Advances in understanding the pathogenesis of congenital erythropoietic porphyria

Abstract

Congenital erythropoietic porphyria (CEP) is a rare genetic disease resulting from the remarkable deficient activity of uroporphyrinogen III synthase, the fourth enzyme of the haem biosynthetic pathway. This enzyme defect results in overproduction of the non-physiological and pathogenic porphyrin isomers, uroporphyrin I and coproporphyrin I. The predominant clinical characteristics of CEP include bullous cutaneous photosensitivity to visible light from early infancy, progressive photomutilation and chronic haemolytic anaemia. The severity of clinical manifestations is markedly heterogeneous among patients; and interdependence between disease severity and porphyrin amount in the tissues has been pointed out. A more pronounced endogenous production of porphyrins concomitant to activation of ALAS2, the first and rate-limiting of the haem synthesis enzymes in erythroid cells, has also been reported. CEP is inherited as autosomal recessive or X-linked trait due to mutations in UROS or GATA1 genes; however an involvement of other causative or modifier genes cannot be ruled out.

Progressive blistering and hypertrichosis in a young child

“…Most patients present at birth or in early infancy with photodistributed skin fragility and blistering . Additional findings include scarring, hyper‐ and hypo‐pigmentation, hyperkeratosis, hypertrichosis, and onycholysis . In severe cases, patients may suffer photo‐induced mutilation of the face and fingertips .…”

“…1 CEP is a rare disorder with only ~280 cases reported in the literature since 1874 when it was first described by Schultz. 2,3 It is most frequently caused by biallelic mutations in the gene encoding uroporphyrinogen III synthase (UROS), or in rare cases, mutations in the X-linked GATA binding factor gene (GATA1). 4 Mutations result in accumulation of porphyrins in erythrocytes, skin, bones, teeth, and eyes due to decreased UROS activity.…”

“…6 Additional findings include scarring, hyper-and hypo-pigmentation, hyperkeratosis, hypertrichosis, and onycholysis. 3,6 In severe cases, patients may suffer photo-induced mutilation of the face and fingertips. 6 Additionally, patients may have mild asymptomatic to severe transfusion-dependent hemolytic anemia, abnormal transaminases, hepatosplenomegaly, corneal ulceration and scarring, erythrodontia, and/or osteoporosis.…”

Porphyrien

“…Porphyrinakkumulation in den Zähnen, die rötlichbraun verfärbt sein können, führt zur "Erythrodontie": Die Zähne fluoreszieren im langwelligen UV-Licht leuchtend rot. Im Hinblick auf Diagnostik und Therapie dieser seltenen Erkrankung verweisen wir auf die Literatur [10].…”

Emerging cellular and gene therapies for congenital anemias

“…Congenital erythroid porphyria results from the deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway [Di Pierro et al, ]. The enzyme defect results in the accumulation of toxic porphyrin metabolites, which cause cutaneous photosensitivity, photo‐mutilation, and chronic hemolytic anemia.…”