Interdependence between degree of porphyrin excess and disease severity in congenital erythropoietic porphyria (Günther's disease)

Abstract

Various clinical and biochemical observations point to a relationship between degree of disease expression and metabolic disturbance in autosomal recessive congenital erythropoietic porphyria (Günther's disease). Although the clinical manifestations have been well described since Günther's fundamental observations, an interdependence between disease severity and porphyrin excess has yet to be elucidated. We investigated porphyrin metabolism in nine Indian patients suffering from the characteristic clinical symptoms: skin photosensitivity, red-colored urine as a sign of extremely elevated porphyrinuria and mild to severe hemolytic anemia. Porphyrins in urine, feces and blood were analysed by HPTLC and HPLC in conjunction with spectrophotometry and spectrofluorometry. Uroporphyrinogen III synthase activities in red blood cells were determined using a coupled-enzyme assay. Biochemical studies revealed varying degrees of porphyrinuria with total urinary porphyrins between 23 and 102 mumol/24 h (normal < 0.2 mumol/24 h) and uroporphyrin predominance. Urinary and fecal coproporphyrin isomer I were markedly elevated to 87-97% and 81-93% (normal < 31%, < 75%), respectively. Overproduction of porphyrins led to a considerable porphyrinemia with mainly copro- and protoporphyrin. A hitherto undescribed fecal porphyrin pattern with increased protoporphyrin levels was found in three patients. This atypical finding was probably related to severe hemolysis since protoporphyrin can be excreted only via the liver with bile in the feces. High porphyrin levels in urine, feces and blood were associated with worse cutaneous symptoms. Activities of uroporphyrinogen III synthase in red blood cell lysates were decreased to between 9% and 30% of controls. Patients showed increased porphobilinogen deaminase activities, up to 190% of control. Deficiency of uroporphyrinogen III synthase activity was reflected by inversion of the relationship between and isomer III leading to dominance of isomer I. Elevation of porphobilinogen deaminase activities is related to hemolysis and, additionally, to regulatory compensation for the enzyme deficiency. Variations in both the severity of photosensitivity and the enhancement of porphyrin production and excretion indicate the molecular heterogeneity of this disease. These findings suggest a close relationship between the metabolic disturbance reflected by porphyrin excess and the severity of disease expression.

Immunological, enzymatic and biochemical studies of uroporphyrinogen III‐synthase deficiency in 20 patients with congenital erythropoietic porphyria

“…Our previous findings suggested a close relationship between the metabolic disturbance reflected by porphyrin excess and the severity of disease expression [15]. The present study demonstrates that the severity of clinical symptoms depends on the degree of metabolic disturbance reflected by the level of porphyrin excretion.…”

“…The homoallelic C73R mutation is associated with a very severe form [10,13]. Our previous studies suggest a close relationship between the metabolic disturbance reflected by porphyrin excess and the severity of disease expression [15]. In this report 20 patients with early onset of clinical symptoms and variable clinical features were metabolically and immunologically investigated to check the correlation between clinical severity, overproduction of porphyrins and URO-III-S activity in erythrocytes.…”

Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2

“…Prior to our report here that IRP2 Ϫ/Ϫ mice develop elevated red cell protoporphyrin IX levels, ferrochelatase mutations were the only well-recognized genetic cause of increased elevated protoporphyrin IX levels in humans 29,34 and mice, 35 although protoporphyrin IX levels can also be elevated in congenital erythropoietic porphyria 36 and in some sideroblastic anemias. 37 Mice with an autosomal recessive ferrochelatase mutation display a mild hemolytic anemia, photosensitivity, cholestasis, and severe hepatic dysfunction, 35 but they lack neurologic symptoms.…”

Congenital Erythropoietic Porphyria

“…The severity of the skin manifestations varies considerably among CEP patients [19,20,32,33] and correlates with the degree of porphyrin excess [34]. Skin photosensitivity most often begins in the first days of life and is induced especially by light of wavelengths around 405 nm (Soret band; table 4) [35].…”