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Ann B. Moser - One of the best experts on this subject based on the ideXlab platform.
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mri surveillance of boys with x linked Adrenoleukodystrophy identified by newborn screening meta analysis and consensus guidelines
Journal of Inherited Metabolic Disease, 2021Co-Authors: Ann B. Moser, Eric J Mallack, Bela R Turk, Helena Yan, Carrie Price, Michelle Demetres, Catherine Becker, Kim Hollandsworth, Laura AdangAbstract:Background Among boys with X-Linked Adrenoleukodystrophy, a subset will develop childhood cerebral Adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic Adrenoleukodystrophy. Methods To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. Results One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI. Conclusion Boys with Adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.
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mri surveillance of boys with x linked Adrenoleukodystrophy identified by newborn screening meta analysis and consensus guidelines
Journal of Inherited Metabolic Disease, 2021Co-Authors: Ann B. Moser, Eric J Mallack, Bela R Turk, Helena Yan, Carrie Price, Michelle Demetres, Catherine Becker, Kim Hollandsworth, Laura AdangAbstract:Background Among boys with X-Linked Adrenoleukodystrophy, a subset will develop childhood cerebral Adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic Adrenoleukodystrophy. Methods To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. Results One hundred twenty-three studies met inclusion criteria yielding 1,285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0 - 9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (1) Obtain an MRI between 12 and 18 months old. (2) Obtain a second MRI 1 year after baseline. (3) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (4) After 12 years, obtain an annual MRI. Conclusion Boys with Adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD. This article is protected by copyright. All rights reserved.
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brain endothelial dysfunction in cerebral Adrenoleukodystrophy
Brain, 2015Co-Authors: Patricia L Musolino, Ann B. Moser, Yi Gong, Juliet M T Snyder, Sandra Jimenez, Josephine Lok, Eric F Grabowski, Matthew P Frosch, Florian EichlerAbstract:See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked Adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral Adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral Adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy.
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bezafibrate for x linked Adrenoleukodystrophy
PLOS ONE, 2012Co-Authors: Marc Engelen, Ann B. Moser, B T Pollthe, Ronald J A Wanders, Rob Ofman, Luc Tran, Josephine Brennecke, Inge M E Dijkstra, Stephan KempAbstract:X-linked Adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene and is characterized by impaired beta-oxidation of very-long-chain fatty acids (VLCFA) and subsequent VLCFA accumulation in tissues. In adulthood X-ALD most commonly manifests as a gradually progressive myelopathy, (adrenomyeloneuropathy; AMN) without any curative or disease modifying treatments. We recently showed that bezafibrate (BF), a drug used for the treatment of hyperlipidaemia, reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1, an enzyme involved in the VLCFA synthesis. We therefore designed a proof-of-principal clinical trial to determine whether BF reduces VLCFA levels in plasma and lymphocytes of X-ALD patients. Ten males with AMN were treated with BF for 12 weeks at a dose of 400 mg daily, followed by 12 weeks of 800 mg daily. Every 4 weeks patients were evaluated for side effects and blood samples were taken for analysis. Adherence was good as indicated by a clear reduction in triglycerides. There was no reduction in VLCFA in either plasma or lymphocytes. Plasma levels of BF did not exceed 25 µmol/L. We concluded that BF, at least in the dose given, is unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients. It is unclear whether this is due to the low levels of BF reached in plasma. Our future work is aimed at the identification of highly-specific inhibitors of ELOVL1 that act at much lower concentrations than BF and are well tolerated. BF appears to have no therapeutic utility in X-ALD.
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investigational methods for peroxisomal disorders
Current protocols in human genetics, 2008Co-Authors: Ann B. Moser, Steven J Steinberg, Richard Jones, Carol W TiffanyAbstract:Peroxisomes play an important role in cellular metabolism. Defects in peroxisome assembly or of a single peroxisomal pathway are associated with a wide variety of inherited disorders, including X-linked Adrenoleukodystrophy, Zellweger spectrum disorders, rhizomelic chondrodysplasia punctata, and Refsum disease. A group of peroxisome-specific biomarkers has been shown to be characteristic of specific defects. Patients with defects in peroxisome fatty acid β-oxidation accumulate very long–chain fatty acids (VLCFA), patients with defects in plasmalogen synthesis are deficient in erythrocyte membrane plasmalogens, and patients with mislocalized pipecolic acid oxidase accumulate pipecolic acid in body fluids. This unit describes three protocols that can be used to measure plasma VLCFA, erythrocyte plasmalogens, and plasma or urine pipecolic acid by capillary gas chromatography (GC) or GC-mass spectrometry. These techniques can be used to identify the majority of patients with known neurogenetic peroxisome disorders. Curr. Protoc. Hum. Genet. 58:17.6.1-17.6.23. © 2008 by John Wiley & Sons, Inc. Keywords: very long–chain fatty acids (VLCFA); pipecolic acid; plasmalogens; gas chromatograph-mass spectrometry (GC-MS); X-linked Adrenoleukodystrophy (X-ALD); peroxisome biogenesis disorder (PBD)
Eric J Mallack - One of the best experts on this subject based on the ideXlab platform.
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mri surveillance of boys with x linked Adrenoleukodystrophy identified by newborn screening meta analysis and consensus guidelines
Journal of Inherited Metabolic Disease, 2021Co-Authors: Ann B. Moser, Eric J Mallack, Bela R Turk, Helena Yan, Carrie Price, Michelle Demetres, Catherine Becker, Kim Hollandsworth, Laura AdangAbstract:Background Among boys with X-Linked Adrenoleukodystrophy, a subset will develop childhood cerebral Adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic Adrenoleukodystrophy. Methods To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. Results One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI. Conclusion Boys with Adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.
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mri surveillance of boys with x linked Adrenoleukodystrophy identified by newborn screening meta analysis and consensus guidelines
Journal of Inherited Metabolic Disease, 2021Co-Authors: Ann B. Moser, Eric J Mallack, Bela R Turk, Helena Yan, Carrie Price, Michelle Demetres, Catherine Becker, Kim Hollandsworth, Laura AdangAbstract:Background Among boys with X-Linked Adrenoleukodystrophy, a subset will develop childhood cerebral Adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic Adrenoleukodystrophy. Methods To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. Results One hundred twenty-three studies met inclusion criteria yielding 1,285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0 - 9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (1) Obtain an MRI between 12 and 18 months old. (2) Obtain a second MRI 1 year after baseline. (3) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (4) After 12 years, obtain an annual MRI. Conclusion Boys with Adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD. This article is protected by copyright. All rights reserved.
Ronald J A Wanders - One of the best experts on this subject based on the ideXlab platform.
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intrinsic acyl coa thioesterase activity of a peroxisomal atp binding cassette transporter is required for transport and metabolism of fatty acids
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Carine De Marcos Lousa, Ronald J A Wanders, Carlo W T Van Roermund, Vincent L G Postis, Daniela Dietrich, Ian D Kerr, Stephen A Baldwin, Alison Baker, Frederica L TheodoulouAbstract:Peroxisomes are organelles that perform diverse metabolic functions in different organisms, but a common function is β-oxidation of a variety of long chain aliphatic, branched, and aromatic carboxylic acids. Import of substrates into peroxisomes for β-oxidation is mediated by ATP binding cassette (ABC) transporter proteins of subfamily D, which includes the human adrenoleukodystropy protein (ALDP) defective in X-linked Adrenoleukodystrophy (X-ALD). Whether substrates are transported as CoA esters or free acids has been a matter of debate. Using COMATOSE (CTS), a plant representative of the ABCD family, we demonstrate that there is a functional and physical interaction between the ABC transporter and the peroxisomal long chain acyl-CoA synthetases (LACS)6 and -7. We expressed recombinant CTS in insect cells and showed that membranes from infected cells possess fatty acyl-CoA thioesterase activity, which is stimulated by ATP. A mutant, in which Serine 810 is replaced by asparagine (S810N) is defective in fatty acid degradation in vivo, retains ATPase activity but has strongly reduced thioesterase activity, providing strong evidence for the biological relevance of this activity. Thus, CTS, and most likely the other ABCD family members, represent rare examples of polytopic membrane proteins with an intrinsic additional enzymatic function that may regulate the entry of substrates into the β-oxidation pathway. The cleavage of CoA raises questions about the side of the membrane where this occurs and this is discussed in the context of the peroxisomal coenzyme A (CoA) budget.
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bezafibrate for x linked Adrenoleukodystrophy
PLOS ONE, 2012Co-Authors: Marc Engelen, Ann B. Moser, B T Pollthe, Ronald J A Wanders, Rob Ofman, Luc Tran, Josephine Brennecke, Inge M E Dijkstra, Stephan KempAbstract:X-linked Adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene and is characterized by impaired beta-oxidation of very-long-chain fatty acids (VLCFA) and subsequent VLCFA accumulation in tissues. In adulthood X-ALD most commonly manifests as a gradually progressive myelopathy, (adrenomyeloneuropathy; AMN) without any curative or disease modifying treatments. We recently showed that bezafibrate (BF), a drug used for the treatment of hyperlipidaemia, reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1, an enzyme involved in the VLCFA synthesis. We therefore designed a proof-of-principal clinical trial to determine whether BF reduces VLCFA levels in plasma and lymphocytes of X-ALD patients. Ten males with AMN were treated with BF for 12 weeks at a dose of 400 mg daily, followed by 12 weeks of 800 mg daily. Every 4 weeks patients were evaluated for side effects and blood samples were taken for analysis. Adherence was good as indicated by a clear reduction in triglycerides. There was no reduction in VLCFA in either plasma or lymphocytes. Plasma levels of BF did not exceed 25 µmol/L. We concluded that BF, at least in the dose given, is unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients. It is unclear whether this is due to the low levels of BF reached in plasma. Our future work is aimed at the identification of highly-specific inhibitors of ELOVL1 that act at much lower concentrations than BF and are well tolerated. BF appears to have no therapeutic utility in X-ALD.
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conservation of targeting but divergence in function and quality control of peroxisomal abc transporters an analysis using cross kingdom expression
Biochemical Journal, 2011Co-Authors: Xuebin Zhang, Ronald J A Wanders, Carine De Marcos Lousa, Stephen A Baldwin, Alison Baker, Stephan Kemp, Rob Ofman, Nellie Schuttelensink, Frederica L TheodoulouAbstract:ABC (ATP-binding cassette) subfamily D transporters are found in all eukaryotic kingdoms and are known to play essential roles in mammals and plants; however, their number, organization and physiological contexts differ. Via cross-kingdom expression experiments, we have explored the conservation of targeting, protein stability and function between mammalian and plant ABCD transporters. When expressed in tobacco epidermal cells, the mammalian ABCD proteins ALDP (Adrenoleukodystrophy protein), ALDR (Adrenoleukodystrophy-related protein) and PMP70 (70 kDa peroxisomal membrane protein) targeted faithfully to peroxisomes and P70R (PMP70-related protein) targeted to the ER (endoplasmic reticulum), as in the native host. The Arabidopsis thaliana peroxin AtPex19_1 interacted with human peroxisomal ABC transporters both in vivo and in vitro , providing an explanation for the fidelity of targeting. The fate of X-linked Adrenoleukodystrophy disease-related mutants differed between fibroblasts and plant cells. In fibroblasts, levels of ALDP in some ‘protein-absent’ mutants were increased by low-temperature culture, in some cases restoring function. In contrast, all mutant ALDP proteins examined were stable and correctly targeted in plant cells, regardless of their fate in fibroblasts. ALDR complemented the seed germination defect of the Arabidopsis cts-1 mutant which lacks the peroxisomal ABCD transporter CTS (Comatose), but neither ALDR nor ALDP was able to rescue the defect in fatty acid β-oxidation in establishing seedlings. Taken together, our results indicate that the mechanism for trafficking of peroxisomal membrane proteins is shared between plants and mammals, but suggest differences in the sensing and turnover of mutant ABC transporter proteins and differences in substrate specificity and/or function.
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lovastatin in x linked Adrenoleukodystrophy
The New England Journal of Medicine, 2010Co-Authors: Marc Engelen, B T Pollthe, Ronald J A Wanders, Rob Ofman, Marcel G W Dijkgraaf, Michiel Hijzen, Lucinda A Van Der Wardt, Bjorn M Van Geel, Marianne De Visser, Stephan KempAbstract:To the Editor: As reported previously in the Journal, lovastatin lowers levels of very-long-chain fatty acids in plasma in patients with X-linked Adrenoleukodystrophy (X-ALD).1 Further studies did ...
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a key role for the peroxisomal abcd2 transporter in fatty acid homeostasis
American Journal of Physiology-endocrinology and Metabolism, 2009Co-Authors: Stephane Fourcade, Ronald J A Wanders, Petra A. W. Mooyer, Montserrat Ruiz, Carme Camps, Agatha Schluter, Sander M Houten, T Pampols, Georges Dacremont, M GirosAbstract:Peroxisomes are essential organelles exerting key functions in fatty acid metabolism such as the degradation of very long-chain fatty acids (VLCFAs). VLCFAs accumulate in X-Adrenoleukodystrophy (X-...
Laura Adang - One of the best experts on this subject based on the ideXlab platform.
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mri surveillance of boys with x linked Adrenoleukodystrophy identified by newborn screening meta analysis and consensus guidelines
Journal of Inherited Metabolic Disease, 2021Co-Authors: Ann B. Moser, Eric J Mallack, Bela R Turk, Helena Yan, Carrie Price, Michelle Demetres, Catherine Becker, Kim Hollandsworth, Laura AdangAbstract:Background Among boys with X-Linked Adrenoleukodystrophy, a subset will develop childhood cerebral Adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic Adrenoleukodystrophy. Methods To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. Results One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI. Conclusion Boys with Adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.
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mri surveillance of boys with x linked Adrenoleukodystrophy identified by newborn screening meta analysis and consensus guidelines
Journal of Inherited Metabolic Disease, 2021Co-Authors: Ann B. Moser, Eric J Mallack, Bela R Turk, Helena Yan, Carrie Price, Michelle Demetres, Catherine Becker, Kim Hollandsworth, Laura AdangAbstract:Background Among boys with X-Linked Adrenoleukodystrophy, a subset will develop childhood cerebral Adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic Adrenoleukodystrophy. Methods To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. Results One hundred twenty-three studies met inclusion criteria yielding 1,285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0 - 9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (1) Obtain an MRI between 12 and 18 months old. (2) Obtain a second MRI 1 year after baseline. (3) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (4) After 12 years, obtain an annual MRI. Conclusion Boys with Adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD. This article is protected by copyright. All rights reserved.
Florian Eichler - One of the best experts on this subject based on the ideXlab platform.
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hematopoietic stem cell gene therapy for cerebral Adrenoleukodystrophy
The New England Journal of Medicine, 2017Co-Authors: Florian Eichler, Patricia L Musolino, Paul J Orchard, Christine Duncan, Satiro N De Oliveira, Adrian J Thrasher, Myriam Armant, Colleen Dansereau, Troy C Lund, Weston P MillerAbstract:BACKGROUND:In X-linked Adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral Adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. METHODS:We enrolled boys with cerebral Adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. RESULTS:A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. CONCLUSIONS:Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral Adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).
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hematopoietic stem cell gene therapy for cerebral Adrenoleukodystrophy
The New England Journal of Medicine, 2017Co-Authors: Florian Eichler, Patricia L Musolino, Paul J Orchard, Christine Duncan, Satiro N De Oliveira, Adrian J Thrasher, Myriam Armant, Colleen Dansereau, Troy C Lund, Weston P MillerAbstract:BackgroundIn X-linked Adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral Adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. MethodsWe enrolled boys with cerebral Adrenoleukodystrophy in a single-group, open-label, phase 2–3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no m...
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brain endothelial dysfunction in cerebral Adrenoleukodystrophy
Brain, 2015Co-Authors: Patricia L Musolino, Ann B. Moser, Yi Gong, Juliet M T Snyder, Sandra Jimenez, Josephine Lok, Eric F Grabowski, Matthew P Frosch, Florian EichlerAbstract:See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked Adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral Adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral Adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy.