Materiały źródłowe

• #1

  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988840/

  Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. […] Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axonglial interactions seem pertinent to the dying-back axonopathy.

• #2 Adrenoleukodystrophy – neuroendocrine pathogenesis and redefinition of natural history | Nature Reviews Endocrinology

  https://www.nature.com/articles/nrendo.2016.90

  Adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder owing to mutations in ABCD1 with a highly complex clinical presentation. […] Cerebral ALD can occur at any age and is most likely defined by the interplay between the primary ABCD1 mutation, a multitude of genetic variants and environmental factors. […] X-Linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, which leads to the accumulation of very long-chain fatty acids in plasma and tissues. […] Virtually all men with ALD develop adrenal insufficiency and myelopathy. […] Approximately 60% of men develop progressive cerebral white matter lesions (known as cerebral ALD). […] This Review describes current knowledge on the clinical presentation, diagnosis and treatment of ALD, and highlights gaps in our knowledge of the natural history of the disease owing to an absence of large-scale prospective cohort studies.

• #3 X-linked adrenoleukodystrophy: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/x-linked-adrenoleukodystrophy/

  X-linked adrenoleukodystrophy is a genetic disorder that mainly affects the nervous system and the adrenal glands, which are located on top of each kidney. In this disorder, the fatty covering (myelin) that insulates nerves in the brain and spinal cord tends to deteriorate (a condition called demyelination). The loss of myelin reduces the ability of the nerves to relay information to the brain. In addition, damage to the outer layer of the adrenal glands (adrenal cortex) causes a shortage of certain hormones (adrenocortical insufficiency). Adrenocortical insufficiency may cause weakness, weight loss, skin changes, vomiting, and coma. […] Variants (also known as mutations) in the ABCD1 gene cause X-linked adrenoleukodystrophy. The ABCD1 gene provides instructions for producing the adrenoleukodystrophy protein (ALDP), which is involved in transporting certain fat molecules called very long-chain fatty acids (VLCFAs) into peroxisomes.

• #4 What Is Adrenoleukodystrophy? – Adrenoleukodystrophy News

  https://adrenoleukodystrophynews.com/what-is-adrenoleukodystrophy/

  Adrenoleukodystrophy (ALD), also known as X-linked adrenoleukodystrophy (X-ALD), is a rare genetic brain disorder that affects about 1 in 15,500 males (and roughly 1 in every 18,000 people if both sexes are included). The disease is characterized by the accumulation of a compound known as saturated very long chain fatty acids (VLCFAs) that, in excess, destroys myelin (a protective sheath that insulates nerve cells in the brain) and damages the adrenal glands (small hormone-producing glands that are located above the kidneys). […] ALD is caused by a mutation in the ABCD1 gene, which is located on the X-chromosome. Several mutations in the ABCD1 gene are known to cause ALD; in some patients, parts of the gene are deleted. Specific mutations or large deletions can even result in the complete absence of the protein this gene works to produce. Currently, it is not known if the type of mutation correlates with the condition’s clinical subtypes or severity.

• #5 The pathology of X-linked adrenoleukodystrophy: tissue specific changes as a clue to pathophysiology | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03105-0

  Although the pathology of X-linked adrenoleukodystrophy (ALD) is well described, it represents the end-stage of neurodegeneration. It is still unclear what cell types are initially involved and what their role is in the disease process. […] The data point to an important role for axons and glia in the pathology of both the myelopathy and leukodystrophy of ALD. In-depth pathological analyses with new techniques could help further unravel the sequence of events behind the pathology of ALD. […] The pathophysiology, i.e. how VLCFA accumulation causes tissue damage, is however still poorly understood. As VLCFA accumulation is the biochemical hallmark, it stands to reason that this plays a crucial role in the disease process. […] Degeneration of the long tracts in the spinal cord (the pyramidal tracts and dorsal columns) and of the zona fasciculata and reticularis of the adrenal cortex is the core pathology that is reflected in the main clinical syndromes.

• #6

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3988840/

  Currently the molecular basis for the clinical heterogeneity of X-linked adrenoleukodystrophy (X-ALD) is poorly understood. The genetic bases for all different phenotypic variants of X-ALD are mutations in the gene encoding the peroxisomal ATP-binding cassette (ABC) transporter, ABCD1 (formerly adrenoleukodystrophy protein, ALDP). ABCD1 transports CoA-activated very long-chain fatty acids from the cytosol into the peroxisome for degradation. […] Although the accumulation of very long-chain fatty acids appears to be essential for the pathomechanism of all phenotypes, the molecular mechanisms underlying these phenotypes are fundamentally different. Cell autonomous processes such as oxidative stress and energy shortage in axons as well as non-cell autonomous processes involving axonglial interactions seem pertinent to the dying-back axonopathy.

• #7

  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988840/

  The lack of a generalized genotypephenotype correlation in X-ALD becomes clear from three major findings: i) the same ABCD1 mutation can lead to all possible clinical phenotypes within a single kindred; ii) a complete loss of ABCD1 protein (e.g. early frameshift, nonsense mutations or large deletions); as well as iii) the most common mutation (a two-base pair deletion at c.1415_16delAG in exon 5), has been found in patients with the entire clinical spectrum of X-ALD. […] The initiation of cerebral demyelination could well be directly related to the amount of VLCFA in complex lipids, such as phosphatidylcholines, sulfatides or gangliosides. […] New and old concepts suggest that the inability to efficiently degrade VLCFA, as well as the incorporation of VLCFA into different complex lipids, is directly involved in the pathology of the cerebral inflammatory form of X-ALD.

• #8

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3988840/

  The lack of a generalized genotypephenotype correlation in X-ALD becomes clear from three major findings: i) the same ABCD1 mutation can lead to all possible clinical phenotypes within a single kindred; ii) a complete loss of ABCD1 protein (e.g. early frameshift, nonsense mutations or large deletions); as well as iii) the most common mutation (a two-base pair deletion at c.1415_16delAG in exon 5), has been found in patients with the entire clinical spectrum of X-ALD. […] The issue of mitochondrial alterations in X-ALD has been intensely investigated in the Abcd1-deficient mouse model, where impaired oxidative phosphorylation has been observed in the spinal cord but not in brain or skeletal muscle, although the relative increase in accumulation of VLCFA is comparable in these tissues. […] Given the expression pattern of ABCD1 in the nervous system, it seems likely that a non-cell autonomous process is at work. Oligodendrocyteaxonal interaction may be disturbed and constitute a primary trigger for axonal degeneration, oxidative stress and mitochondrial dysfunction in the axons of AMN patients.

• #9 Pathophysiology of X-Linked Adrenoleukodystrophy: Updates on Molecular Mechanisms

  https://www.fortunejournals.com/articles/pathophysiology-of-xlinked-adrenoleukodystrophy-updates-on-molecular-mechanisms.html

  X-ALD, an inherited monogenic metabolic disorder affecting the CNS and adrenal white matter, is caused by mutations in ABCD1 gene leading to defective fatty acid oxidation in the peroxisomes. […] A single ABCD1 mutation does not clearly explain the severity and diverse clinical spectrum of X-ALD phenotypes which suggests that not only genetic but also other modifier genes, epigenetic factors, and environmental factors play a role and contribute to neuroinflammation, mitochondrial dysfunctions, oxidative stress, and metabolic defects seen in phenotypes of ALD. […] The definitive molecular basis and underlying mechanisms of clinical variants of X-ALD are yet to be understood. However, biochemical, lipidomic, genetic, and to some extent immunologic mechanisms have been reported which contribute to pathophysiology of X-ALD and its variants.

• #10 Pathophysiology of X-Linked Adrenoleukodystrophy: Updates on Molecular Mechanisms

  https://www.fortunejournals.com/articles/pathophysiology-of-xlinked-adrenoleukodystrophy-updates-on-molecular-mechanisms.html

  Inflammation and oxidative stress are tightly intertwined and regulated by redox sensors which are regulators of inflammatory responses. […] Mutation in ABCD1 gene alone is not adequate to define clinical variants of X-ALD observed in patients. […] Modifier genes/factors such as genetics, epigenetic, and environmental modifiers may change severity and progression of a disease and thus phenotypic variation in X-ALD does not exactly depend on the genetic mutation in ABCD1. […] Inflammatory response to accumulated VLCFA occurring in the brain and spinal cord can be due to underlying genetic factors such as human leukocyte antigen (HLA) class II antigen, DRB1. […] Modifiers of epigenetic nature are DNA methylation, post-translational modifications of histones (methylation, phosphorylation, and acetylation), and post-transcriptional regulation by non-coding RNA. […] The study identified several known and novel miRNAs in postmortem brain white matter from cALD patients. […] This provides a novel line of investigation on role of miRNAs as upstream regulators of neuroinflammatory and demyelination pathways in cALD.

• #11 Easily misdiagnosed X-linked adrenoleukodystrophy | Italian Journal of Pediatrics | Full Text

  https://ijponline.biomedcentral.com/articles/10.1186/s13052-024-01669-y

  X-ALD is caused by an ATP-binding cassette protein subfamily D1 (ABCD1) gene variation, which encodes peroxisomal ATP-binding cassette-transporter adrenoleukodystrophy protein (ALDP). The dysfunctional ABCD1 causes the failure of VLCFA degradation, thus leading to the accumulation of VLCFA in tissues and plasma and mainly involving cerebral white matter, the adrenal cortex, and the spinal cord. The excessive VLCFA leading to the production of reactive oxygen species (ROS) and redox imbalance. In turn, these two effects can lead to oxidative stress, inflammation, and finally manifested as progressive inflammatory demyelination of the brain, axonal degeneration, and adrenal insufficiency. […] Although X-ALD is a monogenic genetic disease, it has significant genetic heterogeneity. Even identical twins can manifest different clinical phenotypes, thus suggesting the role of environmental factors in the pathogenesis of X-ALD with different phenotypes. Reports have demonstrated that the destruction of the blood-brain barrier (BBB) is crucial for the onset of cerebral ALD. ABCD1 variation itself can increase the permeability of brain microvascular endothelial cells and alter white matter microvascular perfusion. More importantly, the brain microvascular endothelial cells are more sensitive to ABCD1 variation under the condition of inflammation.

• #12 The genetic landscape of X-linked adrenoleukodystrophy: inheritance, m | TACG

  https://www.dovepress.com/the-genetic-landscape-of-x-linked-adrenoleukodystrophy-inheritance-mut-peer-reviewed-fulltext-article-TACG

  The observation that within one family or even among monozygotic twins one and the same mutation can lead to different X-ALD phenotypes suggests that, in addition to the primary mutation in the ABCD1 gene, other environmental or genetic factors contribute to the phenotype. […] More likely, several different genetic as well as environmental factors contribute to some extent to the phenotypic variability in X-ALD.

• #13 Pathogenesis of Adrenoleukodystrophy – DoveMed

  https://www.dovemed.com/health-topics/focused-health-topics/pathogenesis-adrenoleukodystrophy

  Adrenoleukodystrophy (ALD) is a genetic disorder characterized by the accumulation of very long-chain fatty acids (VLCFAs) in the body, leading to progressive damage to the myelin sheath of the nervous system and adrenal dysfunction. The condition is primarily caused by mutations in the ABCD1 gene on the X chromosome, which encodes a protein that transports VLCFAs into peroxisomes for degradation. […] The root cause of ALD is a mutation in the ABCD1 gene, which leads to a defective ALD protein (ALDP). ALDP is essential for the transport of VLCFAs into peroxisomes, where they undergo beta-oxidation. […] Without functional ALDP, VLCFAs accumulate in the body, particularly in the brain, adrenal cortex, and testes, leading to the pathological features of ALD. […] The buildup of VLCFAs alters the composition and properties of cell membranes, affecting their fluidity and function. This is particularly detrimental to the myelin sheath, which insulates nerve cells.

• #14

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3988840/

  The main symptoms are adrenal insufficiency, gait difficulties and bowel and bladder problems. The neurological symptoms are related to a myeloneuropathy. Adrenal insufficiency appears independent of the myeloneuropathy in about two-thirds of the AMN patients; there is no correlation between the duration or severity of endocrine dysfunction and the severity of the myeloneuropathy. […] The initiation of cerebral demyelination could well be directly related to the amount of VLCFA in complex lipids, such as phosphatidylcholines, sulfatides or gangliosides. Studies in artificial phospholipid vesicles suggest that the accumulation of VLCFA in myelin could lead to progressive destabilization of myelin sheaths and subsequent demyelination. […] New and old concepts suggest that the inability to efficiently degrade VLCFA, as well as the incorporation of VLCFA into different complex lipids, is directly involved in the pathology of the cerebral inflammatory form of X-ALD.

• #15 Pathophysiology of X-Linked Adrenoleukodystrophy: Updates on Molecular Mechanisms

  https://www.fortunejournals.com/articles/pathophysiology-of-xlinked-adrenoleukodystrophy-updates-on-molecular-mechanisms.html

  The mechanisms of conversion of pure-AMN form into AMN-cerebral form is yet to be disclosed. […] The main symptoms of AMN are adrenal insufficiency, gait difficulties, and bladder and bowel problems. […] About 30% of AMN patients develop neuroinflammation and demyelination and progress to cALD and death. […] VLCFA accumulation disrupts the integrity of the plasma membrane while interdigitating through the lipid bilayer. […] The accumulated VLCFA such as hexacosanoic acid (C26:0) directly increases steady-state ROS production depleting GSH and decreasing mitochondrial membrane potential. […] Not only unsaturated but also monounsaturated VLCFA (C26:1) fatty acid also generate ROS in X-ALD fibroblasts and generate free radicals which result in lipid peroxidation whose byproducts cause severe damage to the cells.

• #16

  https://www.jci.org/articles/view/142500

  X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease caused by mutations in ABCD1, the peroxisomal very longchain fatty acid (VLCFA) transporter. ABCD1 deficiency results in accumulation of saturated VLCFAs. […] The mechanism by which elevated VLCFAs lead to disease pathology has been difficult to determine. […] The third model is saturation status; the structure and function of VLCFAs depends on whether they are saturated or monounsaturated fatty acids. […] Exposure of ALD fibroblasts to saturated VLCFAs (C26:0) resulted in a 16-fold increase in endoplasmic reticulum (ER) stress marker XBP1, whereas exposure to the monounsaturated VLCFA C26:1 caused only a 1.3-fold increase. […] Saturation status is regulated by stearoyl-CoA desaturase-1 (SCD1), which catalyzes the synthesis of monounsaturated fatty acids by the introduction of a cis double bond at the -9 position of C16:0 or C18:0, giving rise to C16:1 and C18:1, respectively.

• #17 Pathogenesis of Adrenoleukodystrophy – DoveMed

  https://www.dovemed.com/health-topics/focused-health-topics/pathogenesis-adrenoleukodystrophy

  Excess VLCFAs can induce oxidative stress, damaging cellular structures and leading to apoptosis or cell death. […] The accumulation of VLCFAs in the nervous system triggers an immune response, leading to inflammation and further damage to the myelin sheath. […] VLCFAs also accumulate in the adrenal gland, disrupting steroid hormone biosynthesis and leading to adrenal insufficiency. […] The damage to the myelin sheath disrupts neural signaling, leading to the neurological symptoms of ALD, such as cognitive decline, motor dysfunction, and seizures. […] Impaired adrenal gland function results in reduced cortisol and aldosterone production, causing symptoms such as fatigue, weight loss, and hypotension. […] The inflammatory response in the brain can exacerbate demyelination and neuronal damage, contributing to the progressive nature of the disease. […] The pathogenesis of Adrenoleukodystrophy is complex, involving genetic mutations that lead to biochemical disruptions and a cascade of cellular and physiological effects. Understanding the mechanisms underlying ALD is crucial for developing targeted therapies and managing the disease.

• #18 Pathophysiology of X-Linked Adrenoleukodystrophy: Updates on Molecular Mechanisms

  https://www.fortunejournals.com/articles/pathophysiology-of-xlinked-adrenoleukodystrophy-updates-on-molecular-mechanisms.html

  Pathologic hallmark of cALD is inflammatory cerebral demyelination. […] The extensive inflammatory demyelinating lesions favor the parieto-occipital regions of the cerebral white matter. […] Studies exist which show that oxidative stress is the main contributor to cerebral inflammation and possibly AMN. […] Elevated levels of saturated, unbranched VLCFAs, particularly tetracosanoic (C24:0) and hexacosanoic acids (C26:0) in tissues and body fluids leads to biochemical alteration in all clinical variants of X-ALD. […] Impaired degradation of VLCFAs and deposition of VLCFAs in complex lipids are directly involved in pathology of the cerebral inflammatory form of X-ALD. […] Blood-brain integrity is important factor in X-ALD. […] While in 10-15% X-ALD patients who develop cerebral demyelination spontaneous arrest of demyelinating process occurs with unaltered blood-brain barrier, majority of cALD patients show disrupted blood-brain barrier.

• #19 Adrenoleukodystrophy: Recent Advances in Treatment and Disease Etiology

  https://www.medscape.com/viewarticle/590158

  X-linked adrenoleukodystrophy (X-ALD) is a debilitating disease caused by mutations in the ABCD1 gene. Approximately 30% of affected boys develop the progressive, neuroinflammatory phenotype, which is characterized by axonal demyelination in the CNS, neuromotor deficits and often death. […] Although the mechanism(s) of disease pathology remains elusive, it is thought that the inability of ALD patients to catabolize these fatty acids results in the formation of membrane lipids and lipidated proteins enriched in VLCFAs. […] The identification of the 'ALD gene’, ABCD1, as a likely peroxisomal transporter and not a VLCS was surprising, and this discovery raised more questions than it answered about the mechanism causing ALD. […] Thus, the role of ALDP in mediating peroxisomal VLCS activity remains a mystery. […] A potential unifying theory of ccALD etiology is proposed whereby ALDP deficiency causes subtle alterations in the ability of peroxisomes to neutralize oxidative insults. In the chronic state (5-10 years), this results in widespread oxidative damage, neuroinflammation, axonal degradation and death.

• #20 Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need

  https://www.mdpi.com/2073-4409/10/12/3427

  The neuroinflammatory process thought to drive cerebral ALD is associated with blood-brain-barrier (BBB) disruption. […] If these findings can be validated, it would be beneficial to sample patients prior to the onset of cerebral ALD to investigate if an increase in these cytokines, MMPs, and chitotriosidase occurs before, or as a consequence of, the neuroinflammation and damage to the BBB, and if it could be an early predictive biomarker for cerebral ALD.

• #21 The pathology of X-linked adrenoleukodystrophy: tissue specific changes as a clue to pathophysiology | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03105-0

  The myeloneuropathy of ALD is characterized by a dying-back axonopathy of the long tracts with subsequent atrophy. […] Axonal damage initiates in the spinal cord and results in Wallerian degeneration. […] Patients with AMN without a leukodystrophy can also develop supraspinal lesions unrelated to long-tract axonopathy. […] The leukodystrophy of ALD has been performed since the late 1890s. […] The four zones described in these pathological studies have also been correlated to quantitative magnetic resonance (MR) techniques such as spectroscopy and diffusion tensor imaging. […] Axonal degeneration therefore appears to be an early step in the sequence of pathological events in leukodystrophy lesions. […] Demyelination is the hallmark of cerebral ALD and immune dysregulation is seen as an important element in its pathology.

• #22 The pathology of X-linked adrenoleukodystrophy: tissue specific changes as a clue to pathophysiology | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03105-0

  The prominent involvement of macrophages suggests an important role for the innate immune system. […] It remains unclear whether these effector cells are monocyte- or microglia-derived. […] Microglia influence synaptic plasticity and neuron homeostasis. […] The positive results of early hematopoietic stem cell transplantation (HSCT) point towards a role for microglia. […] Microglia within spinal cord lesions were present in an activated state and treatment with LPC C26:0 resulted in clear upregulation of phagocytic markers. […] The increase in microglia in NAWM as compared to healthy controls could be due to compensatory recruitment from more distal sites. […] The role of microglia in ALD may therefore differ between brain and spinal cord. […] The mechanisms behind the spatiotemporal distribution of cerebral lesions are poorly understood.

• #23 The pathology of X-linked adrenoleukodystrophy: tissue specific changes as a clue to pathophysiology | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03105-0

  The regional vulnerability may be explained by cell heterogeneity or differential expression of ABCD1. […] The highest flow heterogeneity was found in the splenium of the corpus callosum, which is often the initial site of brain ALD lesions. […] Another poorly understood aspect of ALD pathogenesis is its tissue-specificity. […] The clinical course of ALD is well-defined, but its pathophysiology remains poorly understood. […] In both cases, axons are impacted early on in the disease. […] Both axonal degeneration and microglia dysfunction should therefore be prioritized in future research.

• #24 A novel mouse model of cerebral adrenoleukodystrophy highlights NLRP3 activity in lesion pathogenesis | bioRxiv

  https://www.biorxiv.org/content/10.1101/2023.11.07.564025v1

  Objective We sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. […] Background ALD is caused by mutations in the gene ABCD1 encoding a peroxisomal transporter. More than half of males with an ABCD1 mutation develop the cerebral phenotype (cALD). Incomplete penetrance and absence of a genotype-phenotype correlation imply a role for environmental triggers. Mechanistic studies have been limited by the absence of a cALD phenotype in the Abcd1-null mouse. […] Results MRI studies revealed T2 hyperintensities and post-gadolinium enhancement in the medial corpus callosum of cALD mice, similar to human cALD lesions. […] Interpretation This novel mouse model of cALD suggests loss of Abcd1 function predisposes to more severe cerebral inflammation, oxidative stress, fibrin deposition, and Nlrp3 pathway activation, which parallels the findings seen in humans with cALD.

• #25 Stem cell-transplantation therapy for adrenoleukodystrophy: current pe | JN

  https://www.dovepress.com/stem-cell-transplantation-therapy-for-adrenoleukodystrophy-current-per-peer-reviewed-fulltext-article-JN

  To date, the field has lacked animal models that recapitulate the dramatic inflammatory demyelination seen in boyhood cALD, thus impeding full elucidation of both the pathophysiology and transplants mechanistic effect. […] Regardless of its mechanism, allogeneic HCT is currently considered standard treatment for cALD, based on overwhelming evidence that in select patients it can prolong functional survival. However, given the lack of evidence that HCT can prevent destined cALD, as well as the significant risk profile of allogeneic transplantation, current recommendations are that this therapy be considered only for ALD patients with active cerebral disease (cALD).

• #26 Stem cell-transplantation therapy for adrenoleukodystrophy: current pe | JN

  https://www.dovepress.com/stem-cell-transplantation-therapy-for-adrenoleukodystrophy-current-per-peer-reviewed-fulltext-article-JN

  Most current evidence points to several likely pathologic mechanisms in childhood cALD. First, VLCFA accumulation over time may simply destabilize myelin structure and directly mediate its subsequent loss. With time, supranormal VLCFA-mediated myelin destabilization may expose antigen that triggers the abnormal, mononuclear cellular infiltrate observed on cALD histopathology. Intersecting with these is the effect of blood-brain barrier (BBB) disruption, as trauma has been observed to precede inflammatory cALD and active disease is nearly universally characterized by intravenous (IV) contrast enhancement. […] It is noteworthy that a common observation following successful HCT for boys with cALD is resolution of MRI contrast enhancement. This suggests reestablishment of BBB integrity, perhaps in part by intense immunomodulation, to be a key therapeutic event of HCT. Additionally, oxidative stress and damage likely contribute to cALD pathology.

• #27 Gene Therapy for Childhood Cerebral Adrenoleukodystrophy

  https://www.insights.bio/cell-and-gene-therapy-insights/journal/article/294/Gene-Therapy-for-Childhood-Cerebral-Adrenoleukodystrophy

  X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene resulting in altered expression of the peroxisomal half-transporter ALD protein. The ALD protein is needed to transport very long chain fatty acids (VLCFAs) into the peroxisome for degradation. Mutations in the ABCD1 gene impair VLCFA transport into the peroxisome leading to their accumulation in multiple tissues, most notably the nervous system and adrenal glands. Accumulation of VLCFAs in the adrenal glands can lead to cellular dysfunction by in part inhibiting the effect of ACTH on the adrenocortical cells. The pathology in the central nervous system is complex and characterized by progressive cerebral and cerebellar inflammatory demyelination. […] Gene therapy using modified autologous hematopoietic stem cells has emerged as a promising therapy for children with cALD. Gene therapy involves the insertion of a gene that is free of the defects of the disease being treated into the cellular DNA of the recipient using modified autologous stem cells. It is an attractive potential alternative to allogeneic transplant for those with cALD for multiple reasons. First, the risk for graft-versus-host disease (GVHD) and the need for related immune suppressing medications is eliminated likely decreasing the risk of transplant related mortality. Secondly, gene therapy eliminates the need to find an allogeneic stem cell donor, which may decrease the time from cALD diagnosis to the start of treatment. This is of vital importance as cALD can progress for months after successful cellular therapy. Clinical manifestations present at the start of treatment are not expected to reverse and may worsen during the initial months following therapy. This makes it important that candidates for treatment are identified early in the course of disease and begin cellular therapy as quickly as possible.

• #28 Minoryx publishes mechanism of action of leriglitazone in X-ALD in Science Translational Medicine journal

  https://www.minoryx.com/media/minoryx_publishes_mechanism_of_action_of_leriglitazone_in_x-ald_in_science_translational_medicine_journal/

  Minoryx publishes mechanism of action of leriglitazone in X-ALD in Science Translational Medicine journal 2021-06-03 […] Published results show efficacy in both adrenomyeloneuropathy (AMN) and cerebral ALD (cALD) related models. The data demonstrate the potential of leriglitazone to treat the whole spectrum of the X-linked adrenoleukodystrophy (X-ALD) condition as well as other neurodegenerative and neuroinflammatory conditions. […] The publication provides details of the molecular mechanism of action of leriglitazone, modulating multiple pathways involved in the pathophysiology of X-ALD by delaying or stopping the progression of AMN and cALD. […] The published studies show that leriglitazone modulates the key hallmarks in X-ALD in several in vitro and in vivo models. In those models, leriglitazone exerts neuroprotective and antioxidant effects, improves mitochondrial function and reduces microglial activation. Leriglitazone also increases myelin debris clearance and oligodendrocyte survival and myelination, thus promoting remyelination. Finally, leriglitazone reduces neuroinflammation and prevents the endothelial damage disrupting the blood-brain barrier (BBB) that characterizes the early stages of cALD.

• #29

  https://www.jci.org/articles/view/142500

  These findings suggest that saturation status of VLCFAs may be central to the toxic effects of VLCFAs and that promoting desaturation could be beneficial for ALD. […] We found that activation of SCD1 caused a shift in the synthesis of saturated VLCFAs toward monounsaturated VLCFAs, decreasing levels of saturated VLCFAs in ALD human fibroblasts and mouse tissues. […] These results indicate that saturated VLCFAs mediate key disease pathology in ALD and suggest that metabolic rerouting toward the monounsaturated fatty acids may open a new option toward a therapy for ALD and other peroxisomal disorders.

• #30 Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need

  https://www.mdpi.com/2073-4409/10/12/3427

  The clinical manifestations of ALD include adrenal insufficiency, myelopathy, and/or leukodystrophy. […] Clinical manifestations of the disease are most likely determined by a combination of genetic, epigenetic, and environmental factors. […] Therefore, ALD biomarkers are needed to better understand and predict the progression of the disease, as well as to serve as surrogate outcome measures for clinical trials. […] This review focuses on molecular biomarkers as they may have a (causal) role in disease development, thus providing more insight into disease pathology, since current clinical outcome measures have limitations that make performing clinical trials challenging. […] The introduction of newborn screening provides an ideal opportunity, since follow-up of newborns can begin in the asymptomatic stage of the disease.

• #31 Functional Characterization of IPSC-Derived Brain Cells as a Model for X-Linked Adrenoleukodystrophy | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143238

  Therefore, cALD and AMN IPSC-brain derived cells will possibly allow the identification of markers to predict clinical progression of this disease and gain insight into the prevention of clinical disease onset. […] The differential accumulation of saturated VLCFA (C26:0/C22:0) in these cells carry the same peroxisomal dysfunction in VLCFA suggests that in addition to the genetic defect in ABCD1 some other mechanisms contribute to the observed differences in VLCFA load between cALD OLs and AMN OLs. […] These observations indicate that both genetic (ABCD1 dysfunction based defect) and epigenetic (upregulation of ELOVL1) mechanisms contribute to the differential load of VLCFA observed in X-ALD cells. […] The mechanism for different degrees of inflammatory response between AMN Ast and cALD Ast is not known at present, indicating that cellular mechanisms of cALD Ast are predisposed to inflammatory responses as compared to AMN Ast and control Ast.

• #32 Adrenoleukodystrophy – neuroendocrine pathogenesis and redefinition of natural history | Nature Reviews Endocrinology

  https://www.nature.com/articles/nrendo.2016.90

  Such studies are necessary for the identification of new prognostic biomarkers to improve care for patients with ALD, which is particularly relevant now that newborn screening for ALD is being introduced. […] Characterization of the enzyme responsible for VLCFA synthesis in mammals and demonstration that inhibition of this enzyme is a potential therapeutic target. […] Impaired very long-chain acyl-CoA -oxidation in human X-linked adrenoleukodystrophy fibroblasts is a direct consequence of ABCD1 transporter dysfunction. […] Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture. […] Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy. […] Brain endothelial dysfunction in cerebral adrenoleukodystrophy. […] This article provided new insights into the pathophysiology of ALD.

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