Inducing iron deficiency improves erythropoiesis and photosensitivity in congenital erythropoietic porphyria

Abstract

• Iron deficiency results in symptom improvement in CEP and could be considered a novel therapeutic approach for this disease.• CEP marrow cells demonstrated improved growth and erythroid differentiation in vitro under conditions of relative iron restriction.Congenital erythropoietic porphyria (CEP) is an autosomal recessive disorder of heme synthesis characterized by reduced activity of uroporphyrinogen III synthase and the accumulation of nonphysiologic isomer I porphyrin metabolites, resulting in ineffective erythropoiesis and devastating skin photosensitivity. Management of the disease primarily consists of supportive measures. Increased activity of 5-aminolevulinate synthase 2 (ALAS2) has been shown to adversely modify the disease phenotype.Herein, we present a patient with CEP who demonstrated a remarkable improvement in disease manifestations in the setting of iron deficiency. Hypothesizing that iron restriction improved her symptoms by decreasing ALAS2 activity and subsequent porphyrin production, we treated the patient with off-label use of deferasirox to maintain iron deficiency, with successful results. We confirmed the physiology of her response with marrow culture studies. (Blood. 2015;126(2):257-261) IntroductionCongenital erythropoietic porphyria (CEP) is an autosomal recessive disorder resulting from mutations in the uroporphyrinogen III synthase (UROS) gene, which encodes the fourth enzyme in the heme synthetic pathway. 1 Reduced UROS activity leads to nonenzymatic conversion of hydroxymethylbilane to isomer I porphyrin metabolites, which accumulate in late erythroid precursors, reticulocytes, and red cells, resulting in ineffective erythropoiesis, hemolysis, and splenomegaly and which disseminate into tissues such as skin to cause severe photosensitivity. Management is largely comprised of sun avoidance, splenectomy, and supportive measures, and in some patients, hematopoietic stem cell transplantation has been effective. [2][3][4] More than 45 mutations in UROS have been identified, 5 and disease severity correlates with the degree that enzymatic activity is reduced. [6][7][8][9] As evidence that additional factors may influence the disease phenotype, a gain-of-function mutation in 5-aminolevulinate synthase 2 (ALAS2), which encodes the first and rate-limiting enzyme in the heme biosynthetic pathway, has been associated with more severe CEP symptoms.10 This raises the question of whether decreased ALAS2 activity would lessen disease severity by decreasing porphyrin production. Deficiency of iron impedes heme synthesis upstream of UROS by decreasing ALAS2 translation via binding of an iron regulatory protein to an iron-responsive element in the 59 untranslated region of ALAS2 mRNA, suggesting a possible therapeutic role for iron restriction in the treatment of erythropoietic porphyrias. 11,12Study design Bone marrow cell cultures Marrow was obtained postmortem from CEP patient 1 with parental consent. Marrow was also obtained from her younger sister (patient 2) with institutional review board a...

Advances in understanding erythropoiesis: evolving perspectives

“…This suggested that CEP severity could be modulated by altering ALAS2 activity. Indeed, by restricting iron availability with the iron chelator deferasirox, the translation of ALAS2 mRNA could be reduced, resulting in a decrease in the toxic coproporphyrin 1 byproducts and an amelioration of CEP severity in vivo , at least in one case (Egan et al, 2015). …”

Porphyria: Analysis of Register from Brazilian Association of Porphyria (ABRAPO)

“…13,15,12 Our results showed a frequency of 1.1% with 3cases in females and 2cases in males and the mean age at diagnosis was 38years. HEP was the seventh porphyria type and showed a frequency of 0.9% (four cases).…”

Advances in understanding the pathogenesis of congenital erythropoietic porphyria

“…The anaemia and the accompanying iron overload can induce haem synthesis by increasing ALAS2 activity in consequence of increased translation of ALAS2 mRNA. At the same time a deregulation of the ALAS2 gene with a low rate of porphyrin accumulation has been demonstrated in a patient who showed a remarkable improvement in disease manifestations in a setting of iron restriction (Egan et al, 2015). Hypertransfusion in the treatment of severe anaemia may prevent blister formation as the transfused blood suppresses haematopoiesis and the production of endogenous porphyrins (Piomelli et al, 1986;Hogeling et al, 2011).…”