establishing the effective management of this debilitating disorder.
2025-10-01 | MON-461 X-linked Adrenoleukodystrophy With Mild Imaging And Combined Phenotype In A Family With A Pathogenic ABCD1 Variant
Abstract Disclosure: O.A. Velasco-Espinosa: None. A. Rocha-Haro: None. R. Flores-Cárdenas: None. D. Cuevas-Ramos: None. Background: Adrenoleukodystrophy (ALD) is a rare X-linked disorder caused by mutations in the ABCD1 gene, leading to the toxic accumulation of very long-chain fatty acids (VLCFAs) in the nervous system and adrenal glands. Adrenal insufficiency is a common manifestation, often presenting subtly, even without typical MRI abnormalities, making early diagnosis crucial for management. Clinical Case: A 32-year-old man with a strong family history of ALD presented at age 17 with seizures, which progressed to spastic paraparesis, urinary incontinence, and mild cognitive impairment. Biochemical testing revealed elevated VLCFA levels and adrenal insufficiency. Genetic analysis identified a novel hemizygous mutation in the ABCD1 gene (c.668_669del, p.Ala223Glyfs*77), which was also identified in three family members, including the patient. Brain MRI showed only mild occipital periventricular hyperintensities (Loes score 2), while spinal MRI revealed thoracic cord atrophy. The patient underwent hematopoietic stem cell transplantation (HSCT) from an HLA-matched unrelated donor. Post-transplant, he experienced complications including febrile episodes, cutaneous and systemic graft-versus-host disease (GvHD), adrenal crisis, and infections (CMV, HSV, and E. coli). Seizure frequency decreased with adjustments to antiepileptic therapy and Immunosuppressive therapy was adjusted as needed.At one year post-HSCT, the patient remained clinically stable with no new seizures or radiological progression. Immunosuppression was successfully tapered. Due to ongoing corticosteroid therapy, adrenal function could not be re-evaluated. Chronic oral lichenoid stomatitis persisted. Conclusions: This case highlights the variable and often subtle presentation of ALD, even within families, emphasizing the importance of early diagnosis and genetic testing. Timely HSCT can help stabilize disease progression, though careful multidisciplinary management, particularly with respect to adrenal function and immunosuppressive therapy, is crucial given the risks of complications, including adrenal crisis and graft-versus-host disease. Presentation: Monday, July 14, 2025
2025-07-24 | Cerebral Adrenoleukodystrophy: Characteristics of 10 Cases Including 6 Patients Without Neurologic Symptoms.
The objective of this study is to present the characteristics of cerebral type adrenoleukodystrophy (cALD) and our hematopoietic stem cell transplantation (HSCT) experience in treating cALD. A retrospective analysis and summary of the clinical data pertaining to 10 patients after allogeneic HSCT (allo-HSCT) was conducted from June 2020 to October 2023. Six patients exhibited no neurological symptoms, and MRI of 5 cases revealed no abnormalities at the onset of the disease. The 3-year overall survival (OS) and event-free survival (EFS) rate was 90.0% (95% CI: 69.4-100.0) and 65.6% (95% CI: 35.6-98.4), respectively. Survival analysis showed unrelated donor choice was associated with a superior OS and EFS compared with related donor sources, but these differences were not statistically significant (P=0.414, 0.184). cALD patients without magnetic resonance imaging (MRI) abnormalities at the initial onset of the disease increased the OS compared with the patients with MRI abnormalities, and the OS of patients with NFS=0 was superior before HSCT to those with NFS ≥1, however, the differences were not significant. But the EFS was obviously superior to those cALD patients with abnormal MRI status (P=0.013) at the initial onset of the disease and neurological functional symptoms before HSCT (P=0.023). Early screening is necessary for children with a family history of suspected genetic diseases and atypical neurological symptoms to improve allo-HSCT outcomes.
small molecules
2026-07-27 | PATHOPHYSIOLOGICAL, DIAGNOSTIC, AND THERAPEUTIC INSIGHTS INTO ADRENOLEUKODYSTROPHY AND THE ROLE OF NURSING IN COMPREHENSIVE CARE: A LITERATURE REVIEW
Adrenoleukodystrophy (ALD) is a rare, progressive genetic disorder resulting from mutations in the ABCD1 gene, located on the X chromosome, which impair the metabolism of very-long-chain fatty acids (VLCFAs), leading to adrenal dysfunction and neurodegeneration. Given the pathophysiological complexity and therapeutic limitations of the disease, this study aimed to compile and analyze the main scientific evidence regarding the pathophysiological, diagnostic, and therapeutic aspects of ALD, as well as to highlight the importance of nursing in providing comprehensive and palliative care to affected patients. This is an integrative literature review conducted in the PubMed and Virtual Health Library (BVS) databases, using controlled descriptors combined with Boolean operators. Fourteen studies published between 2020 and 2025 were included and analyzed according to the PRISMA protocol. The results show that early diagnosis is possible through spectroscopic techniques, such as liquid chromatography coupled with mass spectrometry (LC-MS), which allow for the identification of the ALD biomarker. Neonatal screening is also essential for a favorable prognosis, enabling early interventions such as hematopoietic stem cell transplantation. New experimental therapies, such as the use of nervonic acid and N-acetylcysteine, show promise. The role of nursing is highlighted as essential in comprehensive care, especially in the implementation of palliative care practices centered on the dignity, comfort, and well-being of the patient and their family. It is concluded that scientific advances and a multidisciplinary approach are indispensable for the effective management of ALD, with nursing playing a central role in coordinating care and providing humanized support.
2026-07-18 | The complex lipidome as a driver of tissue-specific pathology in adrenoleukodystrophy.
X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal disorder caused by pathogenic variants in the ABCD1 gene, encoding a peroxisomal membrane transporter required for the import of very-long-chain fatty acids (VLCFA) into peroxisomes for degradation. ABCD1 deficiency leads to VLCFA accumulation in plasma and tissues. The resulting disease has a highly variable clinical presentation. In males, this manifests as cerebral demyelination, progressive myelopathy, and adrenal insufficiency, alone or in combination. Women predominantly develop myelopathy, while cerebral disease and adrenal insufficiency are rare, occurring almost exclusively in cases of extreme X-inactivation skewing toward the mutant allele. The lipid-mediated mechanisms linking VLCFA accumulation to tissue-specific pathology remain incompletely understood. Here, we review evidence that VLCFA-containing complex lipids, rather than free VLCFAs alone, are central mediators of tissue-specific pathology in ALD and discuss the therapeutic implications of this lipid-centric perspective. VLCFAs are incorporated into a broad range of complex lipids, including phosphatidylcholines, lysophosphatidylcholines, cholesterol esters, triacylglycerols, sphingomyelins, ceramides, and plasmalogens. The degree of lipid dysregulation increases with acyl chain length and saturation. VLCFA-containing lipid species correlate with disease severity across all clinical phenotypes. In the brain, VLCFA-containing phosphatidylcholines accumulate before demyelination onset, cholesterol ester accumulation is associated with neuroinflammatory cascades, and plasmalogen depletion reflects early oxidative damage. In the spinal cord, VLCFA-containing myelin lipids are associated with non-inflammatory axonopathy, mitochondrial dysfunction, and microglial phagocytic activation. In the adrenal gland, VLCFA accumulation in cholesterol ester-rich lipid droplets impairs ACTH receptor signaling and sequesters cholesterol from steroidogenic pathways. Enzymatic regulators of VLCFA homeostasis, including ELOVL1, SCD1, and the omega-oxidation enzymes CYP4F2 and CYP4F3B, are potential therapeutic targets for substrate reduction. Plasma VLCFA-lipid profiles correlate with disease severity across all affected tissues, positioning lipidomic profiling as a potential clinical instrument for risk stratification and treatment monitoring. Secondary lipid mediators amplify primary VLCFA toxicity through distinct, cell-type-specific pathways. The near-exclusive occurrence of cerebral ALD and adrenal insufficiency in women with extreme X-inactivation skewing suggests that partial reduction of the VLCFA lipid burden, rather than complete normalization, may be sufficient to prevent severe disease manifestations. This has direct implications for substrate-reduction therapy development.
2026-06-07 | Successful treatment of abnormal sensation associated with restless legs syndrome in adrenoleukodystrophy using Gunggwijohyeoleum-Jeilgagam: A case report.
Adrenoleukodystrophy (ALD) is a rare neurodegenerative disorder frequently associated with restless legs syndrome (RLS), particularly in patients with the adrenomyeloneuropathy (AMN) phenotype. RLS can markedly aggravate abnormal sensations, insomnia, and gait dysfunction; however, conventional treatments, such as dopamine agonists or iron supplementation, are often ineffective or inappropriate, especially in patients without iron deficiency. Herein, we report the clinical effects of herbal medicines in a patient with ALD-associated refractory RLS. A 50-year-old Asian man with genetically confirmed AMN-type ALD presented with a 10-year history of persistent tingling and discomfort in both lower extremities, severe RLS, insomnia, and progressive gait impairment. Despite treatment with baclofen and pramipexole, his symptoms remained refractory, with an International Restless Legs Syndrome Rating Scale (IRLS) score of 31, a Short Physical Performance Battery (SPPB) score of 4, and sleep duration limited to 2-3 h per night. The serum ferritin level was 140 μg/L, indicating adequate iron stores. Based on Korean medicine (KM) pattern identification, the herbal prescription Gunggwijohyeoleum-Jeilgagam (GJG) was administered for 21 days. Following treatment, the IRLS score decreased from 31 to 13, falling below the threshold for severe RLS, while the SPPB score improved from 4 to 6. The sleep duration increased to 5 h, and these improvements were maintained for 5 months after discontinuation without recurrence. GJG demonstrated potential benefit in alleviating refractory RLS-associated abnormal sensations and improving physical function in a patient with ALD. This case suggests that KM may represent a complementary therapeutic option for chronic sensory, sleep, and functional impairments in neurodegenerative disorders when conventional treatments are insufficient.
2026-06-05 | Peroxisomal ABCD1 deficiency in mice drives Th1 bias through 25-HC-LXR signaling in CD4+ T cells.
X-linked adrenoleukodystrophy (X-ALD) is driven by ABCD1 dysfunction, causing very-long-chain fatty acid (VLCFA) accumulation and cerebral inflammation, yet the role of T cells in X-ALD remains unclear. Here, we show that Abcd1-deficient CD4+ T cells exhibit a strong Th1 bias, producing more IFN-γ and less IL-10 under antigen-specific immunization in vivo and Th1-polarizing conditions in vitro. Transcriptional profiling revealed early induction of Ifng and Tbx21 (T-bet) and late repression of Prdm1 (Blimp-1), indicating Blimp-1-dependent derepression of IFN-γ and reduced IL-10. Mechanistically, liver X receptor (LXR) signaling was markedly amplified, evidenced by upregulation of Abca1, Srebf1, and the oxysterol 25-hydroxycholesterol (25-HC), driven by increased Ch25h. Pharmacological modulation validated this axis: the LXR antagonist SR9238 restored Blimp-1 and IL-10 while reducing IFN-γ, whereas the LXR agonist T0901317 and exogenous 25-HC recapitulated the Abcd1-deficient phenotype. Thus, 25-HC-LXR signaling suppresses Blimp-1, enforcing Th1 polarization in Abcd1-deficient CD4+ T cells. These findings define an immunometabolic link between peroxisomal lipid metabolism and T cell differentiation and highlight the 25-HC-LXR-Blimp-1 axis as a mechanistic link regulating CD4+ T-cell polarization, with potential relevance to X-ALD-associated neuroinflammation.
2026-06-01 | Nervonic acid and the long arc of therapeutic hope in X-linked adrenoleukodystrophy
The history of X-linked Adrenoleukodystrophy (ALD) is, at its core, a story of both serendipity and persistence - of scientists following biochemical clues from the accidental discovery of very long chain fatty acids (VLCFA) to molecular precision, and of clinicians striving to translate those insights into meaningful therapies. The emergence of nervonic acid as a potential therapeutic strategy must be understood within this broader trajectory, one that has repeatedly oscillated between optimism and limitation.
gene therapies
2026-06-25 | Peroxisomal disorders - incidences in Sweden.
Incidence calculations are crucial for understanding rare disorders, improving healthcare, and public health planning. Our study presents the incidence of peroxisomal disorders in Sweden. All patients diagnosed between 1985 and 2024 at the two existing laboratories, which determine very long-chain fatty acids (VLCFA), phytanic, pristanic, and L-pipecolic acid in plasma, and plasmalogens in erythrocytes, were included in the study. Specifically, the incidence of X-linked adrenoleukodystrophy (X-ALD) is essential for evaluating its inclusion in the national neonatal screening for inborn diseases. Since the incidence of these disorders remained almost constant over the last 20 years of the study, these data were used for calculations. The incidence for the entire cohort (2005-2024) was 1:29,100, excluding female carriers of X-ALD. The most common subgroup was hemizygous X-ALD, with an incidence of 1:65,100, followed by peroxisomal biogenesis disorders (PBDs; Zellweger spectrum disorders) at 1:73,800. These incidences align with other estimates for clinically detected patients, but not for X-ALD detected through neonatal screening, where the incidence is at least three times higher. This discrepancy is partly explained by the discovery of genetic variants of uncertain significance. Over the years, the age at diagnosis and survival time for PBDs have increased, indicating heightened awareness of attenuated forms and improved supportive treatment.
2026-04-26 | Clinical, biochemical and genetic profiling of X-linked adrenoleukodystrophy in Egyptian pediatric patients: a hospital-based study
Abstract Background X-linked adrenoleukodystrophy, the most common peroxisomal disorder, is caused by ABCD1 gene mutations. This genetic disorder is characterized by the defective degradation of very long-chain fatty acids. This study aimed to assess the frequency, clinical spectrum, and molecular background of X-linked adrenoleukodystrophy among a group of Egyptian pediatric patients with clinical suspicion of peroxisomal disorder. Subjects and methods This study included 120 high-risk Egyptian children presented to Cairo University Children’s Hospital (CUCH) with the clinical suspicion of peroxisomal disorder. X-linked adrenoleukodystrophy diagnosis was confirmed by the very long-chain fatty acids testing using gas chromatography/mass spectrometry followed by sequencing of the ABCD1 gene in patients with abnormal very long-chain fatty acids results. Results 6/120(5%) patients (from 4 unrelated families) had a high level of very long-chain fatty acids. The cerebral phenotype was the most common presentation, and white matter demyelination was the most common radiological finding. Three ABCD1 gene pathogenic variants (c.293 C > T (p.Ser98Leu), c.1511T > C (p.Leu504Pro) and c.1415_1416del p.(Gln472Argfs*83)) had been detected in 5 patients and one de novo likely pathogenic variant c.1511T > C (p.Leu504Pro) had been detected in one patient. Conclusions Epidemiological studies regarding the prevalence and genetic basis of peroxisomal disorders among Egyptian children are currently scarce. In our recent study, we investigated the frequency of these disorders within a group of suspected cases.
2026-01-19 | Late-Onset X-linked Adrenoleukodystrophy: A Rare Cause of Progressive Spastic Paraparesis.
X-linked adrenoleukodystrophy (X-ALD) is an uncommon peroxisomal disorder that can manifest in adult women with slowly progressive motor symptoms that often mimic hereditary spastic paraplegia, contributing to delayed diagnosis. We report the case of a 64-year-old woman with a long history of worsening gait impairment who had previously undergone spinal surgery without clinical benefit. She exhibited a spastic paraparesis with upper motor neuron features, and neuroimaging demonstrated white matter abnormalities in the brain with no structural explanation in the spine. Extensive laboratory testing excluded infectious, autoimmune, and metabolic causes. Biochemical evaluation revealed elevated very-long-chain fatty acids, raising suspicion for X-ALD, and genetic testing confirmed a heterozygous ABCD1 c.1849C>T (p.R617C) pathogenic variant. This case highlights the need to consider X-ALD in women presenting with unexplained progressive spastic paraparesis, emphasizing the value of timely biochemical and genetic evaluation to achieve an accurate diagnosis and provide appropriate guidance for affected families.
2026-01-16 | Congenital Inborn Errors of Metabolism: Clinical and Imaging Pearls.
Pediatric neurometabolic imaging is a complex field of pediatric neuroradiology. There are key clinical and imaging features that help the radiologist narrow the differential diagnosis. The first part of this review provides an overview of the current system used for classification of metabolic disorders, focusing on the clinical and imaging features that narrow the differential diagnosis. These features include classifications based on organelle dysfunction, laboratory markers, clinical presentation, and imaging patterns. In the second part of this review, nine pediatric neurometabolic disorders are described on the basis of their clinical and imaging features. These disorders are maple syrup urine disease, Alexander disease, X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, mitochondrial encephalopathy with lactic acidosis and strokelike episodes, nonketotic hyperglycinemia, Zellweger spectrum disorder, and Leigh syndrome. ©RSNA, 2025 Supplemental material is available for this article.
2026-01-13 | O-10 ABCD1 GENE MUTATION IN AN IRANIAN FAMILY WITH X-LINKED ADRENOLEUKODYSTROPHY AND DIVERSE CLINICAL MANIFESTATIONS
Abstract Introduction A hereditary condition known as X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene, which is found at the Xq28 locus. This gene produces a transporter protein that imports very long-chain fatty acids into peroxisomes. ALDP dysfunction causes high amounts of very-long-chain saturated fatty acids (VLCFAs) in the blood and tissues, resulting in the development of ALD. Given the wide range of symptom severity seen in X-ALD, this study aims to understand the clinical manifestations associated with different mutations in the ABCD1 gene among Iranian family with several patients. Clinical Case A 42-year-old male proband, diagnosed with Addison’s disease 15 years ago following a psychotic episode, and has since been managed with glucocorticoid and mineralocorticoid replacement therapy. In 2020, approximately 15 years after the initial diagnosis, the patient developed progressive neurologic symptoms, including paresthesia, gait and balance disturbances, dysphagia, spastic paraparesis, accompanied by brainstem changes observed on neuroimaging. Taking family history and examination revealed a younger brother’s unknown death (suspected adrenal crisis) and another male sibling with motor disorders. A nephew was diagnosed with Addison’s disease and later developed limb spasms and occasional nocturia, he went under the care of a neurologist and occupational therapist. Given the clinical presentation and suspicion of adrenoleukodystrophy, plasma levels of very-long-chain fatty acids (VLCFA) were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the proband. Then the pedigree was drawn, and genomic DNA was isolated from peripheral blood samples. The ten coding exons of the ABCD1 gene were analyzed through conventional Sanger sequencing in the proband. The identified mutation in the proband was then assessed in other family members using the same sequencing method. In addition to VLCFAs imbalance, pathogenic mutation was identified in the exon 5 of the ABCD1 gene, with del AG at nucleotide 1415-1416, corresponding to the frameshift at the residue 472 (c.1415-1416delAG, p. Gln472fs). Segregation confirmed in affected males and carrier females. Conclusion Given the X-linked inheritance pattern, genetic counseling and prenatal diagnosis (PND) are essential for pregnancies in carrier females within this family, in order to prevent the recurrence of the disorder in future offspring.
antibodies
2026-05-19 | Outcomes of an optimized ciclosporin-free haploidentical HSCT protocol in paediatric patients with cerebral adrenoleukodystrophy.
Haploidentical haematopoietic stem cell transplantation (haplo-HSCT) expands donor availability for cerebral adrenoleukodystrophy (cALD). However, conventional graft-versus-host disease (GVHD) prophylaxis based on calcineurin inhibitors like ciclosporin (CsA) poses a potential neurotoxicity risk that may exacerbate neurological injury. We retrospectively analysed 26 cALD patients who underwent haplo-HSCT with an optimized ciclosporin-free GVHD prophylaxis regimen consisting of anti-thymocyte globulin (ATG; 4 mg/kg), post-transplant cyclophosphamide (PTCy) and mycophenolate mofetil. Neutrophil and platelet engraftment each occurred at a median of 15 days (ranges, 13-26 and 9-33 days respectively). The cumulative incidence (CI) of grades II-IV acute GVHD by day 100 was 18.49% ± 8.37%, and the 3-year CI of moderate-to-severe chronic GVHD was 9.32% ± 6.28%. After a median follow-up of 29 months, overall survival was 90.4% ± 6.6% and major functional disability-free survival was 69.0% ± 9.1%. Post-transplantation, plasma C26:0 levels and the C24:0/C22:0 and C26:0/C22:0 ratios were markedly reduced. Magnetic resonance imaging (MRI) at a mean of 7.3 ± 5.9 months post-HSCT showed largely preserved LOES scores without significant progression. Our experience supports the safety and efficacy of this optimized ciclosporin-free haplo-HSCT approach for patients with cALD, warranting further validation in prospective studies.
2025-02-07 | Bodyweight and Absolute Lymphocyte Count-Based Dosing of Rabbit Anti-Thymocyte Globulin Results in Early CD4+ Immune Reconstitution in Patients with Inborn Errors of Metabolism Undergoing Umbilical Cord Blood Transplantation.
Rabbit anti-thymocyte globulin (rATG) decreases the risk of graft failure and graft-versus-host disease (GvHD) in a setting of allogenic hematopoietic cell transplantation (HCT) but has highly variable pharmacokinetics. Recently, it was shown that a dosing nomogram based on recipient bodyweight and absolute lymphocyte count reduced rATG overexposure which led to faster immune reconstitution. The aim of this study is to evaluate the feasibility and benefits of using a rATG dosing nomogram to achieve early CD4+ immune reconstitution in pediatric patients with inborn errors of metabolism (IEM) undergoing umbilical cord blood transplantation. The rATG dosing nomogram in pediatric patients with IEM receiving an umbilical cord blood transplant with busulfan based myeloablative conditioning at the University of Minnesota Masonic Children's Hospital was used prospectively since 2017. The primary endpoint was CD4+ immune reconstitution (>50 CD4+ T-cells/mL) within 100 days after HCT. Secondary endpoints included overall survival, graft failure, acute and chronic GvHD, and viral reactivations RESULTS: 27 patients were included in the study. Median follow-up time was 31 months (IQR 22 to 38) and median age was 1.5 years (IQR 0.7 to 3.9). The underlying disease was Hurler syndrome in 17 (63%), Hunter syndrome in 4 (15%) and cerebral Adrenoleukodystrophy in 4 (15%) patients, two patients were transplanted for other IEM. The CD4+ recovery (>50 CD4+ T-cells/mL) at 100 days post HCT was reached in 22 (85%) of 26 patients. Overall survival was 83% (95% CI 67% to 100%). No graft failure was observed. Two (7%) patients developed acute GvHD grade II to IV and no patients had chronic GvHD. Six patients (22%) had cytomegalovirus viremia. One patient had Epstein-Barr virus reactivation requiring treatment. In patients with IEM individualized dosing of rATG was associated with a robust and early CD4+ immune reconstitution, with no graft failures and low GvHD incidence.
2024-10-28 | A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets.
X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development. We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice. Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-knockout mice displayed more cerebral demyelination, blood-brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity. Our results suggest loss of Abcd1 function in mice predisposes to more severe blood-brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2025;97:296-312.
2024-08-07 | Targeting VEGF-mediated blood-brain barrier disruption in advanced cerebral leukodystrophy.
The earliest clinical manifestation of cerebral adrenoleukodystrophy (CALD) is adrenal insufficiency (AI) characterized by elevations in ACTH and loss of cortisol. We showed high (though physiologically achievable) levels of ACTH increases endothelial permeability, increases anisotropy, and increases VEGF secretion. An ACBD1 knockout endothelial cell line had increased sensitivity to ACTH and VEGF. Inhibition of VEGF via application of anti-VEGF (bevacizumab) improved permeability. Six boys with advanced CALD were treated with bevacizumab combined with dexamethasone and ruxolitinib as immune suppressants. Most boys had decreases in gadolinium enhancement on MRI indicating improvement in endothelial function, though all boys continued to progress symptomatically.
2021-05-21 | Fulminating Autoimmune Demyelination with Optic Neuropathy in a Case of Pediatric Cerebral Adrenoleukodystrophy: Case Report and Review of the Literature
Abstract X-linked adrenoleukodystrophy (ALD) is a leukodystrophy characterized not only by progressive loss of myelin in the central nervous system due to dysmyelination, but also by acute, subacute, or chronic inflammatory demyelination. This results in the phenotypic variability of cerebral ALD (cerALD), which is independent of the genotype. In this article, we reported a fulminant presentation with fluctuating encephalopathy and visual loss in a patient with childhood onset cerALD. Brain MRI showed symmetric confluent occipito-temporal demyelination with severe disruption of the blood–brain barrier and prechiasmal optic neuropathy. The patient's cerebral spinal fluid (CSF) demonstrated an elevated IgG index, myelin basic proteins, and oligoclonal bands. Within 48 hours of receiving immunomodulating therapy, the patient's symptoms of psychomotor slowing, visual impairment, and areflexia partially resolved. High plasma C26:0 levels and high ratios of C24/22 and C26/22 were diagnostic of ALD. It has been shown that environmental factors play an important role in the inflammatory demyelination responsible for the severe phenotypes of cerALD.
other
2024-06-03 | Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy.
The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1- mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients' CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention.
1985-03-20 | Electrophysiologic studies in neonatal adrenoleukodystrophy.
Recent electrophysiologic studies have focussed attention on the X-linked adrenoleukodystrophy (ALD) and its myeloneuropathic variant. No organized studies are, however, yet available on its relatively recently described neonatal variant. We conducted electroencephalographic, electroretinographic and evoked response studies in 2 patients with neonatal ALD. In one patient, an infant, initial EEG, hypsarrhythmic in waking and somewhat periodic in sleep, showed dramatic improvement on ACTH therapy accompanied with a seizure-free status. The EEG and clinical improvement, however, were temporary. No improvement occurred following pyridoxine therapy. Her electroretinogram (ERG), visual evoked responses (VERs) and far-field short latency brain-stem auditory evoked responses were also abnormal. The latter studies probably reflected photoreceptor degeneration, optic nerve involvement, cochlear and/or auditory nerve involvement respectively in neonatal ALD. The other patient, a 3.5-year-old girl, also had an EEG characterized by a moderate- to high-amplitude slow background activity and high-amplitude multifocal, generalized or periodic paroxysmal discharges, but presence of some better formed theta frequencies in background activity precluded a hypsarrhythmic label on her EEG. Her ERGs and VERs were totally extinct but in contrast to the first patient, she had clear-cut optic atrophy and retinitis pigmentosa on ophthalmological examination.
cell therapies
2026-04-16 | Pediatric X-linked adrenoleukodystrophy: phenotypes, variants, and HSCT outcomes.
X-linked adrenoleukodystrophy (ALD) presents variable neurologic and adrenal manifestations. Early diagnosis is critical for effective hematopoietic stem cell transplantation (HSCT). This study aims to characterize clinical phenotypes, expand the ABCD1 mutational spectrum, and evaluate HSCT outcomes in a Chinese pediatric cohort. We retrospectively reviewed 31 male children diagnosed with ALD from 2015 to 2023. Clinical features, adrenal function, brain MRI findings, and ABCD1 mutations were analyzed. Loes scores were determined for cerebral ALD (cALD). Overall survival was compared between early-stage cALD patients who underwent allogeneic HSCT and those who did not. Twenty-four patients had cALD, and seven presented with adrenal-only disease. Neurologic symptoms in cALD included visual/hearing impairment (37.5%), seizures (29.2%), and cognitive decline (16.7%). Adrenal insufficiency occurred in 62.5% of cALD patients. Genetic analysis identified 29 ABCD1 variants, including three novel pathogenic variants (c.77C > G, c.1119_1120insTC, c.1291C > T). While statistical significance was limited by sample size (P = 0.24), early-stage cALD patients receiving HSCT showed a clinically meaningful trend toward improved 5-year OS (78%) compared to non-transplanted patients (29%). A pre-transplant Loes score < 9 was a critical determinant of superior outcomes. We expanded the ABCD1 spectrum with three novel variants. Our findings confirm that early-stage HSCT (Loes < 9) offers a distinct survival advantage. The diagnostic delays observed in our cohort underscore the urgent need for implementing newborn screening to capture patients within the optimal therapeutic window. • X-linked adrenoleukodystrophy (ALD) shows marked clinical heterogeneity; cerebral ALD progresses rapidly, and early HSCT offers the best outcomes. • The Loes score is a key imaging biomarker guiding transplant timing, with lower scores predicting superior prognosis. • We report a Chinese pediatric cohort expanding the ABCD1 mutation spectrum with three novel pathogenic variants. • Survival analyses reinforce that HSCT at Loes < 9 confers a clinically meaningful advantage, highlighting diagnostic delays and the need for newborn screening.
2026-03-28 | Allogeneic Stem Cell Transplant for Cerebral Adrenoleukodystrophy: The Changing Role of Alternative Donors.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a key therapy for stabilizing neurological function and improving survival in cerebral adrenoleukodystrophy (CALD). Identifying a suitable matched related donor (MRD) or unrelated donor remains challenging, especially in countries with limited donor registry representation. These barriers have increased the use of alternative donors, such as haploidentical or umbilical cord blood grafts. Early transplantation is associated with better outcomes. We describe outcomes of seven consecutive children with rapidly progressive CALD who underwent allo-HSCT between January 2015 and December 2023 at a single institution in Colombia, including matched related donor and alternative donors (haploidentical related and umbilical cord blood). Clinical data, imaging, and transplant characteristics were collected retrospectively. Seven children underwent allo-HSCT at a median age of 8 years. The median (range) age at CALD diagnosis was 8 years (4-11), and the median interval from CALD diagnosis to allo-HSCT was 14 months (range, 6-36). Alternative donors were used in six of seven cases (86%). Neutrophil engraftment occurred in six patients (85%) at a median of 15 days (12-29), and platelet engraftment in all evaluable patients at a median of 18 days (12-27). The median follow-up duration after transplant was 24 months. Two patients experienced stable or preserved neurological function, while others showed progression or died from transplant or disease-related complications. This study highlights real-world outcomes of allo-HSCT for CALD in a resource-limited setting. The findings underscore the importance of early diagnosis and expedited donor access to optimize neurological outcomes.
2025-10-26 | Adrenoleukodystrophy: Current understanding of disease mechanisms, diagnosis, and therapeutic advances-a recent review.
Adrenoleukodystrophy (ALD) is a complex and devastating X-linked neurodegenerative disorder classified as rare brain disease with profound effects on patients and their families. It can manifest in various clinical forms, ranging from adult-onset adrenomyeloneuropathy (AMN) to rapidly developing childhood cerebral adrenoleukodystrophy (CCALD), each presenting unique diagnostic and treatment challenges. At the molecular level, ALD results from mutations in the ATP-binding cassette subfamily D member 1 (ABCD1) gene, which disrupts peroxisomal β-oxidation, leading to the accumulation of very long-chain fatty acids (VLCFAs) and subsequent neurological damage. Understanding these pathogenic mechanisms has led to significant improvements in diagnosis and treatment strategies. Advances such as newborn screening and molecular profiling have facilitated early detection and intervention, contributing to improved clinical outcomes. Therapeutic innovations, including gene therapy and hematopoietic stem cell transplantation (HSCT), hold promise for modifying disease progression and enhancing quality of life. Despite these developments, major challenges remain, including the identification of disease modifiers, discovery of new therapeutic targets, and establishing the personalized treatment strategies. This review summarizes the current understanding of ALD, including its clinical spectrum, molecular basis, diagnostic approaches, and emerging therapies. Ongoing research and interdisciplinary collaboration are crucial for establishing the effective management of this debilitating disorder.
2025-10-01 | MON-461 X-linked Adrenoleukodystrophy With Mild Imaging And Combined Phenotype In A Family With A Pathogenic ABCD1 Variant
Abstract Disclosure: O.A. Velasco-Espinosa: None. A. Rocha-Haro: None. R. Flores-Cárdenas: None. D. Cuevas-Ramos: None. Background: Adrenoleukodystrophy (ALD) is a rare X-linked disorder caused by mutations in the ABCD1 gene, leading to the toxic accumulation of very long-chain fatty acids (VLCFAs) in the nervous system and adrenal glands. Adrenal insufficiency is a common manifestation, often presenting subtly, even without typical MRI abnormalities, making early diagnosis crucial for management. Clinical Case: A 32-year-old man with a strong family history of ALD presented at age 17 with seizures, which progressed to spastic paraparesis, urinary incontinence, and mild cognitive impairment. Biochemical testing revealed elevated VLCFA levels and adrenal insufficiency. Genetic analysis identified a novel hemizygous mutation in the ABCD1 gene (c.668_669del, p.Ala223Glyfs*77), which was also identified in three family members, including the patient. Brain MRI showed only mild occipital periventricular hyperintensities (Loes score 2), while spinal MRI revealed thoracic cord atrophy. The patient underwent hematopoietic stem cell transplantation (HSCT) from an HLA-matched unrelated donor. Post-transplant, he experienced complications including febrile episodes, cutaneous and systemic graft-versus-host disease (GvHD), adrenal crisis, and infections (CMV, HSV, and E. coli). Seizure frequency decreased with adjustments to antiepileptic therapy and Immunosuppressive therapy was adjusted as needed.At one year post-HSCT, the patient remained clinically stable with no new seizures or radiological progression. Immunosuppression was successfully tapered. Due to ongoing corticosteroid therapy, adrenal function could not be re-evaluated. Chronic oral lichenoid stomatitis persisted. Conclusions: This case highlights the variable and often subtle presentation of ALD, even within families, emphasizing the importance of early diagnosis and genetic testing. Timely HSCT can help stabilize disease progression, though careful multidisciplinary management, particularly with respect to adrenal function and immunosuppressive therapy, is crucial given the risks of complications, including adrenal crisis and graft-versus-host disease. Presentation: Monday, July 14, 2025
2025-07-24 | Cerebral Adrenoleukodystrophy: Characteristics of 10 Cases Including 6 Patients Without Neurologic Symptoms.
The objective of this study is to present the characteristics of cerebral type adrenoleukodystrophy (cALD) and our hematopoietic stem cell transplantation (HSCT) experience in treating cALD. A retrospective analysis and summary of the clinical data pertaining to 10 patients after allogeneic HSCT (allo-HSCT) was conducted from June 2020 to October 2023. Six patients exhibited no neurological symptoms, and MRI of 5 cases revealed no abnormalities at the onset of the disease. The 3-year overall survival (OS) and event-free survival (EFS) rate was 90.0% (95% CI: 69.4-100.0) and 65.6% (95% CI: 35.6-98.4), respectively. Survival analysis showed unrelated donor choice was associated with a superior OS and EFS compared with related donor sources, but these differences were not statistically significant (P=0.414, 0.184). cALD patients without magnetic resonance imaging (MRI) abnormalities at the initial onset of the disease increased the OS compared with the patients with MRI abnormalities, and the OS of patients with NFS=0 was superior before HSCT to those with NFS ≥1, however, the differences were not significant. But the EFS was obviously superior to those cALD patients with abnormal MRI status (P=0.013) at the initial onset of the disease and neurological functional symptoms before HSCT (P=0.023). Early screening is necessary for children with a family history of suspected genetic diseases and atypical neurological symptoms to improve allo-HSCT outcomes.
small molecules
2026-07-27 | PATHOPHYSIOLOGICAL, DIAGNOSTIC, AND THERAPEUTIC INSIGHTS INTO ADRENOLEUKODYSTROPHY AND THE ROLE OF NURSING IN COMPREHENSIVE CARE: A LITERATURE REVIEW
Adrenoleukodystrophy (ALD) is a rare, progressive genetic disorder resulting from mutations in the ABCD1 gene, located on the X chromosome, which impair the metabolism of very-long-chain fatty acids (VLCFAs), leading to adrenal dysfunction and neurodegeneration. Given the pathophysiological complexity and therapeutic limitations of the disease, this study aimed to compile and analyze the main scientific evidence regarding the pathophysiological, diagnostic, and therapeutic aspects of ALD, as well as to highlight the importance of nursing in providing comprehensive and palliative care to affected patients. This is an integrative literature review conducted in the PubMed and Virtual Health Library (BVS) databases, using controlled descriptors combined with Boolean operators. Fourteen studies published between 2020 and 2025 were included and analyzed according to the PRISMA protocol. The results show that early diagnosis is possible through spectroscopic techniques, such as liquid chromatography coupled with mass spectrometry (LC-MS), which allow for the identification of the ALD biomarker. Neonatal screening is also essential for a favorable prognosis, enabling early interventions such as hematopoietic stem cell transplantation. New experimental therapies, such as the use of nervonic acid and N-acetylcysteine, show promise. The role of nursing is highlighted as essential in comprehensive care, especially in the implementation of palliative care practices centered on the dignity, comfort, and well-being of the patient and their family. It is concluded that scientific advances and a multidisciplinary approach are indispensable for the effective management of ALD, with nursing playing a central role in coordinating care and providing humanized support.
2026-07-18 | The complex lipidome as a driver of tissue-specific pathology in adrenoleukodystrophy.
X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal disorder caused by pathogenic variants in the ABCD1 gene, encoding a peroxisomal membrane transporter required for the import of very-long-chain fatty acids (VLCFA) into peroxisomes for degradation. ABCD1 deficiency leads to VLCFA accumulation in plasma and tissues. The resulting disease has a highly variable clinical presentation. In males, this manifests as cerebral demyelination, progressive myelopathy, and adrenal insufficiency, alone or in combination. Women predominantly develop myelopathy, while cerebral disease and adrenal insufficiency are rare, occurring almost exclusively in cases of extreme X-inactivation skewing toward the mutant allele. The lipid-mediated mechanisms linking VLCFA accumulation to tissue-specific pathology remain incompletely understood. Here, we review evidence that VLCFA-containing complex lipids, rather than free VLCFAs alone, are central mediators of tissue-specific pathology in ALD and discuss the therapeutic implications of this lipid-centric perspective. VLCFAs are incorporated into a broad range of complex lipids, including phosphatidylcholines, lysophosphatidylcholines, cholesterol esters, triacylglycerols, sphingomyelins, ceramides, and plasmalogens. The degree of lipid dysregulation increases with acyl chain length and saturation. VLCFA-containing lipid species correlate with disease severity across all clinical phenotypes. In the brain, VLCFA-containing phosphatidylcholines accumulate before demyelination onset, cholesterol ester accumulation is associated with neuroinflammatory cascades, and plasmalogen depletion reflects early oxidative damage. In the spinal cord, VLCFA-containing myelin lipids are associated with non-inflammatory axonopathy, mitochondrial dysfunction, and microglial phagocytic activation. In the adrenal gland, VLCFA accumulation in cholesterol ester-rich lipid droplets impairs ACTH receptor signaling and sequesters cholesterol from steroidogenic pathways. Enzymatic regulators of VLCFA homeostasis, including ELOVL1, SCD1, and the omega-oxidation enzymes CYP4F2 and CYP4F3B, are potential therapeutic targets for substrate reduction. Plasma VLCFA-lipid profiles correlate with disease severity across all affected tissues, positioning lipidomic profiling as a potential clinical instrument for risk stratification and treatment monitoring. Secondary lipid mediators amplify primary VLCFA toxicity through distinct, cell-type-specific pathways. The near-exclusive occurrence of cerebral ALD and adrenal insufficiency in women with extreme X-inactivation skewing suggests that partial reduction of the VLCFA lipid burden, rather than complete normalization, may be sufficient to prevent severe disease manifestations. This has direct implications for substrate-reduction therapy development.
2026-06-07 | Successful treatment of abnormal sensation associated with restless legs syndrome in adrenoleukodystrophy using Gunggwijohyeoleum-Jeilgagam: A case report.
Adrenoleukodystrophy (ALD) is a rare neurodegenerative disorder frequently associated with restless legs syndrome (RLS), particularly in patients with the adrenomyeloneuropathy (AMN) phenotype. RLS can markedly aggravate abnormal sensations, insomnia, and gait dysfunction; however, conventional treatments, such as dopamine agonists or iron supplementation, are often ineffective or inappropriate, especially in patients without iron deficiency. Herein, we report the clinical effects of herbal medicines in a patient with ALD-associated refractory RLS. A 50-year-old Asian man with genetically confirmed AMN-type ALD presented with a 10-year history of persistent tingling and discomfort in both lower extremities, severe RLS, insomnia, and progressive gait impairment. Despite treatment with baclofen and pramipexole, his symptoms remained refractory, with an International Restless Legs Syndrome Rating Scale (IRLS) score of 31, a Short Physical Performance Battery (SPPB) score of 4, and sleep duration limited to 2-3 h per night. The serum ferritin level was 140 μg/L, indicating adequate iron stores. Based on Korean medicine (KM) pattern identification, the herbal prescription Gunggwijohyeoleum-Jeilgagam (GJG) was administered for 21 days. Following treatment, the IRLS score decreased from 31 to 13, falling below the threshold for severe RLS, while the SPPB score improved from 4 to 6. The sleep duration increased to 5 h, and these improvements were maintained for 5 months after discontinuation without recurrence. GJG demonstrated potential benefit in alleviating refractory RLS-associated abnormal sensations and improving physical function in a patient with ALD. This case suggests that KM may represent a complementary therapeutic option for chronic sensory, sleep, and functional impairments in neurodegenerative disorders when conventional treatments are insufficient.
2026-06-05 | Peroxisomal ABCD1 deficiency in mice drives Th1 bias through 25-HC-LXR signaling in CD4+ T cells.
X-linked adrenoleukodystrophy (X-ALD) is driven by ABCD1 dysfunction, causing very-long-chain fatty acid (VLCFA) accumulation and cerebral inflammation, yet the role of T cells in X-ALD remains unclear. Here, we show that Abcd1-deficient CD4+ T cells exhibit a strong Th1 bias, producing more IFN-γ and less IL-10 under antigen-specific immunization in vivo and Th1-polarizing conditions in vitro. Transcriptional profiling revealed early induction of Ifng and Tbx21 (T-bet) and late repression of Prdm1 (Blimp-1), indicating Blimp-1-dependent derepression of IFN-γ and reduced IL-10. Mechanistically, liver X receptor (LXR) signaling was markedly amplified, evidenced by upregulation of Abca1, Srebf1, and the oxysterol 25-hydroxycholesterol (25-HC), driven by increased Ch25h. Pharmacological modulation validated this axis: the LXR antagonist SR9238 restored Blimp-1 and IL-10 while reducing IFN-γ, whereas the LXR agonist T0901317 and exogenous 25-HC recapitulated the Abcd1-deficient phenotype. Thus, 25-HC-LXR signaling suppresses Blimp-1, enforcing Th1 polarization in Abcd1-deficient CD4+ T cells. These findings define an immunometabolic link between peroxisomal lipid metabolism and T cell differentiation and highlight the 25-HC-LXR-Blimp-1 axis as a mechanistic link regulating CD4+ T-cell polarization, with potential relevance to X-ALD-associated neuroinflammation.
2026-06-01 | Nervonic acid and the long arc of therapeutic hope in X-linked adrenoleukodystrophy
The history of X-linked Adrenoleukodystrophy (ALD) is, at its core, a story of both serendipity and persistence - of scientists following biochemical clues from the accidental discovery of very long chain fatty acids (VLCFA) to molecular precision, and of clinicians striving to translate those insights into meaningful therapies. The emergence of nervonic acid as a potential therapeutic strategy must be understood within this broader trajectory, one that has repeatedly oscillated between optimism and limitation.
gene therapies
2026-06-25 | Peroxisomal disorders - incidences in Sweden.
Incidence calculations are crucial for understanding rare disorders, improving healthcare, and public health planning. Our study presents the incidence of peroxisomal disorders in Sweden. All patients diagnosed between 1985 and 2024 at the two existing laboratories, which determine very long-chain fatty acids (VLCFA), phytanic, pristanic, and L-pipecolic acid in plasma, and plasmalogens in erythrocytes, were included in the study. Specifically, the incidence of X-linked adrenoleukodystrophy (X-ALD) is essential for evaluating its inclusion in the national neonatal screening for inborn diseases. Since the incidence of these disorders remained almost constant over the last 20 years of the study, these data were used for calculations. The incidence for the entire cohort (2005-2024) was 1:29,100, excluding female carriers of X-ALD. The most common subgroup was hemizygous X-ALD, with an incidence of 1:65,100, followed by peroxisomal biogenesis disorders (PBDs; Zellweger spectrum disorders) at 1:73,800. These incidences align with other estimates for clinically detected patients, but not for X-ALD detected through neonatal screening, where the incidence is at least three times higher. This discrepancy is partly explained by the discovery of genetic variants of uncertain significance. Over the years, the age at diagnosis and survival time for PBDs have increased, indicating heightened awareness of attenuated forms and improved supportive treatment.
2026-04-26 | Clinical, biochemical and genetic profiling of X-linked adrenoleukodystrophy in Egyptian pediatric patients: a hospital-based study
Abstract Background X-linked adrenoleukodystrophy, the most common peroxisomal disorder, is caused by ABCD1 gene mutations. This genetic disorder is characterized by the defective degradation of very long-chain fatty acids. This study aimed to assess the frequency, clinical spectrum, and molecular background of X-linked adrenoleukodystrophy among a group of Egyptian pediatric patients with clinical suspicion of peroxisomal disorder. Subjects and methods This study included 120 high-risk Egyptian children presented to Cairo University Children’s Hospital (CUCH) with the clinical suspicion of peroxisomal disorder. X-linked adrenoleukodystrophy diagnosis was confirmed by the very long-chain fatty acids testing using gas chromatography/mass spectrometry followed by sequencing of the ABCD1 gene in patients with abnormal very long-chain fatty acids results. Results 6/120(5%) patients (from 4 unrelated families) had a high level of very long-chain fatty acids. The cerebral phenotype was the most common presentation, and white matter demyelination was the most common radiological finding. Three ABCD1 gene pathogenic variants (c.293 C > T (p.Ser98Leu), c.1511T > C (p.Leu504Pro) and c.1415_1416del p.(Gln472Argfs*83)) had been detected in 5 patients and one de novo likely pathogenic variant c.1511T > C (p.Leu504Pro) had been detected in one patient. Conclusions Epidemiological studies regarding the prevalence and genetic basis of peroxisomal disorders among Egyptian children are currently scarce. In our recent study, we investigated the frequency of these disorders within a group of suspected cases.
2026-01-19 | Late-Onset X-linked Adrenoleukodystrophy: A Rare Cause of Progressive Spastic Paraparesis.
X-linked adrenoleukodystrophy (X-ALD) is an uncommon peroxisomal disorder that can manifest in adult women with slowly progressive motor symptoms that often mimic hereditary spastic paraplegia, contributing to delayed diagnosis. We report the case of a 64-year-old woman with a long history of worsening gait impairment who had previously undergone spinal surgery without clinical benefit. She exhibited a spastic paraparesis with upper motor neuron features, and neuroimaging demonstrated white matter abnormalities in the brain with no structural explanation in the spine. Extensive laboratory testing excluded infectious, autoimmune, and metabolic causes. Biochemical evaluation revealed elevated very-long-chain fatty acids, raising suspicion for X-ALD, and genetic testing confirmed a heterozygous ABCD1 c.1849C>T (p.R617C) pathogenic variant. This case highlights the need to consider X-ALD in women presenting with unexplained progressive spastic paraparesis, emphasizing the value of timely biochemical and genetic evaluation to achieve an accurate diagnosis and provide appropriate guidance for affected families.
2026-01-16 | Congenital Inborn Errors of Metabolism: Clinical and Imaging Pearls.
Pediatric neurometabolic imaging is a complex field of pediatric neuroradiology. There are key clinical and imaging features that help the radiologist narrow the differential diagnosis. The first part of this review provides an overview of the current system used for classification of metabolic disorders, focusing on the clinical and imaging features that narrow the differential diagnosis. These features include classifications based on organelle dysfunction, laboratory markers, clinical presentation, and imaging patterns. In the second part of this review, nine pediatric neurometabolic disorders are described on the basis of their clinical and imaging features. These disorders are maple syrup urine disease, Alexander disease, X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, mitochondrial encephalopathy with lactic acidosis and strokelike episodes, nonketotic hyperglycinemia, Zellweger spectrum disorder, and Leigh syndrome. ©RSNA, 2025 Supplemental material is available for this article.
2026-01-13 | O-10 ABCD1 GENE MUTATION IN AN IRANIAN FAMILY WITH X-LINKED ADRENOLEUKODYSTROPHY AND DIVERSE CLINICAL MANIFESTATIONS
Abstract Introduction A hereditary condition known as X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene, which is found at the Xq28 locus. This gene produces a transporter protein that imports very long-chain fatty acids into peroxisomes. ALDP dysfunction causes high amounts of very-long-chain saturated fatty acids (VLCFAs) in the blood and tissues, resulting in the development of ALD. Given the wide range of symptom severity seen in X-ALD, this study aims to understand the clinical manifestations associated with different mutations in the ABCD1 gene among Iranian family with several patients. Clinical Case A 42-year-old male proband, diagnosed with Addison’s disease 15 years ago following a psychotic episode, and has since been managed with glucocorticoid and mineralocorticoid replacement therapy. In 2020, approximately 15 years after the initial diagnosis, the patient developed progressive neurologic symptoms, including paresthesia, gait and balance disturbances, dysphagia, spastic paraparesis, accompanied by brainstem changes observed on neuroimaging. Taking family history and examination revealed a younger brother’s unknown death (suspected adrenal crisis) and another male sibling with motor disorders. A nephew was diagnosed with Addison’s disease and later developed limb spasms and occasional nocturia, he went under the care of a neurologist and occupational therapist. Given the clinical presentation and suspicion of adrenoleukodystrophy, plasma levels of very-long-chain fatty acids (VLCFA) were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the proband. Then the pedigree was drawn, and genomic DNA was isolated from peripheral blood samples. The ten coding exons of the ABCD1 gene were analyzed through conventional Sanger sequencing in the proband. The identified mutation in the proband was then assessed in other family members using the same sequencing method. In addition to VLCFAs imbalance, pathogenic mutation was identified in the exon 5 of the ABCD1 gene, with del AG at nucleotide 1415-1416, corresponding to the frameshift at the residue 472 (c.1415-1416delAG, p. Gln472fs). Segregation confirmed in affected males and carrier females. Conclusion Given the X-linked inheritance pattern, genetic counseling and prenatal diagnosis (PND) are essential for pregnancies in carrier females within this family, in order to prevent the recurrence of the disorder in future offspring.
antibodies
2026-05-19 | Outcomes of an optimized ciclosporin-free haploidentical HSCT protocol in paediatric patients with cerebral adrenoleukodystrophy.
Haploidentical haematopoietic stem cell transplantation (haplo-HSCT) expands donor availability for cerebral adrenoleukodystrophy (cALD). However, conventional graft-versus-host disease (GVHD) prophylaxis based on calcineurin inhibitors like ciclosporin (CsA) poses a potential neurotoxicity risk that may exacerbate neurological injury. We retrospectively analysed 26 cALD patients who underwent haplo-HSCT with an optimized ciclosporin-free GVHD prophylaxis regimen consisting of anti-thymocyte globulin (ATG; 4 mg/kg), post-transplant cyclophosphamide (PTCy) and mycophenolate mofetil. Neutrophil and platelet engraftment each occurred at a median of 15 days (ranges, 13-26 and 9-33 days respectively). The cumulative incidence (CI) of grades II-IV acute GVHD by day 100 was 18.49% ± 8.37%, and the 3-year CI of moderate-to-severe chronic GVHD was 9.32% ± 6.28%. After a median follow-up of 29 months, overall survival was 90.4% ± 6.6% and major functional disability-free survival was 69.0% ± 9.1%. Post-transplantation, plasma C26:0 levels and the C24:0/C22:0 and C26:0/C22:0 ratios were markedly reduced. Magnetic resonance imaging (MRI) at a mean of 7.3 ± 5.9 months post-HSCT showed largely preserved LOES scores without significant progression. Our experience supports the safety and efficacy of this optimized ciclosporin-free haplo-HSCT approach for patients with cALD, warranting further validation in prospective studies.
2025-02-07 | Bodyweight and Absolute Lymphocyte Count-Based Dosing of Rabbit Anti-Thymocyte Globulin Results in Early CD4+ Immune Reconstitution in Patients with Inborn Errors of Metabolism Undergoing Umbilical Cord Blood Transplantation.
Rabbit anti-thymocyte globulin (rATG) decreases the risk of graft failure and graft-versus-host disease (GvHD) in a setting of allogenic hematopoietic cell transplantation (HCT) but has highly variable pharmacokinetics. Recently, it was shown that a dosing nomogram based on recipient bodyweight and absolute lymphocyte count reduced rATG overexposure which led to faster immune reconstitution. The aim of this study is to evaluate the feasibility and benefits of using a rATG dosing nomogram to achieve early CD4+ immune reconstitution in pediatric patients with inborn errors of metabolism (IEM) undergoing umbilical cord blood transplantation. The rATG dosing nomogram in pediatric patients with IEM receiving an umbilical cord blood transplant with busulfan based myeloablative conditioning at the University of Minnesota Masonic Children's Hospital was used prospectively since 2017. The primary endpoint was CD4+ immune reconstitution (>50 CD4+ T-cells/mL) within 100 days after HCT. Secondary endpoints included overall survival, graft failure, acute and chronic GvHD, and viral reactivations RESULTS: 27 patients were included in the study. Median follow-up time was 31 months (IQR 22 to 38) and median age was 1.5 years (IQR 0.7 to 3.9). The underlying disease was Hurler syndrome in 17 (63%), Hunter syndrome in 4 (15%) and cerebral Adrenoleukodystrophy in 4 (15%) patients, two patients were transplanted for other IEM. The CD4+ recovery (>50 CD4+ T-cells/mL) at 100 days post HCT was reached in 22 (85%) of 26 patients. Overall survival was 83% (95% CI 67% to 100%). No graft failure was observed. Two (7%) patients developed acute GvHD grade II to IV and no patients had chronic GvHD. Six patients (22%) had cytomegalovirus viremia. One patient had Epstein-Barr virus reactivation requiring treatment. In patients with IEM individualized dosing of rATG was associated with a robust and early CD4+ immune reconstitution, with no graft failures and low GvHD incidence.
2024-10-28 | A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets.
X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development. We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice. Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-knockout mice displayed more cerebral demyelination, blood-brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity. Our results suggest loss of Abcd1 function in mice predisposes to more severe blood-brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2025;97:296-312.
2024-08-07 | Targeting VEGF-mediated blood-brain barrier disruption in advanced cerebral leukodystrophy.
The earliest clinical manifestation of cerebral adrenoleukodystrophy (CALD) is adrenal insufficiency (AI) characterized by elevations in ACTH and loss of cortisol. We showed high (though physiologically achievable) levels of ACTH increases endothelial permeability, increases anisotropy, and increases VEGF secretion. An ACBD1 knockout endothelial cell line had increased sensitivity to ACTH and VEGF. Inhibition of VEGF via application of anti-VEGF (bevacizumab) improved permeability. Six boys with advanced CALD were treated with bevacizumab combined with dexamethasone and ruxolitinib as immune suppressants. Most boys had decreases in gadolinium enhancement on MRI indicating improvement in endothelial function, though all boys continued to progress symptomatically.
2021-05-21 | Fulminating Autoimmune Demyelination with Optic Neuropathy in a Case of Pediatric Cerebral Adrenoleukodystrophy: Case Report and Review of the Literature
Abstract X-linked adrenoleukodystrophy (ALD) is a leukodystrophy characterized not only by progressive loss of myelin in the central nervous system due to dysmyelination, but also by acute, subacute, or chronic inflammatory demyelination. This results in the phenotypic variability of cerebral ALD (cerALD), which is independent of the genotype. In this article, we reported a fulminant presentation with fluctuating encephalopathy and visual loss in a patient with childhood onset cerALD. Brain MRI showed symmetric confluent occipito-temporal demyelination with severe disruption of the blood–brain barrier and prechiasmal optic neuropathy. The patient's cerebral spinal fluid (CSF) demonstrated an elevated IgG index, myelin basic proteins, and oligoclonal bands. Within 48 hours of receiving immunomodulating therapy, the patient's symptoms of psychomotor slowing, visual impairment, and areflexia partially resolved. High plasma C26:0 levels and high ratios of C24/22 and C26/22 were diagnostic of ALD. It has been shown that environmental factors play an important role in the inflammatory demyelination responsible for the severe phenotypes of cerALD.
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2024-06-03 | Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy.
The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1- mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients' CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention.
1985-03-20 | Electrophysiologic studies in neonatal adrenoleukodystrophy.
Recent electrophysiologic studies have focussed attention on the X-linked adrenoleukodystrophy (ALD) and its myeloneuropathic variant. No organized studies are, however, yet available on its relatively recently described neonatal variant. We conducted electroencephalographic, electroretinographic and evoked response studies in 2 patients with neonatal ALD. In one patient, an infant, initial EEG, hypsarrhythmic in waking and somewhat periodic in sleep, showed dramatic improvement on ACTH therapy accompanied with a seizure-free status. The EEG and clinical improvement, however, were temporary. No improvement occurred following pyridoxine therapy. Her electroretinogram (ERG), visual evoked responses (VERs) and far-field short latency brain-stem auditory evoked responses were also abnormal. The latter studies probably reflected photoreceptor degeneration, optic nerve involvement, cochlear and/or auditory nerve involvement respectively in neonatal ALD. The other patient, a 3.5-year-old girl, also had an EEG characterized by a moderate- to high-amplitude slow background activity and high-amplitude multifocal, generalized or periodic paroxysmal discharges, but presence of some better formed theta frequencies in background activity precluded a hypsarrhythmic label on her EEG. Her ERGs and VERs were totally extinct but in contrast to the first patient, she had clear-cut optic atrophy and retinitis pigmentosa on ophthalmological examination.
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Drug Discovery Landscape
20 orphan drug designations for X-linked adrenoleukodystrophy, including 1 approved therapy.
20 orphan drug designations for X-linked adrenoleukodystrophy, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Potassium 2-chloro-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-6-oxo-5-phenyl-6,7-dihydrothieno[2,3-b]pyridin-4-olate monohydrate | gene therapies | EMA | 2022-12-09 | — | Poxel |
Pozetaldogene ormesparvovec | gene therapies | EMA | 2022-11-11 | — | Voisin Consulting Life Sciences |
(R)-deuteropioglitazone hydrochloride | small molecules | EMA | 2022-11-10 | — | Poxel |
potassium 2-chloro-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-6-oxo- 5-phenyl-6,7-dihydrothieno[2, 3-b]pyridin-4-olate hydrate | small molecules | FDA | 2022-05-12 | — | SCYNEXIS, Inc. |
(R)-5-({4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl}methyl)-(5-2H)-1,3-thiazolidine-2,4-dione hydrochloride | small molecules | FDA | 2022-04-11 | — | Poxel S.A. |
a non-replicating recombinant adeno-associated virus serotype 9 (AAV9) gene therapy vector containing the human adenosine triphosphate (ATP)-binding cassette (ABC) sub-family D member 1 (ABCD1) gene | gene therapies | FDA | 2022-03-14 | — | SwanBio Therapeutics, Inc. |
Fingolimod | small molecules | EMA | 2021-11-12 | — | Consorcio Centro de Investigación Biomédica en Red |
2?(3,5?dichloro?4?([4?hydroxy?3?(propan?2?yl)phenyl]methyl)phenoxy)?N?methylacetamide | gene therapies | FDA | 2021-07-22 | — | Autobahn Therapeutics, Inc. |
Dimethyl fumarate | small molecules | EMA | 2020-01-09 | — | Consorcio Centro de Investigación Biomédica en Red |
generation 4 hydroxyl-terminated polyamidoamine dendrimer containing an ethylene diamine (EDA) core, amidoamine repate units, and 64 hydroxyl end groups | other | FDA | 2017-03-22 | — | Ashvattha Therapeutics |
hydroxypioglitazone | small molecules | FDA | 2017-01-30 | — | Minoryx Therapeutics S.L. |
((4-(3-benzyl-4-hydroxybenzyl)-3,5-dimethylphenoxy)methyl)phosphonic acid | small molecules | FDA | 2016-12-05 | — | Viking Therapeutics, Inc. |
5-[4-[2-(5-(1-hydroxyethyl)-2-pyridinyl)ethoxy]benzyl]-2,4-thiazolidinedione hydrochloride | small molecules | EMA | 2016-11-18 | — | Minoryx Therapeutics S.L. |
Temsirolimus | small molecules | EMA | 2016-05-30 | — | Consorcio Centro de Investigación Biomédica en Red |
Pioglitazone | small molecules | EMA | 2014-02-19 | — | Minoryx Therapeutics S.L. |
Elivaldogene autotemcel [Skysona] | gene therapies | EMA | 2012-06-06 | — | bluebird bio (Netherlands) B.V. |
elivaldogene autotemcel [Skysona] | gene therapies | FDA | 2012-04-19 | 2022-09-16 | Genetix Biotherapeutics Inc. |
sobetirome | small molecules | FDA | 2011-04-29 | — | Naftali Kaminski, MD |
S-adenosylmethionine | — | FDA | 1998-04-30 | — | Genopia USA, Inc. |
Glyceryl trioleate and glyceryl trierucate | small molecules | FDA | 1995-02-14 | — | Moser, Hugo W. M.D. |
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