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Mary L Williams - One of the best experts on this subject based on the ideXlab platform.
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abnormal barrier function in the pathogenesis of ichthyosis therapeutic implications for lipid metabolic disorders
Clinics in Dermatology, 2012Co-Authors: Mary L Williams, Kenneth R FeingoldAbstract:Abstract Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a "best attempt" by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD Syndrome) and X-linked ichthyosis reflect metabolite accumulation and deficiency of pathway product (ie, cholesterol). We validated this therapeutic approach in two CHILD Syndrome patients who failed to improve with topical cholesterol alone, but cleared with dual treatment with cholesterol plus lovastatin. In theory, the ichthyoses in other inherited lipid metabolic disorders could be treated analogously. This pathogenesis (pathway)-driven approach possesses several inherent advantages: (1) it is mechanism-specific for each disorder; (2) it is inherently safe, because natural lipids and/or approved drugs often are utilized; and (3) it should be inexpensive, and therefore it could be used widely in the developing world.
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abnormal barrier function in the pathogenesis of ichthyosis therapeutic implications for lipid metabolic disorders
Clinics in Dermatology, 2012Co-Authors: Peter M Elias, Mary L Williams, Kenneth R FeingoldAbstract:Abstract Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a "best attempt" by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD Syndrome) and X-linked ichthyosis reflect metabolite accumulation and deficiency of pathway product (ie, cholesterol). We validated this therapeutic approach in two CHILD Syndrome patients who failed to improve with topical cholesterol alone, but cleared with dual treatment with cholesterol plus lovastatin. In theory, the ichthyoses in other inherited lipid metabolic disorders could be treated analogously. This pathogenesis (pathway)-driven approach possesses several inherent advantages: (1) it is mechanism-specific for each disorder; (2) it is inherently safe, because natural lipids and/or approved drugs often are utilized; and (3) it should be inexpensive, and therefore it could be used widely in the developing world.
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peroxisomal abnormality in fibroblasts from involved skin of CHILD Syndrome case study and review of peroxisomal disorders in relation to skin disease
Archives of Dermatology, 1992Co-Authors: Soheyla Emami, William B Rizzo, Karen Hanley, Michael J Taylor, Marc E Goldyne, Mary L WilliamsAbstract:• Background and Design.— Peroxisomal deficiency has been described in a number of Syndromes characterized by chondrodysplasia punctata, including the Conradi-Hunermann (C-H) Syndrome. Because of overlapping clinical features of X-chromosome inheritance, ichthyosis, and limbreduction defects in C-H and CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) Syndromes, we examined peroxisomal content using diaminobenzidine cytochemistry and peroxisomal functions in fibroblasts from involved vs uninvolved skin of CHILD Syndrome. Results.— Fibroblasts from involved skin of a patient with CHILD Syndrome accumulated cytoplasmic lipid, visualized with the fluorescent probe, nile-red. Ultrastructurally, fibroblasts of involved skin of CHILD Syndrome accumulated lamellated membrane and vacuolar structures. By diaminobenzidine ultracytochemistry, fewer peroxisomes were present. Moreover, the activities of two peroxisomal enzymes, catalase and dihydroxyacetone phosphate acyltransferase, were decreased (approximately 30% of normal). However, peroxisomal oxidation of very-long-chain and branched-chain fatty acids was preserved. Moreover, plasma very-long-chain fatty acids, plasma phytanic acid, and erythrocyte plasmalogen content were normal. Conclusions.— The CHILD, C-H, and rhizomelic chondrodysplasia punctata Syndromes are all characterized by ichthyosis, chondrodysplasia punctata, and limb defects, as well as peroxisomal deficiency. Thus, these Syndromes may be related pathogenically. Because peroxisomes are involved in prostaglandin metabolism, peroxisomal deficiency may directly contribute to the previously reported alterations in prostaglandin metabolism in fibroblasts of involved skin of fibroblasts. ( Arch Dermatol. 1992;128:1213-1222)
Kenneth R Feingold - One of the best experts on this subject based on the ideXlab platform.
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abnormal barrier function in the pathogenesis of ichthyosis therapeutic implications for lipid metabolic disorders
Clinics in Dermatology, 2012Co-Authors: Mary L Williams, Kenneth R FeingoldAbstract:Abstract Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a "best attempt" by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD Syndrome) and X-linked ichthyosis reflect metabolite accumulation and deficiency of pathway product (ie, cholesterol). We validated this therapeutic approach in two CHILD Syndrome patients who failed to improve with topical cholesterol alone, but cleared with dual treatment with cholesterol plus lovastatin. In theory, the ichthyoses in other inherited lipid metabolic disorders could be treated analogously. This pathogenesis (pathway)-driven approach possesses several inherent advantages: (1) it is mechanism-specific for each disorder; (2) it is inherently safe, because natural lipids and/or approved drugs often are utilized; and (3) it should be inexpensive, and therefore it could be used widely in the developing world.
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abnormal barrier function in the pathogenesis of ichthyosis therapeutic implications for lipid metabolic disorders
Clinics in Dermatology, 2012Co-Authors: Peter M Elias, Mary L Williams, Kenneth R FeingoldAbstract:Abstract Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a "best attempt" by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD Syndrome) and X-linked ichthyosis reflect metabolite accumulation and deficiency of pathway product (ie, cholesterol). We validated this therapeutic approach in two CHILD Syndrome patients who failed to improve with topical cholesterol alone, but cleared with dual treatment with cholesterol plus lovastatin. In theory, the ichthyoses in other inherited lipid metabolic disorders could be treated analogously. This pathogenesis (pathway)-driven approach possesses several inherent advantages: (1) it is mechanism-specific for each disorder; (2) it is inherently safe, because natural lipids and/or approved drugs often are utilized; and (3) it should be inexpensive, and therefore it could be used widely in the developing world.
Amy S Paller - One of the best experts on this subject based on the ideXlab platform.
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the role of abnormalities in the distal pathway of cholesterol synthesis in the congenital hemidysplasia with ichthyosiform erythroderma and limb defects CHILD Syndrome
Biochimica et Biophysica Acta, 2014Co-Authors: Mark A Seeger, Amy S PallerAbstract:CHILD Syndrome (Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects) is a rare X-linked dominant ichthyotic disorder. CHILD Syndrome results from loss of function mutations in the NSDHL gene, which leads to inhibition of cholesterol synthesis and accumulation of toxic metabolic intermediates in affected tissues. The CHILD Syndrome skin is characterized by plaques topped by waxy scales and a variety of developmental defects in extracutaneous tissues, particularly limb hypoplasia or aplasia. Strikingly, these alterations are commonly segregated to either the right or left side of the body midline with little to no manifestations on the ipsilateral side. By understanding the underlying disease mechanism of CHILD Syndrome, a pathogenesis-based therapy has been developed that successfully reverses the CHILD Syndrome skin phenotype and has potential applications to the treatment of other ichthyoses. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.
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pathogenesis based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism
Journal of Investigative Dermatology, 2011Co-Authors: Amy S Paller, Maurice A M Van Steensel, Marina Rodriguezmartin, Jennifer Sorrell, Candrice Heath, Debra Crumrine, Michel Van Geel, Antonio Noda Cabrera, Peter M EliasAbstract:Identification of the underlying genetic, cellular, and biochemical basis of lipid metabolic disorders provides an opportunity to deploy corrective, mechanism-targeted, topical therapy. We assessed this therapeutic approach in two patients with Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects (CHILD) Syndrome, an X-linked dominant disorder of distal cholesterol metabolism. On the basis of the putative pathogenic role of both pathway-product deficiency of cholesterol and accumulation of toxic metabolic intermediates, we assessed the efficacy of combined therapy with lovastatin and cholesterol. We also evaluated the basis for the poorly understood, unique lateralization of the cutaneous and bone malformations of CHILD Syndrome by analyzing gene activation in abnormal and unaffected skin. Ultrastructural analysis of affected skin showed evidence of both cholesterol depletion and toxic metabolic accumulation. Topical treatment with lovastatin/cholesterol (but not cholesterol alone) virtually cleared skin lesions by 3 months, accompanied by histological and ultrastructural normalization of epidermal structure and lipid secretion. The unusual lateralization of abnormalities in CHILD Syndrome reflects selective clearance of keratinocytes and fibroblasts that express the mutant allele from the unaffected side. These findings validate pathogenesis-based therapy that provides the deficient end product and prevents accumulation of toxic metabolites, an approach of potential utility for other syndromic lipid metabolic disorders.
Peter M Elias - One of the best experts on this subject based on the ideXlab platform.
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abnormal barrier function in the pathogenesis of ichthyosis therapeutic implications for lipid metabolic disorders
Clinics in Dermatology, 2012Co-Authors: Peter M Elias, Mary L Williams, Kenneth R FeingoldAbstract:Abstract Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a "best attempt" by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD Syndrome) and X-linked ichthyosis reflect metabolite accumulation and deficiency of pathway product (ie, cholesterol). We validated this therapeutic approach in two CHILD Syndrome patients who failed to improve with topical cholesterol alone, but cleared with dual treatment with cholesterol plus lovastatin. In theory, the ichthyoses in other inherited lipid metabolic disorders could be treated analogously. This pathogenesis (pathway)-driven approach possesses several inherent advantages: (1) it is mechanism-specific for each disorder; (2) it is inherently safe, because natural lipids and/or approved drugs often are utilized; and (3) it should be inexpensive, and therefore it could be used widely in the developing world.
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pathogenesis based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism
Journal of Investigative Dermatology, 2011Co-Authors: Amy S Paller, Maurice A M Van Steensel, Marina Rodriguezmartin, Jennifer Sorrell, Candrice Heath, Debra Crumrine, Michel Van Geel, Antonio Noda Cabrera, Peter M EliasAbstract:Identification of the underlying genetic, cellular, and biochemical basis of lipid metabolic disorders provides an opportunity to deploy corrective, mechanism-targeted, topical therapy. We assessed this therapeutic approach in two patients with Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects (CHILD) Syndrome, an X-linked dominant disorder of distal cholesterol metabolism. On the basis of the putative pathogenic role of both pathway-product deficiency of cholesterol and accumulation of toxic metabolic intermediates, we assessed the efficacy of combined therapy with lovastatin and cholesterol. We also evaluated the basis for the poorly understood, unique lateralization of the cutaneous and bone malformations of CHILD Syndrome by analyzing gene activation in abnormal and unaffected skin. Ultrastructural analysis of affected skin showed evidence of both cholesterol depletion and toxic metabolic accumulation. Topical treatment with lovastatin/cholesterol (but not cholesterol alone) virtually cleared skin lesions by 3 months, accompanied by histological and ultrastructural normalization of epidermal structure and lipid secretion. The unusual lateralization of abnormalities in CHILD Syndrome reflects selective clearance of keratinocytes and fibroblasts that express the mutant allele from the unaffected side. These findings validate pathogenesis-based therapy that provides the deficient end product and prevents accumulation of toxic metabolites, an approach of potential utility for other syndromic lipid metabolic disorders.
Stephen C Somach - One of the best experts on this subject based on the ideXlab platform.
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a novel somatic mutation of the 3β hydroxysteroid dehydrogenase gene in sporadic cutaneous verruciform xanthoma
Archives of Dermatology, 2005Co-Authors: Shveta Mehra, Chunyang Fan, Bruce R Smoller, Michael B Morgan, Stephen C SomachAbstract:Objective To analyze the 3β-hydroxysteroid dehydrogenase ( NSDHL ) gene in verruciform xanthoma (VX) to elucidate its potential role in the histogenesis of this lesion. Design DNA was extracted from paraffin-embedded tissue, followed by polymerase chain reaction amplification of exons 4 and 6 of the NSDHL gene. The polymerase chain reaction products were then directly sequenced and analyzed for the presence of somatic mutations. Patients Nine lesions of VX from 8 patients and 3 unrelated normal controls were evaluated. Results Two of 9 VXs (22%) demonstrated a novel somatic missense mutation in exon 6 of the NSDHL gene. The mutation was not present in the remaining 7 lesions of VX, nonlesional internal controls, and 3 unrelated normal controls. No mutation of exon 4 was found in any case. Mutations of exons 4 and 6 previously identified in CHILD Syndrome were not seen in our cases. Conclusions (1) A novel missense mutation (R199H) in exon 6 of the NSDHL gene was identified in a small subset of sporadic VXs. (2) Known CHILD Syndrome mutations in exons 4 and 6 of the NSDHL gene do not contribute to the histogenesis of sporadic VXs.