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:
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.
2026-05-25 | 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.
2026-05-19 | 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.
2026-07-27 | 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.
2026-05-25 | 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.
2026-05-19 | 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.
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