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.
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Article info
Footnotes
☆This work was administered by the Northern California Institute for Research and Education, with resources of the Veterans Affairs Medical Center, San Francisco, California.
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