Epidermolysis bullosa simplex : new insights in desmosomal cardiocutaneous syndromes

Epidermolysis bullosa (EB) is a group of hereditary skin blistering disorders. EB children are also called “butterfly children” because of their fragile skin. The different forms of EB vary in blistering level and severity partly related to the underlying DNA-defect. Currently, mutations in 13 genes have been found to underlie the different EB-types. However, still cases with hereditary skin fragility remain unsolved at the molecular level. In this thesis the underlying DNA-defects in several unusual EB cases are discovered, and the lessons that can be learned from the results are discussed. In a group of patients with hereditary intraepidermal blistering, EB simplex (EBS), in which no mutations were found in the usual EBS-associated genes, the underlying DNA-defect was discovered: mutations in the gene encoding the cytolinker protein plectin. Plectin mutations were also found to underlie hereditary cardiac disease (cardiomyopathy) along with EBS. This thesis gives an overview of the genes involved in hereditary cardiocutaneous disease. The skin abnormalities precede cardiac disease (sudden death, cardiac failure) and may therefore provide a warning signal. In this thesis mutations in desmoplakin, an essential protein for cell-cell binding in skin and heart, are confirmed to cause an early lethal form of EBS: lethal acantholytic EB and cardiomyopathy is shown to be part of this syndrome.
Finding the underlying molecular defect in genetic disease makes adequate counselling possible and provides insight in the relation between the genetic defect and eventual clinical outcome, thereby offering ideas for therapeutic interventions. Furthermore, potential future gene/protein therapy in individual patients is only possible when the underlying molecular defect is known.

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