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Acne therapy may treat some forms of icthyosis

A project to sequence the genes of a small number of patients with ichthyoses has identified a set of mutations in the KDSR gene which may be responsible for many cases of the debilitating skin conditions. In two patients, their icthyoses were successfully treated by targeting a mutation-related protein deficiency with a common acne medication.

Published in the American Journal of Human Genetics (June 1, 2017; 100(6):978–984), the paper notes that the mutation causes the entire KDSR gene, which encodes for the production of an enzyme used in ceramide synthesis, to not be expressed. Since the skin cannot effectively produce ceramides—lipids important to the skin’s natural barrier against water loss—the result is the dry, cracked skin seen in icthyosis.

In a press release from Yale University, associate professor of dermatology and the paper’s senior author Dr. Keith Choate noted that while genetic causes are responsible for many forms of icthyosis, approximately 15% of cases still have unexplained origins. This spurred the gene sequencing project.

The KDSR mutations found in each of the study subjects might have been missed by standard analysis methods, according to the release. Three of them would usually be considered harmless, but were demonstrated by the team to disrupt the assembly of gene copies that are translated into proteins. Two had inherited a common variant of KDSR from one parent—common enough that the researchers did not think it could be responsible on its own for the icthyosis. A complete genome sequencing of one of the two subjects found second mutation that inverted the beginning of the KDSR gene which caused the whole protein-coding sequence to be skipped.

“This underscores the importance of comprehensively investigating unsolved genetic diseases,” said lead author Dr. Lynn Boyden of the Yale Department of Genetics.

The investigators tried treating those two patients with systemic isotretinoin therapy—often used in severe cases of acne. They found it achieved nearly complete resolution in the two individuals, which they say is consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

“In both patients who’ve utilized it, the medication has cured the disease,” Dr. Choate said.

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