We had the honor of presenting a family with pseudoxanthoma elasticum (PXE) at the Cooper Medical School of Rowan University session of the Philadelphia Dermatological Society on February 24th, 2017. The proband was referred to confirm the diagnosis of PXE prior to her coronary artery bypass graft surgery. Her classical clinical appearance 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-function mutations in the ABCC6 gene encoding ATP-binding cassette subfamily C, member 6 (ABCC6), a putative transmembrane efflux transporter protein expressed primarily in the basolateral plasma membrane of hepatocytes and in the proximal tubules of the kidney. The molecules transported physiologically 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 hepatocytes, 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 pyrophosphate/inorganic phosphate ratio. This hypothesis is based on the concept that inorganic pyrophosphate inhibits mineralization, whereas inorganic phosphate is a promineralization factor, and an appropriate inorganic pyrophosphate/inorganic phosphate ratio is critical for the prevention 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-phenylbutyrate (4-PBA) is used to treat urea cycle disorders, where it functions as a nitrogen-scavenging molecule. It has been previously demonstrated that 4-PBA promotes the maturation of ABCC6 mutants to the plasma membrane. In a humanized mouse model of pseudoxanthoma elasticum, Pomozi et al investigated whether 4-PBA treatments could rescue the calcification 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 physiological function of ABCC6 mutants, resulting in enhanced calcification inhibition. This study identified 4-PBA treatment as a promising 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 thrombocytopenia. Our patient had coronary artery disease necessitating bypass graft surgery and her brother died from vascular complications of PXE. What a glorious achievement it would be to be able to prevent pathologic vascular mineralization in PXE patients.
- Li Q, et al. Research progress in pseudoxanthoma elasticum and related ectopic mineralization disorders. J Invest Dermatol 2016; 136: 550-6.
- Marconi B, et al. Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanisms, perspective of treatment. Intractable Rare Dis Res 2015; 4: 113-22.
- Pomozi V, et al. Functional rescue of ABCC6 deficiency by 4-phenylbutyrate therapy reduces dystrophic calcification in Abcc6-/- mice. J Invest Dermatol 2017; 137: 595-602.