Pathogenesis-Based Therapy Reverses Cutaneous Abnormalities in an Inherited Disorder of Distal Cholesterol Metabolism
| Autor: | Maurice A.M. van Steensel, Jennifer Sorrell, Amy S. Paller, Michel van Geel, Marina Rodríguez-Martín, Debra Crumrine, Candrice Heath, Peter M. Elias, Antonio Noda Cabrera |
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| Přispěvatelé: | Dermatologie, RS: GROW - School for Oncology and Reproduction |
| Rok vydání: | 2011 |
| Předmět: |
Administration
Topical lovastatin Biochemistry Pathogenesis Congenital 030207 dermatology & venereal diseases chemistry.chemical_compound 0302 clinical medicine Skin Regulation of gene expression 0303 health sciences CHILD syndrome Syndrome Phenotype Ichthyosiform Erythroderma 3. Good health Limb Deformities Cholesterol Treatment Outcome Topical Combination Administration Drug Therapy Combination Female lipids (amino acids peptides and proteins) ichthyosis Lovastatin medicine.drug medicine.medical_specialty Adolescent Clinical Sciences Oncology and Carcinogenesis Limb Deformities Congenital Dermatology Biology Article lipids Young Adult 03 medical and health sciences Pharmacotherapy Drug Therapy Metabolic Diseases Internal medicine medicine Humans lateralization Molecular Biology 030304 developmental biology Dermatology & Venereal Diseases statin Lipid metabolism Cell Biology Ichthyosiform Erythroderma Congenital Lipid Metabolism medicine.disease Endocrinology chemistry Skin Abnormalities X-inactivation |
| Zdroj: | The Journal of investigative dermatology Journal of Investigative Dermatology, 131(11), 2242-2248. Elsevier Science The Journal of investigative dermatology, vol 131, iss 11 |
| ISSN: | 0022-202X |
| DOI: | 10.1038/jid.2011.189 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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