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- Title
Pathogenesis-Based Therapy Reverses Cutaneous Abnormalities in an Inherited Disorder of Distal Cholesterol Metabolism.
- Authors
Paller, Amy S; van Steensel, Maurice A M; Rodriguez-Martín, Marina; Sorrell, Jennifer; Heath, Candrice; Crumrine, Debra; van Geel, Michel; Cabrera, Antonio Noda; Elias, Peter M
- Abstract
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.
- Subjects
SKIN disease treatment; LIPID metabolism disorders; CHOLESTEROL; COMBINED vaccines; KERATINOCYTES; FIBROBLASTS
- Publication
Journal of Investigative Dermatology, 2011, Vol 131, Issue 11, p2242
- ISSN
0022-202X
- Publication type
Article
- DOI
10.1038/jid.2011.189