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Explaining disease variability in Pseudoxanthoma elasticum and related disorders
Book - Dissertation
PXE is a rare autosomal recessive ectopic mineralization disease, leading to multi-organmanifestations, including the skin, eyes and cardiovascular system. When taking into account anestimated prevalence of one in 50U+2019000, at least 140U+2019000 individuals are affected worldwide. Thisnumber probably is an underestimation, given the diseaseU+2019s later onset and distinct clinicalvariability. The observed absence of strong genotype-phenotype correlations in PXE is considereda major limitation for personalized patient care. Hence, a central aim of this dissertation was tocontribute to unraveling disease variability in PXE and in this way pave the way for a morepersonalized approach for PXE patient follow-up. In addition, PXE was used as a starting point toexpand what is known about variability of related rare phenotypes and more common, complexdiseases. This multi-layered approach emphasizes the relevance of rare disease research anddemonstrates how this acquired knowledge can have implications at a larger scale.A first part of this dissertation focused on the identification and validation of modifier genes forthe clinical manifestations of PXE. We were able to validate VEGFA as a genetic modifier for thePXE retinopathy and identify NLRP1, SELE, CSF1R and TRPV1 as candidate modifier genes forthe cardiovascular phenotype. Additionally, IL1B-related signaling was suggested as a new playerin the PXE pathophysiology. Further research is necessary to ascertain the clinical usefulness ofthese findings for patient follow-up and treatment in patient-centered translational studies.A second part was dedicated to other mechanisms to explain disease variability in PXE and GGCXrelateddisorders. Our finding of germline mosaicism as a possible inheritance pattern for PXE andother autosomal recessive genodermatoses can affect patient counseling, especially preconceptioncounseling, as it influences the recurrence risk for future children of affected couples and it is acaveat for implementation of expanded carrier screening programs in the general population. Next,we are the first to suggest genotype-phenotype correlations for GGCX-related disease phenotypes,which led to new research hypotheses and may in the future guide counseling of affected patients.A third part of this dissertation investigated ABCC6 beyond the classic PXE triad, also in morecommon diseases. Our finding of heterozygous pathogenic ABCC6 variants as risk factors forischemic stroke is new evidence for the versatility of the protein and emphasizes the importance ofcarrier detection and follow up. We suggested a proischemic state in the brain as a possible rationalefor the increased stroke risk in the presence of ABCC6 deficiencyU+2013 a novel finding in PXE researchU+2013 and hinted towards a potential role for soluble Endoglin as a biomarker for vascular disease inPXE, which may give rise to translational research projects.These results underline the importance of research in the field of PXE specifically and rare diseasesin general, as advances will lead to a better understanding not only for rare diseases but will havean impact on common diseases, of which vascular disease is just one example.In conclusion, this work contributed to increase what is known about disease variability in PXEand related ectopic mineralization disorders and paved the way for further translational research,with an improved patient care and outcome as ultimate goal.
Pages: vii, 323 p.