PracticeUpdate: Dermatology - Vol 1 - No.1 - 2017

DERMATOLOGY FEATURE 23

Potential treatment of pseudoxanthoma elasticum By Warren R Heymann MD Until now, treating PXE patients involved careful follow-up examinations with retinal specialists and avoiding long-term anticoagulation. Dr Warren Heymann reviews some promising studies and treatments which could be useful in preventing, not reversing, mineralization, confirming the need for early molecular identification and intervention.

W e had the honour of presenting a family with pseudoxanthoma elas- ticum (PXE) at the Cooper Medical School of Rowan University session of the Philadelphia Dermatological Society on February 24, 2017. The proband was referred to confirm the diagnosis of PXE prior to her coronary artery bypass graft surgery. Her classical clinical appear- ance was corroborated by histology, and considerations for treating possible thrombo-hemorrhagic complications were discussed. Before her presentation at the meeting, we conversed about having her specific mutation defined – it might be advantageous to have that information for her family, and perhaps there would be a useful treatment one day. I did not expect to read an article within 48 hours of that encounter that could change the outlook for PXE patients. PXE is caused by loss-of-functionmutations in the ABCC6 gene encoding ATP-binding cassette subfamily C, member 6 (ABCC6), a putative transmembrane efflux trans- porter protein expressed primarily in the basolateral plasma membrane of hepat- ocytes and in the proximal tubules of the kidney. The molecules transported physi- ologically by ABCC6 from the intracellular milieu to the extracellular space have not been identified, but recent studies have demonstrated that ABCC6 is required for the release of ATP from the hepato- cytes, raising the question whether ATP is the physiological target molecule to be transported by ABCC6. Molecular genetic investigations have revealed mutations in the genes physiologically involved in generation of inorganic pyrophosphate and inorganic phosphate, and the findings

suggest a unifying pathomechanism relating to a reduced inorganic pyroph- osphate/inorganic phosphate ratio. This hypothesis is based on the concept that inorganic pyrophosphate inhibits miner- alization, whereas inorganic phosphate is a promineralisation factor, and an appro- priate inorganic pyrophosphate/inorganic phosphate ratio is critical for the preven- tion of ectopic mineralization. 1 To date, treating PXE had focused more on careful follow-up examinations with retinal specialists and avoiding long-term anticoagulation. Maintaining a low-calcium diet, increasing dietary magnesium, and administering phosphate binders such as aluminum hydroxide or sevelamer may yield a modest benefit. 2 The short-chain fatty acid 4-phenylbu- tyrate (4-PBA) is used to treat urea cycle disorders, where it functions as a nitro- gen-scavenging molecule. It has been previously demonstrated that 4-PBA pro- motes the maturation of ABCC6 mutants to the plasma membrane. In a humanized mouse model of pseudoxanthoma elas- ticum, Pomozi et al investigated whether 4-PBA treatments could rescue the cal- cification inhibition potential of selected ABCC6 mutants. They used the dystrophic cardiac calcification phenotype of Abcc6- /- mice as an indicator of ABCC6 function to quantify the effect of 4-PBA on human ABCC6 mutants transiently expressed in the liver. They demonstrated that 4-PBA administrations restored the physiologi- cal function of ABCC6 mutants, resulting in enhanced calcification inhibition. This study identified 4-PBA treatment as a prom- ising strategy for allele-specific therapy of

ABCC6-associated calcification disorders; 3 it would be most useful in preventing, not reversing, mineralization, confirming the need for early molecular identification and intervention. Clearly, studies are required in PXE patients before any recommendations can be made. According to Epocrates, serious adverse reactions to sodium phenylbutyrate include neurotoxicity, anemia, leukopenia, and thrombocyto- penia. Our patient had coronary artery disease necessitating bypass graft sur- gery and her brother died from vascular complications of PXE. What a glorious achievement it would be to be able to prevent pathologic vascular mineraliza- tion in PXE patients. Disclaimer: First published on Dr Warren Heymann’s Dermatology Insights and Inquiries website on March 5, 2017. Republished with permission. References 1. Li Q, Arányi T, Váradi A, et al. J Invest Dermatol 2016;136(3):550-556. 2. Marconi B, Bobyr I, Campanati A, et al. Intractable Rare Dis Res 2015;4(3):113-122. 3. Pomozi V, Brampton C, Szeri F, et al. J Invest Dermatol 2017;137(3):595-602.

Dr Heymann is Professor of Medicine and Pediatrics and Head of the Division of Dermatology at Cooper Medical School of Rowan University. He is also Clinical Professor of Dermatology

at Perelman School of Medicine of the University of Pennsylvania in Philadelphia.

VOL. 1 • NO. 1 • 2017