Treatment of Ectopic Mineralization in Pseudoxanthoma elasticum (TEMP-studie) Wilko Spiering, internist-vasculair geneeskundige Afd. Vasculaire Geneeskunde

Wilko Spiering internist-vasculair geneeskundige Research contracts: Innovatiefonds Zorgverzekeraars Oogvereniging Consulting: - Employment in industry: Stockholder of a healthcare company: Owner of a healthcare company: Other: Voorzitter Internistisch Vasculair Genootschap Secretaris Nederlandse Hypertensie Vereniging

Meisje 13 jaar

Epidemiologie PXE Zeldzame ziekte (<1:2000) Prevalentie patiënten ≈1:25.000-50.000, (≈340-680 in NL) Man:vrouw 1:2 Prevalentie dragers ≈1:400, (≈42.000 in NL) Geen geografische verschillen in prevalentie

Huidafwijkingen

Disc drusen (arrow heads) and angiod streaks (arrows).

Vaatwand

18F-NaF-opname in PXE

Mutaties ABCC6-gen The positions of nonsense, splice junction, insertion and deletion mutations identified in the ABCC6 gene in patients with pseudoxanthoma elasticum (PXE). Vertical blue boxes represent the 31 exons, and every fifth exon is numbered. Splicing, small insertion and deletion mutations are shown above the line, and nonsense mutations below, with the position of the recurrent del23–29 mutation. Dark blue boxes, nucleotide-binding fold domains; bold, recurrent mutations; red, novel mutations.

Landelijk Expertisecentrum PXE (LEP) Gestart in 2013 Multidisciplinair team: Internist-vasculair geneeskundige Oogarts Klinisch geneticus Radioloog Dermatoloog Vaatchirurg >90 patiënten Uitgebreide screening van huid, ogen en bloedvaten Research-database

The role of pyrophosphate in PXE Fig. 4. Effect of the Abcc6 genotype on PPi levels in mouse plasma. Plateletfree plasma was collected and analyzed with a specific PPi assay based on the PPi-dependent conversion of glucose-1-phosphate to glucuronic acid-6- phosphate. Data are mean ± SD. **P < 0.01; ***P < 0.001, one-way ANOVA (n = 7, 8, and 6 for females; n = 7, 6, and 5 for males). Fig. 3. Effect of induced rABCC6, hABCC6, or hABCC6V1289F expression on PPi levels in culture medium. Control cells (Flp-In T-REx 293) and Flp-In T-REx 293 containing inducible rABCC6 (A), hABCC6, or hABCC6V1298F (B) constructs were seeded in 24-well plates (2 Å~ 105 cells/well) and grown to confluence overnight. ABCC6 expression was induced by adding 1 μg/mL of doxycyclin (+dox). Each day, the medium was collected for PPi determination and replaced with fresh medium. Data are mean ± SD (n = 3). LLQ, lower limit of quantitation of the assay. Jansen, PNAS 2013

The role of pyrophosphate in PXE Figure 2. Hepatic ATP-binding cassette subfamily C member 6 (ABCC6) raises inorganic pyrophosphate (PPi) levels via ATP release. Released ATP is rapidly converted into AMP and PPi within the liver vasculature. A, PPi levels in culture medium of sandwich-cultured primary wild-type (WT) and Abcc6−/− hepatocytes (n=3 for WT, n=4 for Abcc6−/−); total amount of (B) PPi, (C) AMP, and (D) ATP in mouse liver perfusates collected from WT and Abcc6−/− livers during 30 minutes (n=5 for WT, n=6 for Abcc6−/−). E, PPi levels in platelet-free plasma samples from healthy subjects (n=14) and patients with PXE (n=12). Patient and control characteristics are given in the online-only Data Supplement. Data are presented as meanÅ}SD. **P<0.01, ***P<0.001. Note that AMP and PPi levels are in nmoles, whereas ATP levels are in pmoles and close to background levels. Jansen, Arterioscler Thromb Vasc Biol 2014

Pyrofosfaat vs. bisfosfonaat

Etidronaat in GACI-syndroom Edouard, Eur J Pediatr 2011

Doel TEMP-studie Leidt behandeling met de bisfosfonaat etidronaat tot stabilisatie (of afname) van verkalking in PXE?

Opzet studie en uitkomsten Gerandomiseerd, dubbelblind, placebo-gecontroleerd PXE, >18 jaar, 2 mutaties ABCC6, arteriële verkalking Etidronaat (n=30) vs. placebo (n=30) gedurende 12 maanden Primaire uitkomst: verandering in 18F-NaF-opname in de femoraal arteriën na 12 maanden behandeling Secundaire uitkomsten: 18F-NaF-opname in andere arteriën Oculaire aspecten (fundusfotografie, OCT) Intima-media-dikte Vaatstijfheid Botdichtheid Kwaliteit van leven

Financiering Veel PXE-patiënten en familieleden! Stichting PXE-fonds

Conclusies Zeldzame aandoening Verkalkingen van elastische weefsels van huid, ogen en bloedvaten Geen oorzakelijke behandeling Afgenomen produktie van pyrofosfaat Behandeling met bisfosfonaat theoretisch effectief

Patiënt met PXE? TEMP-studie! Landelijk Expertisecentrum PXE, Polikliniek Vasculaire Geneeskunde, UMC Utrecht