The acute porphyrias

Elder, George H.; Hift, Richard; Meissner, Peter N.

doi:10.1016/s0140-6736(96)09070-8

Cited by 165 publications

(123 citation statements)

References 40 publications

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…In a relevant clinical setting, some use the finding of increased concentrations of PBG per se to confirm the diagnosis of an acute attack (19,20 ). The European Porphyria Initiative (EPI) (3 ) and Sandberg and Elder (7 ) state that in an attack, the PBG concentration in urine is usually at least 10-fold higher than the upper reference limit, whereas other suggestions are a 2-to 4-fold increase in an individual (4 ) or a 20-to 200-fold increase compared with reference values (4,21 ) or the finding of increased concentrations of 88 -884 mol/L (22 ).…”

Section: Discussionmentioning

confidence: 99%

Estimation and Application of Biological Variation of Urinary δ-Aminolevulinic Acid and Porphobilinogen in Healthy Individuals and in Patients with Acute Intermittent Porphyria

2006

View full text Add to dashboard Cite

Background: Diagnosis of an attack of acute intermittent porphyria (AIP) is based on the demonstration of increased concentrations of porphobilinogen (PBG) and ␦-aminolevulinic acid (ALA) in urine, but many AIP patients also have high baseline concentrations in remission. The aim of this study was to estimate the biological variations of ALA, PBG, and porphyrins in healthy individuals and AIP patients to improve interpretation of test results. Methods: Fifteen healthy individuals and 15 AIP patients were included, and biological variations were calculated based on urine samples collected weekly for 10 consecutive weeks. For the AIP patients, long-term variations were also estimated based on 7 samples collected through a 2-year period. Results: The porphyrin variances were inhomogeneously distributed; biological variations of porphyrins were therefore not calculated. The within-subject biological variations of ALA and PBG were 16%-20% in the short-term settings and for PBG, 25% in the long-term setting, giving reference change values of ϳ50% and 70%, respectively. The probability of detecting a 100% real change in PBG was 97% in the short-term setting and 80% in the long-term setting. Conclusions: In an AIP patient, a 2-fold increase in PBG, independent of the baseline concentration, will be detected with a probability >80% and is most likely related to the patient's disease and not caused only by

show abstract

Section: Discussionmentioning

confidence: 99%

Estimation and Application of Biological Variation of Urinary δ-Aminolevulinic Acid and Porphobilinogen in Healthy Individuals and in Patients with Acute Intermittent Porphyria

2006

View full text Add to dashboard Cite

show abstract

“…The disease is characterized by abdominal pain, neuropsychiatric symptoms, and͞or cutaneous photosensitivity (13). If diagnosed early, HCP can be treated with a high carbohydrate diet and i.v.…”

mentioning

confidence: 99%

Structural basis of hereditary coproporphyria

Lee

Flachsová

Bodnárová

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hereditary coproporphyria is an autosomal dominant disorder resulting from the half-normal activity of coproporphyrinogen oxidase (CPO), a mitochondrial enzyme catalyzing the antepenultimate step in heme biosynthesis. The mechanism by which CPO catalyzes oxidative decarboxylation, in an extraordinary metaland cofactor-independent manner, is poorly understood. Here, we report the crystal structure of human CPO at 1.58-Å resolution. The structure reveals a previously uncharacterized tertiary topology comprising an unusually flat seven-stranded ␤-sheet sandwiched by ␣-helices. In the biologically active dimer (KD ‫؍‬ 5 ؋ 10 ؊7 M), one monomer rotates relative to the second by Ϸ40°to create an intersubunit interface in close proximity to two independent enzymatic sites. The unexpected finding of citrate at the active site allows us to assign Ser-244, His-258, Asn-260, Arg-262, Asp-282, and Arg-332 as residues mediating substrate recognition and decarboxylation. We favor a mechanism in which oxygen serves as the immediate electron acceptor, and a substrate radical or a carbanion with substantial radical character participates in catalysis. Although several mutations in the CPO gene have been described, the molecular basis for how these alterations diminish enzyme activity is unknown. We show that deletion of residues (392-418) encoded by exon six disrupts dimerization. Conversely, harderoporphyria-causing K404E mutation precludes a type I ␤-turn from retaining the substrate for the second decarboxylation cycle. Together, these findings resolve several questions regarding CPO catalysis and provide insights into hereditary coproporphyria.coproporphyrinogen oxidase ͉ oxidative decarboxylation ͉ mitochondria ͉ x-ray crystallography T he terminal three steps of heme biosynthesis occur within the mitochondria (1, 2). First, coproporphyrinogen III is converted to protoporphyrinogen IX in the intermembrane space (3, 4) by coproporphyrinogen oxidase (CPO) (5, 6). Thus, CPO contains an unusually long (110 residues) N-terminal targeting sequence, required for its import into the mitochondria (7,8). The substrate for CPO is generated in the cytosol (9) by uroporphyrinogen decarboxylase, and the precise mechanism by which it enters the mitochondria remains to be elucidated. Second, protoporphyrinogen oxidase mediates the six electron oxidation of protoporphyrinogen to protoporphyrin IX. This enzyme is localized to the cytoplasmic side of the inner mitochondrial membrane. Third, ferrochelatase inserts the ferrous iron to generate heme within the matrix of the mitochondria. Hence, the heme biosynthetic pathway is not only partitioned between mitochondria and cytosol, but the last three enzymes are compartmentalized within the mitochondria.Partial deficiency of CPO leads to hereditary coproporphyria (HCP), an acute hepatic porphyria inherited in an autosomal dominant fashion (10-12). The disease is characterized by abdominal pain, neuropsychiatric symptoms, and͞or cutaneous photosensitivity (13). If diagnosed early, HCP can be treat...

show abstract

“…Thus, acute attacks, including motor neuropathy, invariably are accompanied by increased activity of hepatic ALA synthase and increased plasma levels and urinary excretion of ALA (1,3). Treatments considered effective, such as high carbohydrate intake or heme infusion, lower ALA excretion (7).…”

mentioning

confidence: 99%