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Journal of Inherited Metabolic Disease Jul 2022X-linked adrenoleukodystrophy (ALD) results from ABCD1 gene mutations which impair Very Long Chain Fatty Acids (VLCFA; C26:0 and C24:0) peroxisomal import and...
X-linked adrenoleukodystrophy (ALD) results from ABCD1 gene mutations which impair Very Long Chain Fatty Acids (VLCFA; C26:0 and C24:0) peroxisomal import and β-oxidation, leading to accumulation in plasma and tissues. Excess VLCFA drives impaired cellular functions (e.g. disrupted mitochondrial function), inflammation, and neurodegeneration. Major disease phenotypes include: adrenomyeloneuropathy (AMN), progressive spinal cord axonal degeneration, and cerebral ALD (C-ALD), inflammatory white matter demyelination and degeneration. No pharmacological treatment is available to-date for ALD. Pioglitazone, an anti-diabetic thiazolidinedione, exerts potential benefits in ALD models. Its mechanisms are genomic (PPARγ agonism) and nongenomic (mitochondrial pyruvate carrier-MPC, long-chain acyl-CoA synthetase 4-ACSL4, inhibition). However, its use is limited by PPARγ-driven side effects (e.g. weight gain, edema). PXL065 is a clinical-stage deuterium-stabilized (R)-enantiomer of pioglitazone which lacks PPARγ agonism but retains MPC activity. Here, we show that incubation of ALD patient-derived cells (both AMN and C-ALD) and glial cells from Abcd1-null mice with PXL065 resulted in: normalization of elevated VLCFA, improved mitochondrial function, and attenuated indices of inflammation. Compensatory peroxisomal transporter gene expression was also induced. Additionally, chronic treatment of Abcd1-null mice lowered VLCFA in plasma, brain and spinal cord and improved both neural histology (sciatic nerve) and neurobehavioral test performance. Several in vivo effects of PXL065 exceeded those achieved with pioglitazone. PXL065 was confirmed to lack PPARγ agonism but retained ACSL4 activity of pioglitazone. PXL065 has novel actions and mechanisms and exhibits a range of potential benefits in ALD models; further testing of this molecule in ALD patients is warranted.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Adrenoleukodystrophy; Animals; Deuterium; Fatty Acids; Fatty Acids, Nonesterified; Inflammation; Mice; Mice, Knockout; PPAR gamma; Pioglitazone
PubMed: 35510808
DOI: 10.1002/jimd.12510 -
Molecular Genetics and Metabolism Dec 2023X-linked adrenoleukodystrophy (XALD) is the most common leukodystrophy. It has an estimated incidence of around 1/17.000, and a variable phenotype. Following the passage... (Review)
Review
X-linked adrenoleukodystrophy (XALD) is the most common leukodystrophy. It has an estimated incidence of around 1/17.000, and a variable phenotype. Following the passage of Aidens Law, New York became the first state to implement a newborn screening for XALD in 2013. Since then, 38 American states, Taiwan, and the Netherlands have included XALD in their NBS program, and Japan and Italy have ongoing pilot studies. Screening for XALD allows for early, potentially lifesaving treatment of adrenal insufficiency and cerebral demyelination but is also a complex subject, due to our limited understanding of the natural history and lack of prognostic biomarkers. Screening protocols and algorithms vary between countries and states, and results and experiences gained so far are important for the future implementation of XALD NBS in other countries. In this review, we have examined the algorithms, methodologies, and outcomes used, as well as how common challenges are addressed in countries/states that have experience using NBS for XALD. We identified 14 peer-reviewed reports on NBS for XALD. All studies presented methods for detecting XALD at birth by NBS using a combination of mass spectrometry and ABCD1 gene sequencing. This has allowed for early surveillance of presymptomatic XALD patients, and the possibility for early detection and timely treatment of XALD manifestations. Obstacles to NBS for XALD include how to deal with variants of unknown significance, whether to screen females, and the ethical concerns of an NBS for a disease where we have limited understanding of natural history and phenotype/genotype correlation.
Topics: Infant, Newborn; Female; Humans; Adrenoleukodystrophy; Neonatal Screening; Adrenal Insufficiency; New York; Genetic Association Studies
PubMed: 37979237
DOI: 10.1016/j.ymgme.2023.107734 -
Frontiers in Physiology 2022Peroxisomes are ubiquitous, oxidative subcellular organelles with important functions in cellular lipid metabolism and redox homeostasis. Loss of peroxisomal functions...
Peroxisomes are ubiquitous, oxidative subcellular organelles with important functions in cellular lipid metabolism and redox homeostasis. Loss of peroxisomal functions causes severe disorders with developmental and neurological abnormalities. Zebrafish are emerging as an attractive vertebrate model to study peroxisomal disorders as well as cellular lipid metabolism. Here, we combined bioinformatics analyses with molecular cell biology and reveal the first comprehensive inventory of peroxisomal proteins, which we systematically compared with those of human peroxisomes. Through bioinformatics analysis of all PTS1-carrying proteins, we demonstrate that lacks two well-known mammalian peroxisomal proteins (BAAT and ZADH2/PTGR3), but possesses a putative peroxisomal malate synthase (Mlsl) and verified differences in the presence of purine degrading enzymes. Furthermore, we revealed novel candidate peroxisomal proteins in , whose function and localisation is discussed. Our findings confirm the suitability of zebrafish as a vertebrate model for peroxisome research and open possibilities for the study of novel peroxisomal candidate proteins in zebrafish and humans.
PubMed: 35295584
DOI: 10.3389/fphys.2022.822509 -
Journal of Inherited Metabolic Disease Jan 2023Males with X-linked adrenoleukodystrophy (ALD) are at high risk for developing adrenal insufficiency and/or progressive leukodystrophy (cerebral ALD) at an early age....
Males with X-linked adrenoleukodystrophy (ALD) are at high risk for developing adrenal insufficiency and/or progressive leukodystrophy (cerebral ALD) at an early age. Pathogenic variants in ABCD1 result in elevated levels of very long-chain fatty acids (VLCFA), including C26:0-lysophosphatidylcholine (C26:0-LPC). Newborn screening for ALD enables prospective monitoring and timely therapeutic intervention, thereby preventing irreversible damage and saving lives. The Dutch Health Council recommended to screen only male newborns for ALD without identifying untreatable conditions associated with elevated C26:0-LPC, like Zellweger spectrum disorders and single peroxisomal enzyme defects. Here, we present the results of the SCAN (Screening for ALD in the Netherlands) study which is the first sex-specific newborn screening program worldwide. Males with ALD are identified based on elevated C26:0-LPC levels, the presence of one X-chromosome and a variant in ABCD1, in heel prick dried bloodspots. Screening of 71 208 newborns resulted in the identification of four boys with ALD who, following referral to the pediatric neurologist and confirmation of the diagnosis, enrolled in a long-term follow-up program. The results of this pilot show the feasibility of employing a boys-only screening algorithm that identifies males with ALD without identifying untreatable conditions. This approach will be of interest to countries that are considering ALD newborn screening but are reluctant to identify girls with ALD because for girls there is no direct health benefit. We also analyzed whether gestational age, sex, birth weight and age at heel prick blood sampling affect C26:0-LPC concentrations and demonstrate that these covariates have a minimal effect.
Topics: Child; Female; Humans; Male; Infant, Newborn; Adrenoleukodystrophy; Neonatal Screening; Prospective Studies; Adrenal Insufficiency; Lysophosphatidylcholines; Fatty Acids
PubMed: 36256460
DOI: 10.1002/jimd.12571 -
Survey of Ophthalmology 2019A 45-year-old white woman presented with chronic bilateral, painless, progressive, peripheral vision loss. She was found to have bilateral optic atrophy and nonenhancing...
A 45-year-old white woman presented with chronic bilateral, painless, progressive, peripheral vision loss. She was found to have bilateral optic atrophy and nonenhancing multifocal white matter lesions on magnetic resonance imaging of the brain. Cerebrospinal fluid analysis showed an elevated level of myelin basic protein. She was diagnosed as having the carrier state of X-linked adrenoleukodystrophy. X-linked adrenoleukodystrophy can mimic the clinical and radiographic features of multiple sclerosis in a female carrier. To our knowledge, this is the first case report of bilateral optic atrophy in a female X-linked adrenoleukodystrophy carrier in the English ophthalmic literature.
Topics: Adrenoleukodystrophy; Carrier State; Female; Humans; Middle Aged; Optic Atrophy
PubMed: 30521817
DOI: 10.1016/j.survophthal.2018.11.003 -
Journal of Neurology Sep 2020Epilepsy might be one of the manifestations in children with leukodystrophies, but the incidence of epilepsy in different types of leukodystrophies is unclear yet. (Observational Study)
Observational Study
BACKGROUND
Epilepsy might be one of the manifestations in children with leukodystrophies, but the incidence of epilepsy in different types of leukodystrophies is unclear yet.
METHODS
A retrospective observational cohort study was performed on children diagnosed with leukodystrophies in Peking University First Hospital from January 2004 to June 2019, and the patients were followed for 5.5 years (0.4-14.2 years) after the first visit.
RESULTS
A total of 333 patients were included. The overall incidence of epilepsy was 30.6% (102/333). Alexander disease had the highest incidence (77.3%, 51/66), followed by vanishing white matter disease (41.2%, 21/51), Canavan disease (33.3%, 1/3), megalencephalic leukoencephalopathy with subcortical cysts (32.1%, 9/28), X-linked adrenoleukodystrophy (23.1%, 3/13), Krabbe disease (18.8%, 3/16), metachromatic leukodystrophy (14.3%, 6/42), and Pelizaeus-Merzbacher disease (7.0%, 8/114). The incidence of epilepsy in leukodystrophies classified as astrocytopathies was higher than that in myelin disorders (55.9% vs. 11.2%, P < 0.001). Of the 102 patients with epilepsy, seizures were the chief complaint in 61.8% (63/102) and the initial symptom in 22.5% (23/102). The median age at seizure onset was 20.5 months (1 day-176 months). A total of 63.7% (65/102) of children were treated with antiepileptic drugs (AEDs), and the responder rate was 90.8% (59/65) at the last follow-up, including 71.2% (42/59) of children who were seizure free.
CONCLUSIONS
Epilepsy was not uncommon in children with leukodystrophies. Children with Alexander disease had the highest incidence; whereas, children with Pelizaeus-Merzbacher disease had the lowest incidence. Children with leukodystrophies classified as astrocytopathies were more prone to have epilepsy than those classified as myelin disorders. Most children with leukodystrophies who presented with epilepsy showed a good response to antiepileptic drugs.
Topics: Adrenoleukodystrophy; Child; Demyelinating Diseases; Epilepsy; Humans; Leukodystrophy, Metachromatic; Retrospective Studies
PubMed: 32388833
DOI: 10.1007/s00415-020-09889-y -
Nature Communications Apr 2023Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene...
Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation. We found widespread and sustained normalization of white matter permeability and microvascular flow. We demonstrate that ABCD1 functional bone marrow-derived cells can engraft in the cerebral vascular and perivascular space. Inverse correlation between gene dosage and lesion growth suggests that corrected cells contribute long-term to remodeling of brain microvascular function. Further studies are needed to explore the longevity of these effects.
Topics: Male; Humans; Adrenoleukodystrophy; White Matter; Hematopoietic Stem Cells; Genetic Therapy; Hematopoietic Stem Cell Transplantation
PubMed: 37019892
DOI: 10.1038/s41467-023-37262-w -
International Journal of Neonatal... Mar 2022Adrenoleukodystrophy (ALD) is a peroxisomal disorder affecting the nervous system, adrenal cortical function, and testicular function. Newborn screening for ALD has the... (Review)
Review
Adrenoleukodystrophy (ALD) is a peroxisomal disorder affecting the nervous system, adrenal cortical function, and testicular function. Newborn screening for ALD has the potential to identify patients at high risk for life-threatening adrenal crisis and cerebral ALD. The current understanding of the natural history of endocrine dysfunction is limited. Surveillance guidelines for males with ALD were developed to address the unpredictable nature of evolving adrenal insufficiency. Early recognition and management of adrenal insufficiency can prevent adrenal crisis. While testicular dysfunction in ALD is described, the natural history and complications of low testosterone, as well as the management, are not well described.
PubMed: 35323197
DOI: 10.3390/ijns8010018 -
Microbial Pathogenesis Jan 2023Viruses utilize clever strategies of interacting with various cellular factors, to remodel an organelle function, for the establishment of successful infection. In...
Viruses utilize clever strategies of interacting with various cellular factors, to remodel an organelle function, for the establishment of successful infection. In recent decades, numerous studies revealed the exploitation of the peroxisomal compartment by viruses. Epstein-Barr virus (EBV) is a ubiquitous virus linked with various cancers and neurological disorders. Till now, there is no report regarding the impacts of EBV infection on peroxisomal compartment. Therefore, we investigate the modulation of peroxisomal proteins in EBV transformed cell lines and during acute EBV infection. EBV positive Burkitt lymphoma cells of different origins as EBV transformed cells along with EBV negative Burkitt lymphoma cells as a control were used in this study. For acute EBV infection experiments, we infected peripheral blood mononuclear cells with EBV for three days. Thereafter, analyzed the gene expression patterns of peroxisomal proteins using qPCR. In addition, quantification of lipid content was performed by using fluorescence microscopy and biochemical assay. Our results revealed that, the peroxisomal proteins were distinctly regulated in EBV transformed cells and during acute EBV infection. Interestingly, PEX19 was significantly upregulated in EBV infected cells. Further, in correlation with the altered expression of peroxisomes proteins involved in lipid metabolism, the EBV transformed cells showed lower lipid abundance. Conversely, the lipid levels were increased during acute EBV infection. Our study highlights the importance of investigating the manipulation of the peroxisomal compartment by putting forward various differentially expressed proteins upon EBV infection. This study provides a base for further investigation to delve deeper into EBV and peroxisomal interactions. The future research in this direction could provide involvement of novel signaling pathways to understand molecular changes during EBV mediated pathologies.
Topics: Humans; Herpesvirus 4, Human; Burkitt Lymphoma; Epstein-Barr Virus Infections; Leukocytes, Mononuclear; Lipids
PubMed: 36526038
DOI: 10.1016/j.micpath.2022.105946 -
Orphanet Journal of Rare Diseases Sep 2021Zellweger spectrum disorders (ZSDs) are a rare, heterogenous group of autosomal recessively inherited disorders characterized by reduced peroxisomes numbers, impaired... (Review)
Review
BACKGROUND
Zellweger spectrum disorders (ZSDs) are a rare, heterogenous group of autosomal recessively inherited disorders characterized by reduced peroxisomes numbers, impaired peroxisomal formation, and/or defective peroxisomal functioning. In the absence of functional peroxisomes, bile acid synthesis is disrupted, and multisystem disease ensues with abnormalities in the brain, liver, kidneys, muscle, eyes, ears, and nervous system.
MAIN BODY
Liver disease may play an important role in morbidity and mortality, with hepatic fibrosis that can develop as early as the postnatal period and often progressing to cirrhosis within the first year of life. Because hepatic dysfunction can have numerous secondary effects on other organ systems, thereby impacting the overall disease severity, the treatment of liver disease in patients with ZSD is an important focus of disease management. Cholbam® (cholic acid), approved by the U.S. Food and Drug Administration in March 2015, is currently the only therapy approved as adjunctive treatment for patients with ZSDs and single enzyme bile acid synthesis disorders. This review will focus on the use of CA therapy in the treatment of liver disease associated with ZSDs, including recommendations for initiating and maintaining CA therapy and the limitations of available clinical data supporting its use in this patient population.
CONCLUSIONS
Cholbam is a safe and well-tolerated treatment for patients with ZSDs that has been shown to improve liver chemistries and reduce toxic bile acid intermediates in the majority of patients with ZSD. Due to the systemic impacts of hepatic damage, Cholbam should be initiated in patients without signs of advanced liver disease.
Topics: Bile Acids and Salts; Cholic Acid; Humans; Liver Diseases; United States; Zellweger Syndrome
PubMed: 34521419
DOI: 10.1186/s13023-021-01940-z