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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.
DERMATOLOGY FEATURE
23
VOL. 1 • NO. 1 • 2017