Submitted on January 16, 2008
Accepted on February 2, 2008
Pathogenesis of permeability barrier abnormalities in the ichthyoses: Inherited disorders of lipid metabolism
Peter M. Elias, Mary L. Williams, Walter M. Holleran, Yan J. Jiang, and Matthias Schmuth
Dermatology, VA Medical Center, San Francisco, CA 94121
Corresponding Author: eliasp{at}derm.ucsf.edu
Many of the ichthyoses are associated with inherited disorders of lipid metabolism. These disorders have provided unique models to dissect physiologic processes in normal epidermis, and the pathophysiology of more common scaling conditions. In most of these disorders, a permeability barrier abnormality ‘drives’ pathophysiology through stimulation of epidermal hyperplasia. Among primary abnormalities of non-polar lipid metabolism, triglyceride accumulation in neutral lipid storage disease due to a lipase mutation, provokes a barrier abnormality via lamellar/non-lamellar phase separation within the extracellular matrix of the in SC. Similar mechanisms account for the barrier abnormalities (and subsequent ichthyosis) in inherited disorders of polar lipid metabolism. For example, in recessive X-linked ichthyosis (RXLI), cholesterol sulfate accumulation also produces a permeability barrier defect through lamellar/non-lamellar phase separation. However, in RXLI, the desquamation abnormality is in part attributable to the plurifunctional roles of cholesterol sulfate as a regulator of both epidermal differentiation and corneodesmosome degradation. Phase separation also occurs in type II Gaucher disease (from accumulation of glucosylceramides due to -glucocerebrosidase deficiency). Finally, failure to assemble both lipids and desquamatory enzymes into nascent epidermal lamellar bodies accounts for both the permeability barrier and desquamation abnormalities in Harlequin ichthyosis. The barrier abnormality provokes the clinical phenotype in these disorders not only by stimulating epidermal proliferation, but also by inducing inflammation.
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