Two Brothers With Mild Congenital Erythropoietic Porphyria Due to a Novel Genotype

Abstract

Background: Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disease caused by the deficient activity of the heme biosynthetic enzyme, uroporphyrinogen III synthase (URO-synthase), and the accumulation of the nonphysiologic and phototoxic porphyrin I isomers. Clinical manifestations range from severe mutilation to mild erosions and blisters on sun-exposed areas. Evaluation of the URO-synthase mutation and residual enzyme activity has been correlated with the phenotypic expression of the disease.Observations: We describe 16-and 4-year-old brothers with CEP with a mild phenotype due to a novel genotype, one allele having a promoter mutation (−76G→A) and the other having an exonic missense mutation (G225S). The father and a 4-year-old fraternal twin brother were carriers of the −76G→A mutation, whereas the mother and a 15-year-old brother were carriers of the G225S mutation. Previous in vitro expression studies demonstrated that the G225S mutation severely decreased URO-synthase activity to 1.2% of normal, whereas the promoter mutation decreased the activity to approxi-mately50% of wild type, accounting for the mild clinical phenotype. Conclusion:The mild disease phenotype in these patients is a further example of the clinical heterogeneity seen in CEP and is additional proof that in vitro enzyme expression studies provide dependable genotypephenotype correlations.

Dental-craniofacial manifestation and treatment of rare diseases

“…Severe cutaneous photosensitivity due to massive porphyrin accumulation in the skin, characterized by subepidermal blistering with inflammatory infiltration, is the most frequently observed manifestation in CEP patients, although significant phenotypic variability in CEP has been reported. 52 The severity of skin photosensitivity depends on the amount of porphyrin in the tissue, 53 and thickened skin with hyperpigmentation as well as the rapid development of vesicles and bullae can be observed in any sun-exposed areas. 50 Additionally, facial scabs and scars and the destruction of auricular and nasal cartilages, cheeks, lips and forehead can be severe due to repetitive skin damage and bone resorption, resulting in unique facial features.…”

Porphyria Diagnostics—Part 1: A Brief Overview of the Porphyrias

“…Multiple UROS mutations have been described in different families with CEP, including single base substitutions, insertions, deletions, and splicing defects (Warner et al, ; Xu et al, ; Ged et al, ; Desnick et al, ; Shady et al, ; Ged et al, , ; Berry et al, ). Most mutations were identified in one or a few unrelated families, the exceptions being C73R, L4F, and T228M, which occurred in about 33%, 8%, and 7% of the mutant alleles studied, respectively.…”

Uroporphyrinogen III Synthase Mutations Related to Congenital Erythropoietic Porphyria Identify a Key Helix for Protein Stability

“…ActiVity for the 25 Mutants in UROIIIS Related to CEP. UROIIIS missense mutants reported in the literature (4,(9)(10)(11)(12)(27)(28)(29) span throughout the enzyme with only two mutants originating at the same amino acid (G188R and G188W) (7,30). Wild-type UROIIIS and the 25 point mutants were expressed in E. coli and isolated with a final purity beyond 97% as determined by SDS gel electrophoresis (some examples are shown in the Supporting Information).…”

“…The distribution of mutants among patients is quite homogeneous (with a mean value of two patients per mutation) except for C73R that is present in about one-third of the total reported cases (see Table ) . The phenotype of the pathology varies extensively among patients, but common symptoms include hemolitic anemia produced by the decreased heme levels, scars, and bullous lesions generated by the accumulation of UROI or its derivatives in the body and skin photosensitization caused by the photoreactive nature of the accumulated precursors − . In principle, the severity of the pathology should be related to the residual enzyme activity, reported in the literature for some of the deleterious mutants.…”