11/16. Molecular defects in erythropoietic protoporphyria with terminal liver failure.We identified two additional mutations in the ferrochelatase gene in two Swiss patients with erythropoietic protoporphyria (EPP). ferrochelatase cDNA from patients was amplified by the polymerase chain reaction (PCR) and subjected to mutation analysis by sequencing PCR products either directly or after subcloning. The first patient, who underwent liver transplantation because of terminal liver failure, was identified as having a single point mutation (C to T) at nucleotide 175 that resulted in a Gln to stop codon conversion in one allele of the gene. In the second case, in which the patient has so far no liver involvement, a two-base deletion (T899G900) was found in one allele. Frameshift as a result of the deletion creates a stop codon. This study presents two new genotypes of EPP, including one with liver failure, a rare and fatal form of EPP.- - - - - - - - - - ranking = 1keywords = gene (Clic here for more details about this article) |
12/16. Evidence for neurological dysfunction in end-stage protoporphyric liver disease.Protoporphyria is a genetic disorder characterized by a defect in the enzyme ferrochelatase, which catalyzes the chelation of iron to protoporphyrin. This causes excessive accumulation and excretion of protoporphyrin. The predominant clinical feature is photosensitivity. Progressive and fatal liver disease occurs in a small percentage of cases. We report our experience with eight patients with end-stage protoporphyric liver disease in whom a syndrome developed before transplantation that resembled the neurological crises of the acute porphyrias. This syndrome was characterized by abdominal pain, hypertension, tachycardia, extremity pain and weakness, constipation and nausea and vomiting. Erythrocyte and serum protoporphyrin levels were markedly increased in all patients. In one patient, profound hemolysis developed during the anhepatic phase of transplantation and continued over a period of 72 hr, causing an extreme increase in the serum protoporphyrin level. Progressive weakness deteriorated to paralysis in this patient. This phenomenon suggests that protoporphyrin may gain access to neural tissue when serum levels are markedly increased, causing neurotoxicity.- - - - - - - - - - ranking = 0.5keywords = gene (Clic here for more details about this article) |
13/16. Terminal hepatic failure in erythropoietic protoporphyria.Erythropoietic protoporphyria is an inherited disorder characterized biochemically by a deficiency of ferrochelatase, the enzyme that catalyzes the incorporation of ferrous iron into protoporphyrin to form heme. We describe a patient who illustrates the unpredictability of the course of liver disease in erythropoietic protoporphyria. She remained stable for several years after her first evidence of liver function abnormalities. Then, in a period of weeks, hepatic failure developed and she died. Findings of serial liver biopsy specimens showed extensive hepatocellular degeneration and inflammation that appeared in a 10-day period. The factors that cause this rapid deterioration in hepatic function remain unknown. Reported cases of fatal hepatic failure in patients with erythropoietic protoporphyria are reviewed.- - - - - - - - - - ranking = 0.5keywords = gene (Clic here for more details about this article) |
14/16. Molecular defect in human erythropoietic protoporphyria with fatal liver failure.We investigated the molecular basis of ferrochelatase in a Japanese patient with erythropoietic protoporphyria (EPP), complicated by fatal liver failure, and defined a novel point mutation in the ferrochelatase gene. cDNAs were synthesized using Epstein-Barr-virus-transformed lymphoblastoid cells from the proband. cDNA clones encoding ferrochelatase in the proband were isolated by amplification using the polymerase chain reaction. There were two sizes of ferrochelatase cDNAs; one was normal in size, the other being smaller. sequence analysis of the abnormally sized cDNA clones revealed that they lacked exon 9 of the ferrochelatase gene. Genomic dna analysis demonstrated that the proband had the abnormal allele and that it contained a G to A point mutation at the first position of the donor site of intron 9. An identical mutation was detected in the affected family members of the proband by allele-specific oligonucleotide hybridization analysis. EPP is inherited in an autosomal dominant manner in this family.- - - - - - - - - - ranking = 1keywords = gene (Clic here for more details about this article) |
15/16. A novel mutation in the ferrochelatase gene associated with erythropoietic protoporphyria.Erythropoietic protoporphyria (EPP) is a hereditary disorder caused by mutations of the ferrochelatase gene. We investigated a Japanese patient with a dominant form of erythropoietic protoporphyria for a ferrochelatase mutation. sequence analysis of the proband's ferrochelatase cDNA revealed a T to C point mutation at nucleotide 557. This mutation resulted in the replacement of Ile by Thr at amino acid position 186, a novel mutation in erythropoietic protoporphyria. An increase in ferrochelatase activity was not observed in the crude extract of E. coli over-expressing the mutant protein compared with the control, whereas a marked increase in activity was observed in that over-expressing the wild type. Prediction of the secondary structure of ferrochelatase suggested that the Ile186-->Thr mutation changed the original beta-sheet structure to an alpha helix in the region including amino acid residue of mutation. We conclude that, in the patient, the Ile186-->Thr mutation had abolished enzyme activity, possibly by disrupting the secondary structure, thereby causing erythropoietic protoporphyria.- - - - - - - - - - ranking = 2.5keywords = gene (Clic here for more details about this article) |
16/16. liver failure in erythropoietic protoporphyria associated with choledocholithiasis and severe post-transplantation polyneuropathy.In a 58-year-old woman with erythropoietic protoporphyria, asymptomatic liver involvement had been diagnosed 12 years earlier. For more than 20 years the patient had been known to have symptomatic gallstones. A mild polyneuropathy of the lower limbs had been diagnosed several years ago. In December 1992, she presented with colicky upper abdominal pain, dyspepsia and mild jaundice. diagnosis of beginning cholestasis in erythrohepatic protoporphyria and coincidental choledocholithiasis was made. A causal relation between choledocholithiasis and deterioration of liver function was assumed. Endoscopic extraction of the bile duct stones, however, could not prevent the development of terminal hepatic failure. Biochemically, an excessive protoporphyrinemia and coproporphyrinuria were found. Five weeks after presentation, the patient underwent orthotopic liver transplantation. Immediately after the operation she developed a severe axonal neuropathy with cranial nerve involvement. One year after transplantation, her general condition has markedly improved, but there is still a disabling polyneuropathy. Recently, there were single reports on patients with very similar neurological symptoms following liver transplantation in erythropoietic protoporphyria. This case supports the assumption of a distinct protoporphyrin-induced neural damage in severe hepatic failure.- - - - - - - - - - ranking = 0.5keywords = gene (Clic here for more details about this article) |
| <- Previous | |