CEP is a rare, devastating disorder resulting from an autosomal recessive inheritance of mutations in the uroporphyrinogen III synthase (UROS) gene, encoding the fourth enzyme in the heme synthetic pathway. The disease is characterized by photosensitivity with blistering, skin fragility and disfiguration, as well as ineffective erythropoiesis and chronic hemolysis. The severity of disease is variable and directly related to the reduction in enzyme activity with different mutations in UROS. Other factors also modulate disease severity, including the activity of 5-aminolevulinate synthase 2 (ALAS2), the rate-limiting enzyme in erythroid heme production (To-Figueras et al, Blood 118:1443, 2011). Management of CEP is largely comprised of sun avoidance and supportive measures, though hematopoietic stem cell transplantation has been effective in some patients. We present a patient with severe CEP who demonstrated a two-year sustained improvement in hemolysis and photosensitivity with iron deficiency induced by chelation therapy and spontaneous iron losses, underscoring the hypothesis that clinical interventions that decrease heme synthesis may dramatically improve the disease phenotype.
Case Report and Correlative Studies: A 33 year-old woman with CEP presented to clinic in 2010 and reported improvement in photosensitivity over the preceding 5 months. She was diagnosed with CEP at the age of one, after presenting with erythrodontia and skin blisters. Genetic testing revealed heterozygosity for the C73R and A104V mutations in UROS. Her history was notable for severe photosensitivity and resultant scarring of the face and sun-exposed areas. She underwent splenectomy at age 26 for worsening chronic hemolysis. Between January and May of 2010, she had a marked reduction in the severity of skin blisters, and a lighter urine color, which was normally dark from hemolysis. Blood work revealed a ferritin of 13 ng/mL. Endoscopy was negative for occult bleeding and no cause was identified.
The patient’s ferritin normalized by July 2010 and her CEP symptoms recurred. Noting the association between iron deficiency and symptom improvement, we proposed a therapeutic trial of iron chelation. In August 2010, at a ferritin level of 208 ng/mL, deferasirox was started. Over the next 8 months, targeting a ferritin of 10-15 ng/mL, she showed improvement by laboratory and clinical parameters. With deferasirox, lactate dehydrogenase decreased from 540 to 144 ng/mL, reticulocyte count decreased from 163 to 25 billion/L, and hematocrit remained between 25-31%. Total urine porphyrins decreased from 108,364.0 to 5,896.3 µg/24 h.
The patient’s subsequent course was complicated by episodic gastric bleeding, and she remained iron-deficient without chelation for another 15 months, though continued to enjoy improved symptoms during this time. In early 2013, the ferritin abruptly increased, presumably from resolution of occult GI bleeding. Reinitiation of chelation was delayed because of logistical issues. In February 2013, she had an acute worsening of hemolysis accompanied by exacerbation of underlying hepatic and renal disease, resulting in her unfortunate death.
With permission of the family, bone marrow was obtained post-mortem for use in IRB-approved studies to better define the mechanism of response. In iron-replete erythroid culture, CEP marrow cells matured poorly past the CD71+, CD36+, GlyA- stage and expressed extremely high levels of FLVCR, presumably in attempt to increase porphyrin export. Total cell expansion after 10 days of culture was 17-fold for CEP marrow and 22-fold for control marrow, but 41.7% of CEP cells and 13.0% of control cells were at the CD71+, CD36+, GlyA- stage, demonstrating impaired erythroid differentiation in CEP. FLVCR expression was 2.1-fold higher in CEP vs. control CD71+, CD36+, GlyA- cells and 12.0-fold higher in CEP vs. control CD71+, CD36+, GlyA+ cells. Additional marrow culture studies with iron depletion are in progress.
We hypothesize that iron restriction impedes heme synthesis upstream of UROS by decreasing ALAS2 translation through the increased binding of IRP2 to ALAS2 mRNA (5’ UTR contains an IRE). There also could be less succinyl CoA availability since the TCA cycle enzyme aconitase contains a 4Fe-4S cluster. Iron restriction might therapeutically benefit other patients with CEP and perhaps patients with other erythroid disorders of the heme synthetic pathway.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.