RARE DISEASE
Neonatal adrenoleukodystrophy
Neonatal adrenoleukodystrophy
Neonatal adrenoleukodystrophy
Synonyms: Intermediate PBD-ZSD, Intermediate peroxisome biogenesis disorder-Zellweger spectrum disorder, NALD
Synonyms: Intermediate PBD-ZSD, Intermediate peroxisome biogenesis disorder-Zellweger spectrum disorder, NALD
Synonyms: Intermediate PBD-ZSD, Intermediate peroxisome biogenesis disorder-Zellweger spectrum disorder, NALD
Drug discovery
0
drugs
With orphan designations
Overview
Neonatal adrenoleukodystrophy (NALD) is a rare autosomal recessive peroxisome biogenesis disorder within the Zellweger spectrum (ZSD), caused by mutations in PEX genes [1][14][17]. It presents at birth or infancy with hypotonia, seizures, adrenal insufficiency, sensorineural hearing loss, retinal degeneration, and progressive neurologic decline [1][6][17]. Diagnosis involves elevated plasma very-long-chain fatty acids (VLCFAs), reduced plasmalogens, and genetic testing [1][17]. Prognosis is poor, with most deaths occurring before age 3, though non-progressive cases may survive into childhood [1][14][17].
Burden
High mortality: 77% die in infancy/early childhood; survivors face severe disability (e.g., blindness, mobility loss) [1][14].
Multisystem morbidity: Hepatic dysfunction, adrenal crises, fractures, and neurodevelopmental regression [4][17].
Psychosocial impact: Families endure complex care needs and emotional strain due to progressive decline [4][14].
Therapies
Symptomatic management: Adrenal hormone replacement, antiepileptics, vitamin K/phytanic acid-restricted diets, and nutritional support (e.g., gastrostomy tubes) [1][14][17].
Supportive interventions: Hearing aids, cataract surgery, and physical/occupational therapy [1][14].
No disease-modifying therapies; palliative care is often required [1][3].
Categories: rare endocrine diseases, rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
327 drug discovery papers about Neonatal adrenoleukodystrophy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
327 drug discovery papers about Neonatal adrenoleukodystrophy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
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.
2026-07-22 | Peroxisomal ether lipid synthesis regulates cortical neurogenesis and maintains mitochondrial energy homeostasis in radial glial cells.
Neurogenesis is characterized by dynamic structural changes and functional remodeling of multiple organelles, which interact to form an intricate network that precisely modulates processes including neural progenitor cell self-renewal, neurogenesis, and terminal neuronal development. However, the spatiotemporal dynamics of peroxisomes and their functional contributions within this regulatory network remain incompletely defined during mammalian cortical development. Here, we found that radial glial cells (RGCs) exhibit enriched peroxisome abundance, whereas neural differentiation is associated with reduced peroxisome numbers and increased pexophagy, accompanied by the remodeling of lipid metabolic programs. Acute disruption of peroxisomes by PLAAT3-PEX11 impaired neural differentiation in the embryonic mouse cortex, while PEX7 knockout compromised neurogenic progression in human cortical organoids, supporting a conserved requirement for peroxisomal function during cortical development. Lipidomic and imaging analyses revealed that peroxisome-derived ether lipids were essential for driving neural differentiation and were specifically enriched in mitochondria. Consistently, knockdown of Gnpat, which catalyzes the initial step of ether lipid biosynthesis, reduced neural differentiation, and disrupted mitochondrial structure and function, while batyl alcohol supplementation partially restored these defects. Mechanistically, the ether lipids maintain the structural integrity of mitochondrial cristae and thereby support respiratory chain activity, which in turn promotes oxidative phosphorylation and activates the NAD+ associated signaling. Collectively, this work highlights the precise spatiotemporal regulation of neurogenesis through peroxisomal dynamics and interorganelle crosstalk and identifies ether lipids as a potential therapeutic target for neurodevelopmental disorders.
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.
2026-05-19 | 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.
2026-05-09 | A comprehensive discovery platform for ELOVL1 small-molecule inhibitors targeting very long-chain fatty acid synthesis in adrenoleukodystrophy.
Adrenoleukodystrophy (ALD or X-ALD) is a rare devastating neurological disease caused by mutations in the ATP binding cassette D1 (ABCD1) gene, the product of which is involved in the transport of very long-chain fatty acids (VLCFAs) into peroxisomes for degradation by β-oxidation. Deficiency in ABCD1 results in VLCFAs accumulation in many tissues, including the brain and spinal cord. Elevated VLCFA levels, specifically C26:0, are consistent biochemical markers of ALD and are implicated in the ALD pathogenesis. ALD disease is manifested by multiple phenotypes: the most severe cerebral disease (cerebral ALD, cALD), adrenomyeloneuropathy (AMN) and adrenal insufficiency (Addison disease). VLCFA accumulation is a hallmark of all ALD phenotypes, and reduction/normalization of VLCFA levels is an attractive approach for the treatment of all ALD manifestations. VLCFAs synthesis involves enzymes from elongase of very long-chain fatty acids (ELOVL) enzyme family with ELOVL1 being a rate-limiting enzyme in C26:0 synthesis, making ELOVL1 an attractive target for medical intervention in ALD via Substrate Reduction Therapy (SRT). In this paper, we describe the in vitro assays established to support medicinal chemistry efforts to develop small-molecule ELOVL1 inhibitors for ALD. Notably, we developed novel, breakthrough in vitro methods to monitor enzymatic and cellular ELOVL1 activity, enabling high-throughput screening (HTS) of Sanofi library collections. We successfully identified CNS-active, small-molecule ELOVL1 inhibitors shown to be efficacious in the reduction of C26:0 VLCFA levels in cells and multiple tissues, including brain and spinal cord, in animal models.
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.
2025-09-02 | Successful Treatment of Severe Hepatopulmonary Syndrome as a Rare Complication of Zellweger Spectrum Disorder.
We report the case of an 11-year-old girl who developed hepatopulmonary syndrome (HPS) as a rare complication of Zellweger spectrum disorder and was successfully treated with liver transplantation. Our patient presented with neonatal sensorineural hearing loss. Muscular hypotonia, global developmental delay, and pigmentary retinopathy in infancy led to a diagnosis of peroxisomal biogenesis disorder due to compound heterozygous PEX1 variants. Despite feeding disorder, poor weight gain, mild liver disease with subclinical coagulopathy, she had a relatively uneventful course, attaining developmental milestones till 7 years of age, when she was noted to have persistent central cyanosis (TcSO2 72%) with poor oxygen response. Echocardiogram and CT chest were normal. Liver ultrasound demonstrated mild portal hypertension with a small spleen. An ultrasound bubble test established extracardiac right-left shunting, and perfusion scintigraphy confirmed the diagnosis of HPS. Angiography showed increased portal pressure with normal right atrial pressures, ruling out porto-pulmonary hypertension. Due to the limited prognosis of HPS and inadequate oxygenation on 2 L/min oxygen supplementation, after multidisciplinary discussion, a decision was made to proceed with an orthotopic liver transplant (OLT). Seven months later, she underwent OLT, following which her saturation normalized. At age 11 years, she continues to be clinically stable without oxygen supplementation. HPS being a rare complication of liver disease, is not easily recognized in the pediatric population. OLT proved beneficial in this child with an intermediately severe disorder of peroxisomal biogenesis.
2024-10-09 | Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy.
Gene therapy with elivaldogene autotemcel (eli-cel) consisting of autologous CD34+ cells transduced with lentiviral vector containing ABCD1 complementary DNA (Lenti-D) has shown efficacy in clinical studies for the treatment of cerebral adrenoleukodystrophy. However, the risk of oncogenesis with eli-cel is unclear. We performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral-blood and bone marrow samples from patients who received eli-cel therapy in two completed phase 2-3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304) involving the patients in both ALD-102 and ALD-104. Hematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either MECOM-EVI1 (MDS and EVI1 complex protein EVI1 [ecotropic virus integration site 1], in 5 patients) or PRDM16 (positive regulatory domain zinc finger protein 16, in 1 patient). Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations (KRAS, NRAS, WT1, CDKN2A or CDKN2B, or RUNX1), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem-cell transplantation (HSCT), 4 patients remain free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML is alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS is alive and awaiting HSCT. Hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.).
proteins
2026-03-11 | MOTS-c primes adrenal cortex metabolism without directly driving steroidogenesis.
Mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c), a 16-amino acid mitochondrial-derived peptide, regulates cellular metabolism through AMPK and mTOR signaling and exerts protective effects across multiple endocrine tissues. However, its role in adrenal physiology remains unexplored. We hypothesized that MOTS-c establishes "steroidogenic readiness" by priming metabolic pathways rather than directly activating hormone synthesis. Adult male Wistar rats (n = 16) received continuous MOTS-c (0.1 μmol/24 h) or saline via subcutaneous micro-osmotic pumps for 24 hours. Adrenal tissues were analyzed using qRT-PCR, immunohistochemistry, ELISA, and RNA-sequencing. MOTS-c showed significantly higher expression in ZF/ZR vs. ZG. MOTS-c treatment did not alter classical steroidogenic genes or circulating corticosterone and aldosterone levels. RNA-seq identified 39 differentially expressed genes, notably upregulation of purinergic receptor P2ry4 (4.3-fold, P < 0.05) - a novel MOTS-C target enhancing calcium signaling. Additional changes included upregulation of Apoc4 and downregulation of stress markers Bag3 and Smurf2, mitochondrial carrier Slc25a30, and peroxisomal factor Pex11a. Gene Set Enrichment Analysis revealed inhibition of cAMP response, mitophagy, and histone deacetylation pathways, alongside activation of cell proliferation, indicating metabolic reprogramming without steroidogenic activation. MOTS-c functions as a metabolic conductor that primes adrenocortical cells for enhanced steroidogenic responsiveness without stimulating basal hormone synthesis. By upregulating calcium signaling, modulating lipid metabolism, downregulating stress-response proteins, and inhibiting mitophagy, MOTS-c establishes a preparatory metabolic state optimized for subsequent ACTH or stress stimulation. These findings reveal a novel preparatory mechanism in adrenal physiology and identify MOTS-c as a potential therapeutic target for HPA axis disorders requiring enhanced adrenal reserve capacity without basal hypercortisolemia.
2024-12-23 | PEX1G843D remains functional in peroxisome biogenesis but is rapidly degraded by the proteasome.
The PEX1/PEX6 AAA-ATPase is required for the biogenesis and maintenance of peroxisomes. Mutations in HsPEX1 and HsPEX6 disrupt peroxisomal matrix protein import and are the leading cause of Peroxisome Biogenesis Disorders (PBDs). The most common disease-causing mutation in PEX1 is the HsPEX1G843D allele, which results in a reduction of peroxisomal protein import. Here we demonstrate that in vitro the homologous yeast mutant, ScPex1G700D, reduces the stability of Pex1's active D2 ATPase domain and impairs assembly with Pex6, but can still form an active AAA-ATPase motor. In vivo, ScPex1G700D exhibits only a slight defect in peroxisome import. We generated model human HsPEX1G843D cell lines and show that PEX1G843D is rapidly degraded by the proteasome, but that induced overexpression of PEX1G843D can restore peroxisome import. Additionally, we found that the G843D mutation reduces PEX1's affinity for PEX6, and that impaired assembly is sufficient to induce degradation of PEX1WT. Lastly, we found that fusing a deubiquitinase to PEX1G843D significantly hinders its degradation in mammalian cells. Altogether, our findings suggest a novel regulatory mechanism for PEX1/PEX6 hexamer assembly and highlight the potential of protein stabilization as a therapeutic strategy for PBDs arising from the G843D mutation and other PEX1 hypomorphs.
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.
2021-08-05 | The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder
Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs—Zellweger spectrum disorder (ZSD)—is caused by mutations in peroxin genes that result in both non‐functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter‐organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.
2018-12-11 | Peroxisome-targeted Supramolecular Nanoprobes Assembled with Pyrene-labelled Peptide Amphiphiles.
Despite the versatile metabolic functions of peroxisomes such as lipid synthesis and fatty acid oxidation and their relevance to genetically inherited diseases, namely, peroxisome biogenesis disorders and peroxisomal enzyme deficiency, there is not much research on peroxisome-targeting therapeutics. Herein we present supramolecular nanostructured probes based on the self-assembly of peptide amphiphiles (PAs) having peroxisome-targeting ability in mammalian cells. The PA was designed to include the peroxisome-targeting tripeptide (SKL) and a fluorescent dye (pyrene). It was revealed that the presence of the SKL-appended carboxyl terminal group of PA, the extent of α-helical nature of the peptide block, and the fibrillar morphology of nano-assemblies affected the targeting efficiency of PA supramolecular nanoprobe. The simple modification of PAs by the peroxisome-targeting strength prediction showed an enhanced peroxisome specificity, as expected. This work provides important insights into designing subcellular organelle-targeting nanoparticles for next-generation nanomedicines.
gene therapies
2026-05-25 | Clinically relevant AAV8- PEX1 gene therapy preserves retinal integrity and function long-term in a murine model of Zellweger spectrum disorder.
Inherited retinal diseases (IRDs) are a heterogeneous group of genetic disorders that cause progressive vision loss. A subset of IRDs is associated with ubiquitously expressed genes involved in fundamental cellular processes, often resulting in multisystem disease. Among these is Zellweger spectrum disorder (ZSD), caused by pathogenic variants in PEX genes required for peroxisome biogenesis and function. There are no proven targeted disease-modifying treatments for ZSD, and it is unclear whether localized restoration of peroxisome function is sufficient to mitigate retinal degeneration. We previously demonstrated that HsPEX1 retinal gene augmentation therapy in a mouse model of mild ZSD homozygous for the murine equivalent (PEX1-p.[Gly844Asp]) of the most common deleterious allele in patients ( PEX1 -c.[2528G>A], PEX1-p.[Gly843Asp]), improved retinal electrophysiological response. Here, we present a comprehensive, dose-range evaluation of a re-designed, clinically relevant AAV8-delivered HsPEX1 subretinal gene therapy, employing expanded outcome measures. We observed a marked improvement in functional vision, retinal response, photoreceptor structure, retinal pigment epithelium integrity, subretinal inflammation, and peroxisomal metabolites, durable to the endpoint of 6 months post single subretinal injection. These studies provide preclinical proof-of-concept that localized retinal gene replacement can mitigate vision loss in peroxisome-mediated IRD.
2026-04-15 | In vivo base editing rescues liver pathophysiology and peroxisome dysfunction in a mouse model of Zellweger spectrum disorder.
Zellweger spectrum disorder (ZSD) is caused by biallelic loss-of-function variants in PEX genes required for peroxisome biogenesis, which is critical for normal cellular metabolism and signalling. The PEX1-p.G843D (c.2528G>A) allele, present in approximately 30% of individuals with ZSD, frequently results in chronic liver disease that can progress to cirrhosis, hepatocellular carcinoma and degraded neurological health. Here we report the development and application of an adenine base editing strategy to correct an established homozygous Pex1-p.G844D ZSD mouse model that manifests liver pathologies and metabolic dysfunction found in patients. Through intravenous delivery of AAV9 encoding ABE8e-V106W into both neonatal and 4-week-old mice, we achieved up to 60% pathogenic allele correction in the bulk liver. By restoring peroxisome function, base editing eliminated bulk accumulation of very long-chain and branched-chain fatty acids, and toxic C27-bile acid intermediates. Increased levels of phytanic acid, a branched-chain fatty acid that becomes harmful when accumulated, were normalized in blood, liver and brain tissue. Treatment of homozygous Pex1-p.G844D mice resulted in the progressive, dose-dependent normalization of liver transcriptomes and histopathology, accompanied by gains in body weight. Non-viral lipid nanoparticle delivery of ABE8e-V106W mRNA to 4-week-old mice also yielded correction of the Pex1-p.G844D allele in 27% of bulk liver cells. In patient-derived fibroblasts, base editing corrected >80% of PEX1-p.G843D alleles and restored peroxisome homeostasis. Genome-wide experimental and computational off-target analyses found minimal off-target editing in the mouse or human genome. Collectively, these findings suggest that liver base editing over a range of ages may benefit individuals with ZSD and provides a foundation for developing precision gene correction treatments that address the root cause of a wide range of peroxisomal disorders.
2025-12-23 | New multiplex LC-MS/MS method for lipid biomarker analysis of inherited neurodegenerative metabolic diseases.
A significant number of inherited neurodegenerative metabolic diseases (NMDs) arise from altered lipid metabolism, including impaired degradation of sphingolipids and dysfunction in organelle-related machineries involved in lipid processing and trafficking. These lipid dysregulations profoundly impact cellular membranes, signaling pathways, and myelin integrity, contributing to the complex and multisystemic clinical phenotypes characteristic of NMD, which often complicate diagnosis and delay treatment initiation. Here, we present a high-throughput, multiplex LC-MS/MS method for the analysis of an extended panel of NMD biomarkers in plasma and dried blood spots. One-step sample extraction and targeted LC-MS/MS acquisitions in positive and negative ionization allowed the simultaneous measurement of 13 diagnostic biomarkers associated with GM1 and GM2 gangliosidosis, Fabry, Gaucher, and Krabbe diseases, acid sphingomyelinase deficiency, Niemann-Pick disease type C, X-linked adrenoleukodystrophy, peroxisomal biogenesis disorders (Zellweger syndrome), metachromatic leukodystrophy, and mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratoderma (MEDNIK)/MEDNIK-like syndromes, a disorder of cellular trafficking. The method was analytically and clinically validated, confirming the diagnosis of all targeted NMDs in samples from 89 patients. Additionally, the method allowed the differentiation of X-linked adrenoleukodystrophy from peroxisomal biogenesis disorder and revealed the elevation of C18- and C16-sulfatides in Krabbe disease and MEDNIK syndrome, respectively. This multiplex assay enhances diagnostic efficiency and expands the discovery of novel biomarkers, enabling the quantification of diagnostic markers for a wide range of NMDs. The method is suitable for diagnosis of NMD, as a first- or second-tier test in neonatal screening, as confirmatory testing of variant of unknown significance in genetic panels and for longitudinal monitoring in treatable diseases.
2025-12-11 | An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy.
X-linked adrenoleukodystrophy (X-ALD) is a monogenic progressive neurodegenerative disorder, being simultaneously a systemic metabolic disease and demonstrating severe neurological manifestations with effects to the brain and spinal cord. The objective of the current review is to provide a detailed approach to adeno-associated virus (AAV)-based gene therapy for neurological manifestations of X-ALD. The development of a successful AAV-mediated gene therapy hinges on its ability to deliver ABCD1 cDNA effectively to the relevant organs and cell types, induce therapeutic levels of protein expression, and ultimately, restore normal very-long chain fatty acids (VLCFA) metabolic function. Thus, several key considerations should be addressed when designing AAV-based gene therapy for X-ALD, including the genetic background of the disease and requisite transgene expression levels, the biochemical function of the adrenoleukodystrophy protein (ALDP), the identification of target cells and their role in pathogenesis, the regulation of expression within the genetic construct, the route of administration, the selection of an AAV serotype with high tropism for the central and peripheral nervous systems, and the development of robust in vitro and in vivo models.
2025-07-07 | Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders.
Peroxisomal biogenesis disorders (PBD) are autosomal recessive diseases caused by mutations in specific PEX genes that impair peroxisome formation, leading to multi-systemic failure. Symptoms vary, even in patients with variants in the same PEX gene. Our goal is to select PEX mutations and use Drosophila to model a severity spectrum based on genotype-phenotype correlations. Utilizing KozakGAL4 (KZ) cassettes, we replaced the coding sequence of Pex with a GAL4 driver, ideal for making 'humanized' flies in which human PEX can replace the fly loss. We generated Pex2KZ and Pex16KZ lines and assessed them in various behavior assays, confirming their severe phenotypes. We performed rescue with human reference, variant PEX2 and PEX16 alleles, and phenotypic rescue was observed when human PEX2Ref or PEX16Ref were expressed in Pex2KZ or Pex16KZ flies, respectively. We identified a severity spectrum for PEX2 and PEX16 alleles, with some missense mutations exhibiting severity comparable to truncations. Alleles linked to mild PBD showed partial rescue, while variants associated with atypical ataxia could fully rescue. Drosophila humanization is an effective method to study the range of severity of PBD.
other
2025-01-18 | Zellweger spectrum disorder presenting with opsoclonus-myoclonus-ataxia syndrome: a case report on immunotherapy.
Zellweger spectrum disorder (ZSD) refers to a group of autosomal recessive genetic disorders that affect multiple organ systems and are predominantly caused by pathogenic variants in PEX genes. ZSD present a wide clinical spectrum, ranging from the most severe form, Zellweger syndrome, to the mildest form, Heimler syndrome. A 14-month-old male patient was brought to our clinic with recent-onset ocular tremors and unsteady gait. Based on the preliminary suspicion of an infection-related autoimmune disease, the patient received intravenous immunoglobulin (IVIG) and pulse steroid therapy. Although initial clinical improvement was observed in opsoclonus and ataxia, ocular symptoms later recurred. Peroxisomal profile revealed elevated plasma levels of phytanic acid, pristanic acid, and very long-chain fatty acids (C26), raising suspicion for ZSD. Consequently, dietary restrictions for very long-chain fatty acids, phytanic acid, and pristanic acid, along with vitamin supplementation (A, D, E, and K), were initiated. Molecular genetic testing identified a homozygous c.2528G > A, p.(Gly843Asp) pathogenic variant in the PEX1 gene, confirming the diagnosis. Zellweger spectrum disorder presents with a wide range of clinical manifestations. While no effective treatment currently exists, a diet restricted in very long-chain and branched-chain fatty acids, supplementation with vitamins A, D, E, and K, and bile acid therapy are commonly used. In our patient, IVIG and pulse steroid therapy were administered due to a preliminary suspicion of an autoimmune process, resulting in a short-term partial clinical response. To our knowledge, the use of immunotherapy in ZSD has not been previously reported in the literature.
2022-04-07 | Modulation of mitochondrial and inflammatory homeostasis through RIP140 is neuroprotective in an adrenoleukodystrophy mouse model.
Mitochondrial dysfunction and inflammation are at the core of axonal degeneration in several multifactorial neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. The transcriptional coregulator RIP140/NRIP1 (receptor-interacting protein 140) modulates these functions in liver and adipose tissue, but its role in the nervous system remains unexplored. Here, we investigated the impact of RIP140 in the Abcd1- mouse model of X-linked adrenoleukodystrophy (X-ALD), a genetic model of chronic axonopathy involving the convergence of redox imbalance, bioenergetic failure, and chronic inflammation. We provide evidence that RIP140 is modulated through a redox-dependent mechanism driven by very long-chain fatty acids (VLCFAs), the levels of which are increased in X-ALD. Genetic inactivation of RIP140 prevented mitochondrial depletion and dysfunction, bioenergetic failure, inflammatory dysregulation, axonal degeneration and associated locomotor disabilities in vivo in X-ALD mouse models. Together, these findings show that aberrant overactivation of RIP140 promotes neurodegeneration in X-ALD, underscoring its potential as a therapeutic target for X-ALD and other neurodegenerative disorders that present with metabolic and inflammatory dyshomeostasis.
2017-10-23 | Microglial dysfunction as a key pathological change in adrenomyeloneuropathy
Objective Mutations in ABCD1 cause the neurodegenerative disease, adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease, but its role in the spinal cord is unclear. Methods We assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. Because mutations in ABCD1 lead to incorporation of very‐long‐chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia. Results Within the spinal cord of humans and mice with AMN, upregulation of several phagocytosis‐related markers, such as MFGE8 and TREM2, precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1‐deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis, and leads to neuronal injury. Furthermore, exposure to a MFGE8‐blocking antibody reduces phagocytic activity. Interpretation Spinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. Ann Neurol 2017;82:813–827
2012-08-03 | Elevated cerebral spinal fluid cytokine levels in boys with cerebral adrenoleukodystrophy correlates with MRI severity.
X-linked adrenoleukodystrophy (ALD) is a metabolic, peroxisomal disease that results from a mutation in the ABCD1 gene. The most severe course of ALD progression is the cerebral inflammatory and demyelinating form of the disease, cALD. To date there is very little information on the cytokine mediators in the cerebral spinal fluid (CSF) of these boys. Measurement of 23 different cytokines was performed on CSF and serum of boys with cerebral ALD and patients without ALD. Significant elevations in CSF IL-8 (29.3±2.2 vs 12.8±1.1 pg/ml, p = 0.0001), IL-1ra (166±30 vs 8.6±6.5 pg/ml, p = 0.005), MCP-1 (610±47 vs 328±34 pg/ml, p = 0.002), and MIP-1b (14.2±1.3 vs 2.0±1.4 pg/ml, p<0.0001) were found in boys with cALD versus the control group. The only serum cytokine showing an elevation in the ALD group was SDF-1 (2124±155 vs 1175±125 pg/ml, p = 0.0001). The CSF cytokines of IL-8 and MCP-1b correlated with the Loes MRI severity score (p = 0.04 and p = 0.008 respectively), as well as the serum SDF-1 level (p = 0.002). Finally, CSF total protein was also significantly elevated in boys with cALD and correlated with both IL-8, MCP-1b (p = 0.0001 for both), as well as Loes MRI severity score (p = 0.0007). IL-8, IL-1ra, MCP-1, MIP-1b and CSF total protein were significantly elevated in patients with cALD; IL-8, MCP-1b, and CSF total protein levels correlated with disease severity determined by MRI. This is the largest report of CSF cytokine levels in cALD to date, and identification of these key cytokines will provide further insight into disease progression and perhaps lead to improved targeted therapies.
2007-03-09 | Immunopathogenesis of adrenoleukodystrophy: current understanding.
Adrenoleukodystrophy is a neurometabolic disease with a decreased ability to degrade very long chain fatty acids (VLCFA) and significant phenotypic variation. Unlike most neurometabolic diseases, the success of hematopoietic stem cell transplantation (HSCT) is based on acquiring a new immune system rather than enzyme replacement. VLCFA accumulation appears necessary but not sufficient for pathogenesis. Evidence for the involvement of different components of the immune system in the pathogenesis of the cerebral lesions (cellular, cytokines, humoral, and complement) is reviewed, along with both HSCT and non-HSCT immunologic approaches to treatment and future directions.
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.
2026-07-22 | Peroxisomal ether lipid synthesis regulates cortical neurogenesis and maintains mitochondrial energy homeostasis in radial glial cells.
Neurogenesis is characterized by dynamic structural changes and functional remodeling of multiple organelles, which interact to form an intricate network that precisely modulates processes including neural progenitor cell self-renewal, neurogenesis, and terminal neuronal development. However, the spatiotemporal dynamics of peroxisomes and their functional contributions within this regulatory network remain incompletely defined during mammalian cortical development. Here, we found that radial glial cells (RGCs) exhibit enriched peroxisome abundance, whereas neural differentiation is associated with reduced peroxisome numbers and increased pexophagy, accompanied by the remodeling of lipid metabolic programs. Acute disruption of peroxisomes by PLAAT3-PEX11 impaired neural differentiation in the embryonic mouse cortex, while PEX7 knockout compromised neurogenic progression in human cortical organoids, supporting a conserved requirement for peroxisomal function during cortical development. Lipidomic and imaging analyses revealed that peroxisome-derived ether lipids were essential for driving neural differentiation and were specifically enriched in mitochondria. Consistently, knockdown of Gnpat, which catalyzes the initial step of ether lipid biosynthesis, reduced neural differentiation, and disrupted mitochondrial structure and function, while batyl alcohol supplementation partially restored these defects. Mechanistically, the ether lipids maintain the structural integrity of mitochondrial cristae and thereby support respiratory chain activity, which in turn promotes oxidative phosphorylation and activates the NAD+ associated signaling. Collectively, this work highlights the precise spatiotemporal regulation of neurogenesis through peroxisomal dynamics and interorganelle crosstalk and identifies ether lipids as a potential therapeutic target for neurodevelopmental disorders.
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.
2026-05-19 | 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.
2026-05-09 | A comprehensive discovery platform for ELOVL1 small-molecule inhibitors targeting very long-chain fatty acid synthesis in adrenoleukodystrophy.
Adrenoleukodystrophy (ALD or X-ALD) is a rare devastating neurological disease caused by mutations in the ATP binding cassette D1 (ABCD1) gene, the product of which is involved in the transport of very long-chain fatty acids (VLCFAs) into peroxisomes for degradation by β-oxidation. Deficiency in ABCD1 results in VLCFAs accumulation in many tissues, including the brain and spinal cord. Elevated VLCFA levels, specifically C26:0, are consistent biochemical markers of ALD and are implicated in the ALD pathogenesis. ALD disease is manifested by multiple phenotypes: the most severe cerebral disease (cerebral ALD, cALD), adrenomyeloneuropathy (AMN) and adrenal insufficiency (Addison disease). VLCFA accumulation is a hallmark of all ALD phenotypes, and reduction/normalization of VLCFA levels is an attractive approach for the treatment of all ALD manifestations. VLCFAs synthesis involves enzymes from elongase of very long-chain fatty acids (ELOVL) enzyme family with ELOVL1 being a rate-limiting enzyme in C26:0 synthesis, making ELOVL1 an attractive target for medical intervention in ALD via Substrate Reduction Therapy (SRT). In this paper, we describe the in vitro assays established to support medicinal chemistry efforts to develop small-molecule ELOVL1 inhibitors for ALD. Notably, we developed novel, breakthrough in vitro methods to monitor enzymatic and cellular ELOVL1 activity, enabling high-throughput screening (HTS) of Sanofi library collections. We successfully identified CNS-active, small-molecule ELOVL1 inhibitors shown to be efficacious in the reduction of C26:0 VLCFA levels in cells and multiple tissues, including brain and spinal cord, in animal models.
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.
2025-09-02 | Successful Treatment of Severe Hepatopulmonary Syndrome as a Rare Complication of Zellweger Spectrum Disorder.
We report the case of an 11-year-old girl who developed hepatopulmonary syndrome (HPS) as a rare complication of Zellweger spectrum disorder and was successfully treated with liver transplantation. Our patient presented with neonatal sensorineural hearing loss. Muscular hypotonia, global developmental delay, and pigmentary retinopathy in infancy led to a diagnosis of peroxisomal biogenesis disorder due to compound heterozygous PEX1 variants. Despite feeding disorder, poor weight gain, mild liver disease with subclinical coagulopathy, she had a relatively uneventful course, attaining developmental milestones till 7 years of age, when she was noted to have persistent central cyanosis (TcSO2 72%) with poor oxygen response. Echocardiogram and CT chest were normal. Liver ultrasound demonstrated mild portal hypertension with a small spleen. An ultrasound bubble test established extracardiac right-left shunting, and perfusion scintigraphy confirmed the diagnosis of HPS. Angiography showed increased portal pressure with normal right atrial pressures, ruling out porto-pulmonary hypertension. Due to the limited prognosis of HPS and inadequate oxygenation on 2 L/min oxygen supplementation, after multidisciplinary discussion, a decision was made to proceed with an orthotopic liver transplant (OLT). Seven months later, she underwent OLT, following which her saturation normalized. At age 11 years, she continues to be clinically stable without oxygen supplementation. HPS being a rare complication of liver disease, is not easily recognized in the pediatric population. OLT proved beneficial in this child with an intermediately severe disorder of peroxisomal biogenesis.
2024-10-09 | Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy.
Gene therapy with elivaldogene autotemcel (eli-cel) consisting of autologous CD34+ cells transduced with lentiviral vector containing ABCD1 complementary DNA (Lenti-D) has shown efficacy in clinical studies for the treatment of cerebral adrenoleukodystrophy. However, the risk of oncogenesis with eli-cel is unclear. We performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral-blood and bone marrow samples from patients who received eli-cel therapy in two completed phase 2-3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304) involving the patients in both ALD-102 and ALD-104. Hematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either MECOM-EVI1 (MDS and EVI1 complex protein EVI1 [ecotropic virus integration site 1], in 5 patients) or PRDM16 (positive regulatory domain zinc finger protein 16, in 1 patient). Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations (KRAS, NRAS, WT1, CDKN2A or CDKN2B, or RUNX1), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem-cell transplantation (HSCT), 4 patients remain free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML is alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS is alive and awaiting HSCT. Hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.).
proteins
2026-03-11 | MOTS-c primes adrenal cortex metabolism without directly driving steroidogenesis.
Mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c), a 16-amino acid mitochondrial-derived peptide, regulates cellular metabolism through AMPK and mTOR signaling and exerts protective effects across multiple endocrine tissues. However, its role in adrenal physiology remains unexplored. We hypothesized that MOTS-c establishes "steroidogenic readiness" by priming metabolic pathways rather than directly activating hormone synthesis. Adult male Wistar rats (n = 16) received continuous MOTS-c (0.1 μmol/24 h) or saline via subcutaneous micro-osmotic pumps for 24 hours. Adrenal tissues were analyzed using qRT-PCR, immunohistochemistry, ELISA, and RNA-sequencing. MOTS-c showed significantly higher expression in ZF/ZR vs. ZG. MOTS-c treatment did not alter classical steroidogenic genes or circulating corticosterone and aldosterone levels. RNA-seq identified 39 differentially expressed genes, notably upregulation of purinergic receptor P2ry4 (4.3-fold, P < 0.05) - a novel MOTS-C target enhancing calcium signaling. Additional changes included upregulation of Apoc4 and downregulation of stress markers Bag3 and Smurf2, mitochondrial carrier Slc25a30, and peroxisomal factor Pex11a. Gene Set Enrichment Analysis revealed inhibition of cAMP response, mitophagy, and histone deacetylation pathways, alongside activation of cell proliferation, indicating metabolic reprogramming without steroidogenic activation. MOTS-c functions as a metabolic conductor that primes adrenocortical cells for enhanced steroidogenic responsiveness without stimulating basal hormone synthesis. By upregulating calcium signaling, modulating lipid metabolism, downregulating stress-response proteins, and inhibiting mitophagy, MOTS-c establishes a preparatory metabolic state optimized for subsequent ACTH or stress stimulation. These findings reveal a novel preparatory mechanism in adrenal physiology and identify MOTS-c as a potential therapeutic target for HPA axis disorders requiring enhanced adrenal reserve capacity without basal hypercortisolemia.
2024-12-23 | PEX1G843D remains functional in peroxisome biogenesis but is rapidly degraded by the proteasome.
The PEX1/PEX6 AAA-ATPase is required for the biogenesis and maintenance of peroxisomes. Mutations in HsPEX1 and HsPEX6 disrupt peroxisomal matrix protein import and are the leading cause of Peroxisome Biogenesis Disorders (PBDs). The most common disease-causing mutation in PEX1 is the HsPEX1G843D allele, which results in a reduction of peroxisomal protein import. Here we demonstrate that in vitro the homologous yeast mutant, ScPex1G700D, reduces the stability of Pex1's active D2 ATPase domain and impairs assembly with Pex6, but can still form an active AAA-ATPase motor. In vivo, ScPex1G700D exhibits only a slight defect in peroxisome import. We generated model human HsPEX1G843D cell lines and show that PEX1G843D is rapidly degraded by the proteasome, but that induced overexpression of PEX1G843D can restore peroxisome import. Additionally, we found that the G843D mutation reduces PEX1's affinity for PEX6, and that impaired assembly is sufficient to induce degradation of PEX1WT. Lastly, we found that fusing a deubiquitinase to PEX1G843D significantly hinders its degradation in mammalian cells. Altogether, our findings suggest a novel regulatory mechanism for PEX1/PEX6 hexamer assembly and highlight the potential of protein stabilization as a therapeutic strategy for PBDs arising from the G843D mutation and other PEX1 hypomorphs.
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.
2021-08-05 | The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder
Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs—Zellweger spectrum disorder (ZSD)—is caused by mutations in peroxin genes that result in both non‐functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter‐organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.
2018-12-11 | Peroxisome-targeted Supramolecular Nanoprobes Assembled with Pyrene-labelled Peptide Amphiphiles.
Despite the versatile metabolic functions of peroxisomes such as lipid synthesis and fatty acid oxidation and their relevance to genetically inherited diseases, namely, peroxisome biogenesis disorders and peroxisomal enzyme deficiency, there is not much research on peroxisome-targeting therapeutics. Herein we present supramolecular nanostructured probes based on the self-assembly of peptide amphiphiles (PAs) having peroxisome-targeting ability in mammalian cells. The PA was designed to include the peroxisome-targeting tripeptide (SKL) and a fluorescent dye (pyrene). It was revealed that the presence of the SKL-appended carboxyl terminal group of PA, the extent of α-helical nature of the peptide block, and the fibrillar morphology of nano-assemblies affected the targeting efficiency of PA supramolecular nanoprobe. The simple modification of PAs by the peroxisome-targeting strength prediction showed an enhanced peroxisome specificity, as expected. This work provides important insights into designing subcellular organelle-targeting nanoparticles for next-generation nanomedicines.
gene therapies
2026-05-25 | Clinically relevant AAV8- PEX1 gene therapy preserves retinal integrity and function long-term in a murine model of Zellweger spectrum disorder.
Inherited retinal diseases (IRDs) are a heterogeneous group of genetic disorders that cause progressive vision loss. A subset of IRDs is associated with ubiquitously expressed genes involved in fundamental cellular processes, often resulting in multisystem disease. Among these is Zellweger spectrum disorder (ZSD), caused by pathogenic variants in PEX genes required for peroxisome biogenesis and function. There are no proven targeted disease-modifying treatments for ZSD, and it is unclear whether localized restoration of peroxisome function is sufficient to mitigate retinal degeneration. We previously demonstrated that HsPEX1 retinal gene augmentation therapy in a mouse model of mild ZSD homozygous for the murine equivalent (PEX1-p.[Gly844Asp]) of the most common deleterious allele in patients ( PEX1 -c.[2528G>A], PEX1-p.[Gly843Asp]), improved retinal electrophysiological response. Here, we present a comprehensive, dose-range evaluation of a re-designed, clinically relevant AAV8-delivered HsPEX1 subretinal gene therapy, employing expanded outcome measures. We observed a marked improvement in functional vision, retinal response, photoreceptor structure, retinal pigment epithelium integrity, subretinal inflammation, and peroxisomal metabolites, durable to the endpoint of 6 months post single subretinal injection. These studies provide preclinical proof-of-concept that localized retinal gene replacement can mitigate vision loss in peroxisome-mediated IRD.
2026-04-15 | In vivo base editing rescues liver pathophysiology and peroxisome dysfunction in a mouse model of Zellweger spectrum disorder.
Zellweger spectrum disorder (ZSD) is caused by biallelic loss-of-function variants in PEX genes required for peroxisome biogenesis, which is critical for normal cellular metabolism and signalling. The PEX1-p.G843D (c.2528G>A) allele, present in approximately 30% of individuals with ZSD, frequently results in chronic liver disease that can progress to cirrhosis, hepatocellular carcinoma and degraded neurological health. Here we report the development and application of an adenine base editing strategy to correct an established homozygous Pex1-p.G844D ZSD mouse model that manifests liver pathologies and metabolic dysfunction found in patients. Through intravenous delivery of AAV9 encoding ABE8e-V106W into both neonatal and 4-week-old mice, we achieved up to 60% pathogenic allele correction in the bulk liver. By restoring peroxisome function, base editing eliminated bulk accumulation of very long-chain and branched-chain fatty acids, and toxic C27-bile acid intermediates. Increased levels of phytanic acid, a branched-chain fatty acid that becomes harmful when accumulated, were normalized in blood, liver and brain tissue. Treatment of homozygous Pex1-p.G844D mice resulted in the progressive, dose-dependent normalization of liver transcriptomes and histopathology, accompanied by gains in body weight. Non-viral lipid nanoparticle delivery of ABE8e-V106W mRNA to 4-week-old mice also yielded correction of the Pex1-p.G844D allele in 27% of bulk liver cells. In patient-derived fibroblasts, base editing corrected >80% of PEX1-p.G843D alleles and restored peroxisome homeostasis. Genome-wide experimental and computational off-target analyses found minimal off-target editing in the mouse or human genome. Collectively, these findings suggest that liver base editing over a range of ages may benefit individuals with ZSD and provides a foundation for developing precision gene correction treatments that address the root cause of a wide range of peroxisomal disorders.
2025-12-23 | New multiplex LC-MS/MS method for lipid biomarker analysis of inherited neurodegenerative metabolic diseases.
A significant number of inherited neurodegenerative metabolic diseases (NMDs) arise from altered lipid metabolism, including impaired degradation of sphingolipids and dysfunction in organelle-related machineries involved in lipid processing and trafficking. These lipid dysregulations profoundly impact cellular membranes, signaling pathways, and myelin integrity, contributing to the complex and multisystemic clinical phenotypes characteristic of NMD, which often complicate diagnosis and delay treatment initiation. Here, we present a high-throughput, multiplex LC-MS/MS method for the analysis of an extended panel of NMD biomarkers in plasma and dried blood spots. One-step sample extraction and targeted LC-MS/MS acquisitions in positive and negative ionization allowed the simultaneous measurement of 13 diagnostic biomarkers associated with GM1 and GM2 gangliosidosis, Fabry, Gaucher, and Krabbe diseases, acid sphingomyelinase deficiency, Niemann-Pick disease type C, X-linked adrenoleukodystrophy, peroxisomal biogenesis disorders (Zellweger syndrome), metachromatic leukodystrophy, and mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratoderma (MEDNIK)/MEDNIK-like syndromes, a disorder of cellular trafficking. The method was analytically and clinically validated, confirming the diagnosis of all targeted NMDs in samples from 89 patients. Additionally, the method allowed the differentiation of X-linked adrenoleukodystrophy from peroxisomal biogenesis disorder and revealed the elevation of C18- and C16-sulfatides in Krabbe disease and MEDNIK syndrome, respectively. This multiplex assay enhances diagnostic efficiency and expands the discovery of novel biomarkers, enabling the quantification of diagnostic markers for a wide range of NMDs. The method is suitable for diagnosis of NMD, as a first- or second-tier test in neonatal screening, as confirmatory testing of variant of unknown significance in genetic panels and for longitudinal monitoring in treatable diseases.
2025-12-11 | An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy.
X-linked adrenoleukodystrophy (X-ALD) is a monogenic progressive neurodegenerative disorder, being simultaneously a systemic metabolic disease and demonstrating severe neurological manifestations with effects to the brain and spinal cord. The objective of the current review is to provide a detailed approach to adeno-associated virus (AAV)-based gene therapy for neurological manifestations of X-ALD. The development of a successful AAV-mediated gene therapy hinges on its ability to deliver ABCD1 cDNA effectively to the relevant organs and cell types, induce therapeutic levels of protein expression, and ultimately, restore normal very-long chain fatty acids (VLCFA) metabolic function. Thus, several key considerations should be addressed when designing AAV-based gene therapy for X-ALD, including the genetic background of the disease and requisite transgene expression levels, the biochemical function of the adrenoleukodystrophy protein (ALDP), the identification of target cells and their role in pathogenesis, the regulation of expression within the genetic construct, the route of administration, the selection of an AAV serotype with high tropism for the central and peripheral nervous systems, and the development of robust in vitro and in vivo models.
2025-07-07 | Distinguishing PEX2 and PEX16 gene variant severity for mild, severe and atypical peroxisome biogenesis disorders.
Peroxisomal biogenesis disorders (PBD) are autosomal recessive diseases caused by mutations in specific PEX genes that impair peroxisome formation, leading to multi-systemic failure. Symptoms vary, even in patients with variants in the same PEX gene. Our goal is to select PEX mutations and use Drosophila to model a severity spectrum based on genotype-phenotype correlations. Utilizing KozakGAL4 (KZ) cassettes, we replaced the coding sequence of Pex with a GAL4 driver, ideal for making 'humanized' flies in which human PEX can replace the fly loss. We generated Pex2KZ and Pex16KZ lines and assessed them in various behavior assays, confirming their severe phenotypes. We performed rescue with human reference, variant PEX2 and PEX16 alleles, and phenotypic rescue was observed when human PEX2Ref or PEX16Ref were expressed in Pex2KZ or Pex16KZ flies, respectively. We identified a severity spectrum for PEX2 and PEX16 alleles, with some missense mutations exhibiting severity comparable to truncations. Alleles linked to mild PBD showed partial rescue, while variants associated with atypical ataxia could fully rescue. Drosophila humanization is an effective method to study the range of severity of PBD.
other
2025-01-18 | Zellweger spectrum disorder presenting with opsoclonus-myoclonus-ataxia syndrome: a case report on immunotherapy.
Zellweger spectrum disorder (ZSD) refers to a group of autosomal recessive genetic disorders that affect multiple organ systems and are predominantly caused by pathogenic variants in PEX genes. ZSD present a wide clinical spectrum, ranging from the most severe form, Zellweger syndrome, to the mildest form, Heimler syndrome. A 14-month-old male patient was brought to our clinic with recent-onset ocular tremors and unsteady gait. Based on the preliminary suspicion of an infection-related autoimmune disease, the patient received intravenous immunoglobulin (IVIG) and pulse steroid therapy. Although initial clinical improvement was observed in opsoclonus and ataxia, ocular symptoms later recurred. Peroxisomal profile revealed elevated plasma levels of phytanic acid, pristanic acid, and very long-chain fatty acids (C26), raising suspicion for ZSD. Consequently, dietary restrictions for very long-chain fatty acids, phytanic acid, and pristanic acid, along with vitamin supplementation (A, D, E, and K), were initiated. Molecular genetic testing identified a homozygous c.2528G > A, p.(Gly843Asp) pathogenic variant in the PEX1 gene, confirming the diagnosis. Zellweger spectrum disorder presents with a wide range of clinical manifestations. While no effective treatment currently exists, a diet restricted in very long-chain and branched-chain fatty acids, supplementation with vitamins A, D, E, and K, and bile acid therapy are commonly used. In our patient, IVIG and pulse steroid therapy were administered due to a preliminary suspicion of an autoimmune process, resulting in a short-term partial clinical response. To our knowledge, the use of immunotherapy in ZSD has not been previously reported in the literature.
2022-04-07 | Modulation of mitochondrial and inflammatory homeostasis through RIP140 is neuroprotective in an adrenoleukodystrophy mouse model.
Mitochondrial dysfunction and inflammation are at the core of axonal degeneration in several multifactorial neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. The transcriptional coregulator RIP140/NRIP1 (receptor-interacting protein 140) modulates these functions in liver and adipose tissue, but its role in the nervous system remains unexplored. Here, we investigated the impact of RIP140 in the Abcd1- mouse model of X-linked adrenoleukodystrophy (X-ALD), a genetic model of chronic axonopathy involving the convergence of redox imbalance, bioenergetic failure, and chronic inflammation. We provide evidence that RIP140 is modulated through a redox-dependent mechanism driven by very long-chain fatty acids (VLCFAs), the levels of which are increased in X-ALD. Genetic inactivation of RIP140 prevented mitochondrial depletion and dysfunction, bioenergetic failure, inflammatory dysregulation, axonal degeneration and associated locomotor disabilities in vivo in X-ALD mouse models. Together, these findings show that aberrant overactivation of RIP140 promotes neurodegeneration in X-ALD, underscoring its potential as a therapeutic target for X-ALD and other neurodegenerative disorders that present with metabolic and inflammatory dyshomeostasis.
2017-10-23 | Microglial dysfunction as a key pathological change in adrenomyeloneuropathy
Objective Mutations in ABCD1 cause the neurodegenerative disease, adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease, but its role in the spinal cord is unclear. Methods We assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. Because mutations in ABCD1 lead to incorporation of very‐long‐chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia. Results Within the spinal cord of humans and mice with AMN, upregulation of several phagocytosis‐related markers, such as MFGE8 and TREM2, precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1‐deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis, and leads to neuronal injury. Furthermore, exposure to a MFGE8‐blocking antibody reduces phagocytic activity. Interpretation Spinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. Ann Neurol 2017;82:813–827
2012-08-03 | Elevated cerebral spinal fluid cytokine levels in boys with cerebral adrenoleukodystrophy correlates with MRI severity.
X-linked adrenoleukodystrophy (ALD) is a metabolic, peroxisomal disease that results from a mutation in the ABCD1 gene. The most severe course of ALD progression is the cerebral inflammatory and demyelinating form of the disease, cALD. To date there is very little information on the cytokine mediators in the cerebral spinal fluid (CSF) of these boys. Measurement of 23 different cytokines was performed on CSF and serum of boys with cerebral ALD and patients without ALD. Significant elevations in CSF IL-8 (29.3±2.2 vs 12.8±1.1 pg/ml, p = 0.0001), IL-1ra (166±30 vs 8.6±6.5 pg/ml, p = 0.005), MCP-1 (610±47 vs 328±34 pg/ml, p = 0.002), and MIP-1b (14.2±1.3 vs 2.0±1.4 pg/ml, p<0.0001) were found in boys with cALD versus the control group. The only serum cytokine showing an elevation in the ALD group was SDF-1 (2124±155 vs 1175±125 pg/ml, p = 0.0001). The CSF cytokines of IL-8 and MCP-1b correlated with the Loes MRI severity score (p = 0.04 and p = 0.008 respectively), as well as the serum SDF-1 level (p = 0.002). Finally, CSF total protein was also significantly elevated in boys with cALD and correlated with both IL-8, MCP-1b (p = 0.0001 for both), as well as Loes MRI severity score (p = 0.0007). IL-8, IL-1ra, MCP-1, MIP-1b and CSF total protein were significantly elevated in patients with cALD; IL-8, MCP-1b, and CSF total protein levels correlated with disease severity determined by MRI. This is the largest report of CSF cytokine levels in cALD to date, and identification of these key cytokines will provide further insight into disease progression and perhaps lead to improved targeted therapies.
2007-03-09 | Immunopathogenesis of adrenoleukodystrophy: current understanding.
Adrenoleukodystrophy is a neurometabolic disease with a decreased ability to degrade very long chain fatty acids (VLCFA) and significant phenotypic variation. Unlike most neurometabolic diseases, the success of hematopoietic stem cell transplantation (HSCT) is based on acquiring a new immune system rather than enzyme replacement. VLCFA accumulation appears necessary but not sufficient for pathogenesis. Evidence for the involvement of different components of the immune system in the pathogenesis of the cerebral lesions (cellular, cytokines, humoral, and complement) is reviewed, along with both HSCT and non-HSCT immunologic approaches to treatment and future directions.
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