Functional skin barrier requires sphingolipid homeostasis; 3-ketodihydrosphingosine reductase or KDSR is a key enzyme of sphingolipid anabolism catalyzing the reduction of 3-ketodihydrosphingosine to sphinganine. Biallelic mutations in the KDSR gene may cause erythrokeratoderma variabilis et progressive-4, later specified as PERIOPTER syndrome, emphasizing a characteristic periorifical and ptychotropic erythrokeratoderma. We report another patient with compound heterozygous mutations in KDSR, born with generalized harlequin ichthyosis, which progressed into palmoplantar keratoderma. To determine whether patient-associated KDSR mutations lead to KDSR substrate accumulation and/or unrecognized sphingolipid downstream products in stratum corneum (SC), we analyzed lipids of this and previously published patients with non-identical biallelic mutations in KDSR. In SC of both patients, we identified 'hitherto' unobserved skin ceramides with an unusual keto-type sphingoid base in lesional and non-lesional areas, which accounted for up to 10% of the measured ceramide species. Furthermore, an overall shorter mean chain length of free and bound sphingoid bases was observed-shorter mean chain length of free sphingoid bases was also observed in lesional psoriasis vulgaris SC, but not generally in lesional atopic dermatitis SC. Formation of keto-type ceramides is probably due to a bottle neck in metabolic flux through KDSR and a bypass by ceramide synthases, which highlights the importance of tight intermediate regulation during sphingolipid anabolism and reveals substrate deprivation as potential therapy.

Centre de Génétique Humaine Université de Franche Comté 25000 Besançon France

Clinical Investigation Center 1431 National Institute of Health and Medical Research University Hospital 25000 Besançon France

Department of Dermatology Medical Faculty of the University of Heidelberg 69120 Heidelberg Germany

Department of Dermatology University Hospital Nancy 54000 Nancy France

Faculty of Biosciences Heidelberg University 69120 Heidelberg Germany

Institute of Human Genetics Medical Center Faculty of Medicine University of Freiburg 79106 Freiburg im Breisgau Germany

Lipid Pathobiochemistry Group German Cancer Research Center 69120 Heidelberg Germany

Service de Dermatologie et INSERM 1098 RIGHT CHU et UFR Santé 25000 Besançon France

Skin Barrier Research Group Department of Organic and Bioorganic Chemistry Faculty of Pharmacy in Hradec Králové Charles University 500 05 Hradec Králové Czech Republic

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