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. May-Jun 2012;30(3):311-22.
doi: 10.1016/j.clindermatol.2011.08.017.

Abnormal Barrier Function in the Pathogenesis of Ichthyosis: Therapeutic Implications for Lipid Metabolic Disorders

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Abnormal Barrier Function in the Pathogenesis of Ichthyosis: Therapeutic Implications for Lipid Metabolic Disorders

Peter M Elias et al. Clin Dermatol. .
Free PMC article

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.

Figures

Fig. 1
Fig. 1
Scaffold abnormalities account for barrier abnormality in lamellar ichthyosis and loricrin keratoderma. Milder clinical phenotype in loricrin keratoderma correlates with compensatory cross-linking of other cornified envelope (CE) precursors. In contrast, CE is absent or defective throughout stratum corneum (SC) in transglutaminase 1-negative lamellar ichthyosis, correlating with a more severe phenotype.
Fig. 2
Fig. 2
Assessment of disease pathogenesis in patients and animal models: algorithm and approach. ABCA12, aSMase, acid sphingomyelinase; ATP-binding cassette sub-family A member 12; β-GlcCer’ase, β-glucocerebrosidase; Cer, ceramide; EM, electron microscope; FA, fatty acid; GLC, gas liquid chromatography; shRNA, short hairpin RNA; TLC, thin layer chromatography.
Fig. 3
Fig. 3
Enzymatic stages in distal cholesterol metabolites and their associated clinical disorders. Syndromic disorders occur with mutations in 8 of the 10 post-lanosterol steps in cholesterol synthesis (bold), and ichthyosis occurs in 7 of these diseases (bold). *Neonatal lethal. CHILD, congenital hemidysplasia with ichthyosiform erythroderma and limb defects. (Adapted with permission from Elias PM, Crumrine D, Paller A, Rodriguez-Martin M, Williams ML. Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: therapeutic implications for topical treatment of these disorders. Dermatoendocrinol 2011;3:100-6.)
Fig. 4
Fig. 4
Pathogenesis of x-linked ichthyosis. HMG CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A. (Adapted with permission from Lai-Cheong JE, Elias PM, Paller AM. Pathogenesis-based therapies in ichthyosis. Dermatol Ther 2012; in press.)
Fig. 5
Fig. 5
Metabolic steps leading to the formation of corneocyte lipid envelope (CLE). The two arachidonate lipoxygenases (ALOX) enzymes sequentially oxygenate the linoleate moiety in acyl ceramides, which then allows an as-yet-unidentified lipase to de-esterify acyl ceramide. The resultant pool of ω-OH-ceramide can then be covalently linked to the outer surface of the CE, forming the CLE.
Fig. 6
Fig. 6
(A) Abnormal lamellar bodies (arrows) and (B) lamellar bilayer architecture (arrows) in Dhcr7+/− mice (Mag bars = 0.2 μm).
Fig. 7
Fig. 7
Pathogenesis-based therapy for inherited disorders of distal cholesterol metabolism (modified from Paller et al). HMG CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A. (Adapted with permission from Elias PM, Crumrine D, Paller A, Rodriguez-Martin M, Williams ML. Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: therapeutic implications for topical treatment of these disorders. Dermatoendocrinol 2011;3:100-6.)
Fig. 8
Fig. 8
Congenital hemidysplasia with ichthyosiform erythro-derma and limb defects (CHILD) syndrome: Response to topical cholesterol and lovastatin (modified from Paller et al).

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