Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.61 (porphobilinogen deaminase)
 637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The porphyrias are a group of inborn or acquired disorders of haem synthesis that can result in neurovisceral or dermatological symptoms. Diagnosis is usually made using a combination of clinical presentation and biochemical parameters. This case report describes a 25-year-old woman clinically presenting with a rash and then found to have elevated porphobilinogen concentrations in her urine. The initial presumptive diagnosis of variegate porphyria was not supported by analysis of her plasma, urine and faeces, which suggested a combination of acute intermittent porphyria and porphyria cutanea tarda. Sequencing of the hydroxymethylbilane synthase and uroporphyrinogen decarboxylase genes confirmed the relatively rare diagnosis of dual porphyria, and revealed a novel uroporphyrinogen decarboxylase mutation.
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PMID:Dual porphyria with mutations in both the UROD and HMBS genes. 1639 Jun 15

Acute intermittent porphyria (AIP) is a metabolic disease with a variable prevalence among different countries. In some areas of southern Europe it remains to be fully evaluated. We undertook a genetic and biochemical study of 16 unrelated Spanish AIP patients and relatives. The genetic analyses showed they harboured the following mutations in the porphobilinogen deaminase gene: R173W, G111R, L278P, L238P, R116W, R26C, 340insT, 730delCT, 691del30bp, and IVS14+1g>a. The mutation R173W was found in 6 patients (37.5%), including the only patients of our series with >3 recurrent porphyria attacks. While in clinical remission, all AIP patients exhibited sustained increased excretion of porphyrins and precursors. PBG excretion showed a high between-subject variation and was not related to erythrocyte PBG deaminase activity. The study of family members allowed the identification of 22 asymptomatic AIP carriers. These included 8 persons harbouring the R173W mutation belonging to four different families. Six of these latent AIP subjects showed increased PBG elimination, and in two the urinary levels were >10-fold the normal limit. These results reinforce the hypothesis that the R173W mutation may have a high biochemical and clinical penetrance among AIP patients.
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PMID:Genetic and biochemical characterization of 16 acute intermittent porphyria cases with a high prevalence of the R173W mutation. 1681 12

Acute intermittent porphyria (AIP) is the most common of the four forms of neuroporphyria. AIP mimics a variety of disorders and thus poses a diagnostic quagmire. Abdominal pain occurs in 90-95% of the attacks. Some patients develop psychiatric symptoms such as psychosis similar to schizophrenia. The diagnostic difficulty may lead to under-diagnosis of patients who present with strictly psychiatric symptoms. This assumption is supported by a high prevalence of AIP in psychiatric hospitals. Therefore, we encourage a high index of suspicion for AIP in psychiatric patients in order to prevent false psychiatric diagnosis. In addition we discuss psychotropic drugs that may exacerbate acute attacks in undiagnosed patients. We report a case in which the diagnosis of AIP was clouded by the presence of only psychiatric symptoms. The clue for diagnosis was an anamnestic detail of the use of a porphyrogenic drug prior to the admission. The diagnosis of AIP was supported by excess of alpha aminolevulinic acid (ALA) and porphobilinogen (PBG) in urine concomitantly with a decrease in porphobilinogen deaminase (PBGD) activity in erythrocytes. The diagnosis was further strengthened by the fact that the patient's father was identified as an AIP carrier. However, in the absence of typical organic symptoms of porphyria, one cannot definitely rule out the presence of schizophrenia in this patient in addition to AIR
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PMID:Acute intermittent porphyria: psychosis as the only clinical manifestation. 1691 Mar 86

Acute intermittent porphyria (AIP) is an inherited metabolic disorder caused by deficiency of porphobilinogen deaminase, an enzyme found in the synthetic pathway of heme. Acute attack of AIP may be precipitated by many factors during operation and anesthesia, including fasting, dehydration, stress, infection, and drugs. Acute attack of AIP is likely fatal. Therefore, the drugs recommended as being safe in anesthesia for porphyria patients are up-to-dately refreshed and renovated and the identification of whether a drug is safe or not is based on cumulative anecdotal experiences. Here, we report the safe use of rocuronium and sevoflurane for long exposure in a patient affected with acute intermittent porphyria.
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PMID:The use of rocuronium and sevoflurane in acute intermittent porphyria--a case report. 1703 5

The porphyrias arise from predominantly inherited catalytic deficiencies of specific enzymes in heme biosynthesis. All genes encoding these enzymes have been cloned and several mutations underlying the different types of porphyrias have been reported. Traditionally, the diagnosis of porphyria is made on the basis of clinical symptoms, characteristic biochemical findings, and specific enzyme assays. In some cases however, these diagnostic tools reveal overlapping findings, indicating the existence of dual porphyrias with two enzymes of heme biosynthesis being deficient simultaneously. Recently, it was reported that the so-called Chester porphyria shows features of both variegate porphyria and acute intermittent porphyria. Linkage analysis revealed a novel chromosomal locus on chromosome 11 for the underlying genetic defect in this disease, suggesting that a gene that does not encode one of the enzymes of heme biosynthesis might be involved in the pathogenesis of the porphyrias. After excluding candidate genes within the linkage interval, we identified a nonsense mutation in the porphobilinogen deaminase gene on chromosome 11q23.3, which harbors the mutations causing acute intermittent porphyria, as the underlying genetic defect in Chester porphyria. However, we could not detect a mutation in the coding or the promotor region of the protoporphyrinogen oxidase gene that is mutated in variegate porphyria. Our results indicate that Chester porphyria is neither a dual porphyria, nor a separate type of porphyria, but rather a variant of acute intermittent porphyria. Further, our findings largely exclude the possibility that a hitherto unknown gene is involved in the pathogenesis of the porphyrias.
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PMID:Demystification of Chester porphyria: a nonsense mutation in the Porphobilinogen Deaminase gene. 1729 17

The porphyrias are group of mostly inherited disorders in which a specific spectrum of accumulated and excreted porphyrins and heme precursors are associated with characteristic clinical features. There are eight enzymes involved in the heme synthesis and defects in seven of them cause porphyria. Four of them are described as acute hepatic porphyrias, which share possible precipitation of acute attacks with symptoms engaging the nervous system. Acute intermittent porphyria (AIP), caused by partial deficiency of the porphobilinogen deaminase (PBGD), is the most frequent among hepatic porphyrias. Clinical expression is highly variable and ~ 90 % of AIP heterozygotes remain asymptomatic throughout life. During systematic genetic analysis of the AIP patients diagnosed in the Czech and Slovak Republics, we found a special case of AIP. In a 15-year-old boy with abdominal and subsequent neurological symptomatology, we identified de novo mutation 966insA within the PBGD gene leading to a stop codon after 36 completely different amino acids compared to the wt-sequence. To establish the effects of this mutation on the protein structure, we expressed mutant constructs with described mutation in E. coli and analyzed their biochemical and enzymatic properties. Moreover, computer-assisted protein structure prediction was performed.
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PMID:De Novo mutation found in the porphobilinogen deaminase gene in Slovak acute intermittent porphyria patient: molecular biochemical study. 1729 18

The porphyrias are inherited or acquired metabolic disorders caused by a partial deficiency in one of the enzymes of the heme biosynthetic pathway. Eight enzymes are utilized in the synthesis of heme. An enzyme defect in one of the last seven enzymes will result in one of the seven different forms of porphyria, some of which have similar signs and symptoms. This article describes six diabetic, azotemic patients with no prior history of porphyria, who developed a syndrome similar to acute intermittent porphyria after initiation of treatment with erythropoietin. One of the patients developed the syndrome predialysis, whereas the remaining patients were on maintenance hemodialysis. The symptoms varied but all resolved when erythropoietin was discontinued and reappeared in four cases when erythropoietin was restarted. In all of the patients, the enzyme aminolevulinic acid-dehydratase (ALA-D) was low and the uroporphyrinogen synthase was normal. This enzyme abnormality suggests an acquired form of delta-aminolevulinic acid dehydratase porphyria (ADP). Lead toxicity, succinylacetone, and zinc deficiency are known to depress ALA-D, but these conditions were not present. The development of the acute porphyria syndrome while the patients were receiving pharmacological doses of erythropoietin, which resolved when the drug was stopped, suggests that by stimulating heme synthesis, erythropoietin may unmask an enzyme deficiency resulting in the clinical expression of ADP. The patients responded favorably to a regimen that included discontinuation of erythropoietin, tight blood sugar control, maintaining the hematocrit above 30%, and a KT/V, a measure of dialysis adequacy, of 1.5 in the hemodialysis group. Plasmapheresis accelerated the recovery when used in two patients.
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PMID:Porphyria syndrome associated with diabetic nephrosclerosis and erythropoietin. 1743 69

Acute intermittent porphyria is an autosomal dominant inherited disorder resulting from a deficiency of porphobilinogen deaminase activity, the third enzyme in the heme biosynthesis pathway. This disease is uncommon, although the prevalence is higher in asymptomatic heterozygotic carriers; however, this prevalence is difficult to establish because of the absence of symptoms. Although acute intermittent porphyria is a multisystemic disease, its most common form of presentation is abdominal pain and neurological or mental symptoms, which can sometimes be due to precipitating factors such as reduced energy intake, smoking, alcohol, some drugs, and stress. Diagnosis can be made by testing urinary porphobilinogen levels, with subsequent measurement of enzyme activity and DNA testing. Treatment is based on prevention of porphyria attacks by avoiding precipitating factors and early administration of intravenous glucose or hemin therapy. We present the case of a patient diagnosed with acute intermittent porphyria based on study of chronic mild alanine aminotransferase (ALT) elevation.
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PMID:[Acute intermittent porphyria and chronic transaminase elevation]. 1840 88

Acute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis caused by molecular defects in the hydroxymethylbilane synthase (HMBS) gene. In this study, we report two novel missense sequence variations in the HMBS gene, T59I (C176T) and V215M (G643A), in two patients with clinical symptoms compatible with acute attacks of porphyria. However, only the patient who carried V215M presented with full AIP-affirming biochemical evidence. Both variant proteins were expressed in a prokaryotic system and characterized in vitro. Recombinant T59I and V215M had residual activity of 80.6% and 19.4%, respectively, of that of the wild type enzyme. Moreover, changes in K(m), V(max) and thermostability observed in the recombinant V215M suggest a causal relationship between V215M and AIP. The association between the T59I substitution and AIP is less obvious. Based on our investigation, substitution T59I is more likely to be a mutation with a weak effect than a rare form of polymorphism. This study demonstrates that in vitro characterization of missense variations in the HMBS gene can provide valuable information for the interpretation of clinical, biochemical and genetic data, for establishing a diagnosis of AIP. It also highlights the fact that there are still many aspects to be investigated concerning AIP and corroborates the need to report new data that can help to clarify the genotype-phenotype relationship.
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PMID:Characterization of two missense variants in the hydroxymethylbilane synthase gene in the Israeli population, which differ in their associations with acute intermittent porphyria. 1840 50

Acute intermittent porphyria (AIP), an inherited disease of heme biosynthesis, is one of the most common types of porphyria. Reduced activity of the enzyme porphobilinogen deaminase (PBGD), which catalyzes the sequential condensation of 4 molecules of porphobilinogen to yield preuroporphyrinogen, has been linked to the symptoms of AIP. We have determined the 3-dimensional structure of human PBGD at 2.2 A resolution. Analysis of the structure revealed a dipyrromethane cofactor molecule covalently linked to C261, sitting in a positively charged cleft region. In addition to the critical catalytic D99, a number of other residues are seen hydrogen bonded to the cofactor and play a role in catalysis. Sequential entry of 4 pyrrole molecules into the active site is accomplished by movement of the domains around the hinges. H120P mutation resulted in an inactive enzyme, supporting the role of H120 as a hinge residue. Interestingly, some of the mutations of the human PBGD documented in patients suffering from AIP are located far away from the active site. The structure provides insights into the mechanism of action of PBGD at the molecular level and could aid the development of potential drugs for the up-regulation of PBGD activity in AIP.
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PMID:Structural insight into acute intermittent porphyria. 1893 96


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