Identification of novel UROS mutations in a patient with congenital erythropoietic porphyria and efficient treatment by phlebotomy.

Congenital erythropoietic porphyria (CEP) is an autosomal recessive disorder of the heme biosynthetic pathway that is characterized by uroporphyrinogen III synthase (UROS) deficiency and the accumulation of non-physiological isomer I porphyrins. These phototoxic metabolites predominantly produced by the erythron result in ineffective erythropoiesis, chronic hemolysis and splenomegaly, but they also disseminate in tissues causing bullous photosensitivity to UV light and skin fragility that may progress to scarring with photo mutilation. Therapeutic management is currently limited to supportive care and bone marrow transplantation is reserved for the most severe cases. We describe here a 26-year-old women previously diagnosed with CEP harbouring two novel UROS gene mutations whose pathogenic mechanism was investigated by extensive molecular analysis. Clinical features included disabling hypertrichosis and skin photosensitivity without hemolysis. The first and rate-limiting 5-aminolevulinate synthase 2 (ALAS2) enzyme controls heme synthesis and porphyrin production in erythroid cells, while iron availability modulates its expression through a post-transcriptional mechanism. We performed iterative phlebotomies over 26 months to induce iron depletion in the patient and investigated the effectiveness and tolerance of this cost-effective approach. We observed a progressive decrease in plasma ferritin and urinary porphyrins upon treatment without inducing anemia. The patient reported improved quality of life and photosensitivity. Our data confirm recent reports highlighting the benefit of iron restriction on the disease phenotype through a reduction in porphyrin accumulation. This new strategy may represent an efficient and well-tolerated treatment for CEP patients with skin involvement and limited hematological component if iron restriction is carefully monitored.

Characteristics of cells with engraftment capacity within CD34+ cell population upon G-CSF and Plerixafor mobilization.

In the context of hematopoietic cell transplantation, hematopoietic stem cells and progenitor cells (HSC and HPC) are usually collected by apheresis following their mobilization by G-CSF alone or in combination with Plerixafor® when patients fail to respond to G-CSF alone. In medical practice, the quality of the hematopoietic graft is based on CD34+ cell content that is used to define "Good Mobilizer (GM)" or "Poor Mobilizer (PM)" patients but does not report the real HSC content of grafts. In this study, we assessed the HSC content within the CD34+ fraction of graft samples from 3 groups of patients: 1-GM patients receiving G-CSF only (GMG-CSF), 2-PM patients receiving G-CSF only (PMG-CSF), 3-PM patients receiving G-CSF + Plerixafor (PMG-CSF+P). Although HSC from the 3 groups of patients displayed very similar phenotypic profiles, expression of "stemness" genes and metabolic characteristics, their capacity to engraft NSG mice differed revealing differences in terms of HSC between groups. Indeed according to mobilization regimen, we observed differences in migration capacity of HSC, as well as differences in engraftment intensity depending on the initial pathology (myeloma versus lymphoma) of patients. This suggests that mobilization regimen could strongly influence the long term engraftment efficiency of hematopoietic grafts.