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Congenital erythropoietic porphyria (CEP: MIM#263700) is an extremely rare disorder inherited as an autosomal recessive trait. The cause of this disease is the deficient activity of uroporphyrinogen III synthase (UROS: EC 220.127.116.11).1 Since a cloning of UROS gene (UROS: Genebank NM000375), efforts have been made to clarify underlying mutations that cause CEP.1 To date, more than 20 mutations of UROS have been described.2 Identification of UROS mutations at the molecular level is important for genetic counselling and prenatal diagnosis of affected families.
Clinically, CEP is characterised by severe cutaneous photosensitivity, chronic haemolysis, and massive porphyrinuria resulting from the accumulation in the bone marrow, peripheral blood, and other organs of large amounts of predominantly type I porphyrins, which are not substrates for haem synthesis.2 Red urine may be observed from infancy, and the teeth become stained red. Haemolytic anaemia, an additional complication, may be helped by splenectomy. Besides such classic manifestations ocular involvement, including scleral change, has been reported in patients with CEP.3,4 Furthermore, we recently reported the evidence of the accumulation of porphyrins in teardrops in a Japanese patient with CEP who showed scleral changes.5 To confirm whether the accumulation of porphyrins is a common feature and is a direct cause of ocular involvement, we analysed and confirmed the presence of porphyrins in teardrops in an additional three Japanese patients with CEP.
We analysed three Japanese patients with CEP, all of whom were diagnosed by their typical clinical manifestations and by the elevation of porphyrins (uroporphyrin I and coproporphyrin I) in urine (Table 1). For case 2, we performed sequence analysis of UROS and identified a T to C transition of nucleotide 634, which predicted a serine to proline substitution at residue 212 (S212P), and a C to T transition of nucleotide 745 that predicted a glutamine to premature stop codon (Q249X).6 All patients were observed to have sclerotic necrosis of the limbus and pigmentation of eyelids (Fig 1), but in case 4 (KT), these changes were relatively mild. No patients showed visual disturbance and other ocular changes, such as pigmentation of eye lids and cornea.
Analysis of teardrop porphyrins was performed in three patients, after obtaining informed consent. In normal controls, no porphyrin isomer was observed, whereas in all patients remarkable elevation of porphyrins, especially of uroporphyrin I and coproporphyrin I, were observed. Interestingly, in case 4, the accumulation of porphyrins was relatively mild compared with other patients.
Sclerotic changes at the body surface lesions in CEP are mainly caused by the accumulation of porphyrins.1 Here, we demonstrated the first evidence that the accumulation of porphyrins in teardrops is a common feature in patients with CEP. No accumulation was observed in normal control, whereas the elevation of porphyrins in teardrops was observed in all patients with CEP. Furthermore, in case 4, who manifested relatively mild phenotype of ocular involvement, also showed mild accumulation of porphyrins, suggesting that the accumulation of porphyrins, especially uroporphyrin and coproporphyrin in teardrops directly causes ocular involvement, and that its severity depends on the level of porphyrins accumulated in teardrop. Therefore, it is important to measure porphyrins in teardrops of patients with CEP. We strongly recommend the use of ultraviolet spectacles to protect against sunlight and to prevent the initiation and progression of scleral lesions, although some patients do not have eye involvement.
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