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. 2011 Apr;3(2):100-6.
doi: 10.4161/derm.3.2.14831. Epub 2011 Apr 1.

Pathogenesis of the Cutaneous Phenotype in Inherited Disorders of Cholesterol Metabolism: Therapeutic Implications for Topical Treatment of These Disorders

Free PMC article

Pathogenesis of the Cutaneous Phenotype in Inherited Disorders of Cholesterol Metabolism: Therapeutic Implications for Topical Treatment of These Disorders

Peter M Elias et al. Dermatoendocrinol. .
Free PMC article


Molecular geneticists tend to conceptualize disease pathogenesis from the mutated gene outward, an approach that does not take into account the impact of barrier requirements in determining disease phenotype. An 'outside-to-inside' perspective has provided quite different explanations for the ichthyoses, including several of the disorders of distal cholesterol metabolism. Elucidation of responsible pathogenic mechanisms also is pointing to appropriate, pathogenesis (pathway)-based therapeutic strategies. In the case of the lipid metabolic disorders, it takes full advantage of new molecular, genetic and cellular pathogenesis information to correct or bypass the metabolic abnormality. This approach fully exploits the unique accessibility of the skin to a topical approach. Moreover, since it will utilize topical lipids and lipid-soluble, and often generic, lipid-soluble drugs, these treatments should be readily transported across the stratum corneum. If successful, this approach could initiate an entirely new departure for the therapy of the ichthyoses. Finally, because these agents are relatively safe and inexpensive, this form of treatment has the potential to be widely-deployed, even in the developing world.

Keywords: CDPX2; CHH syndrome; CHILD syndrome; SC4MOL; SC5D; SLOS; barrier function; cholesterol; desmosterolosis; ichthyosis; statin.


Figure 1
Figure 1
Enzymatic stages in distal cholesterol metabolites and their associated clinical disorders. Syndromic disorders occur with mutations in 7 of the 9 post-lanosterol steps in late cholesterol synthesis (indicated by bold/italics). A prominent cutaneous phenotype (ichthyosis) occurs in 6 of these diseases (indicated by bold/italics & underline).
Figure 2
Figure 2
Pathogenesis-based therapy for disorders of distal cholesterol metabolites: Bases for improvement in clinical studies.

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