Human hereditary hepatic porphyrias

Nordmann, Y; Puy, Hervé

doi:10.1016/s0009-8981(02)00276-0

Cited by 69 publications

(55 citation statements)

References 79 publications

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“…AIP has been referred to as ''the little imitator'' because sometimes non-specific symptoms are easily mistaken for other subjective health complaints (Crimlisk 1997). A range of medications can trigger symptoms, in addition to hormones, alcohol, physical and psychological stress, hunger and fasting (Normann and Puy 2002). Inheritance is autosomal dominant, with reduced penetrance (Badminton and Elder 2005).…”

Section: Acute Intermittent Porphyriamentioning

confidence: 99%

Psychosocial Aspects of Predictive Genetic Testing for Acute Intermittent Porphyria in Norwegian Minors

et al. 2011

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Objective: The Norwegian Porphyria Centre routinely offers genetic counselling and predictive genetic testing in families diagnosed with porphyria. The aim of this study was to investigate the subjective experiences of adolescents and young adults who were genetically tested for acute intermittent porphyria (AIP) as minors. What were the psychosocial consequences and how were these handled?Methods: Qualitative interviews of ten Norwegians aged 16-21 years were performed and analysed based on interpretive description. All participants were initially predictively tested for AIP as minors, but three had subsequently developed manifest disease.Results: The participants considered early diagnosis and lifestyle moderation advantageous, but finding motivation for precaution was difficult. AIP inflicted few psychosocial challenges and was a small part of the participants' identity, but risk of manifest disease was, nevertheless, a cause for concern for two participants with latent AIP. The participants were content with their present level of knowledge and they felt capable of obtaining relevant information when needed. AIP was experienced as a vague condition, and participants and their relatives attributed a variety of symptoms to the disease. Conclusion and implications:Being genetically tested as a minor was experienced as useful and entailed relatively few adverse psychosocial consequences, although there was a potential for concern. Appropriate and individually tailored genetic counselling and written consent is subsequently advised. What constitutes a suitable age for testing will differ from individual to individual, but these results suggest that parents in collaboration with their children may be suited to decide what age is appropriate.

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Section: Acute Intermittent Porphyriamentioning

confidence: 99%

Psychosocial Aspects of Predictive Genetic Testing for Acute Intermittent Porphyria in Norwegian Minors

et al. 2011

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“…Partial deficiency of CPO leads to hereditary coproporphyria (HCP), an acute hepatic porphyria inherited in an autosomal dominant fashion (10)(11)(12). The disease is characterized by abdominal pain, neuropsychiatric symptoms, and͞or cutaneous photosensitivity (13).…”

mentioning

confidence: 99%

Structural basis of hereditary coproporphyria

Lee

Flachsová

Bodnárová

et al. 2005

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

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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...

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“…About 80% of heme produced in the liver is consumed by cytochromes which participate in the metabolism of corticosteroids and other drugs (as microsomal cytochrom P450) and electron transport in citric acid cycle (as mitochondrial respiratory cytochromes). The remaining 20% of heme produced in liver is consumed by tryptophan oxidation (as tryptophan pyrrolase), nitric oxide synthesis (as nitric oxide synthase), hydrogen peroxide metabolism (as catalase and peroxidase) and other processes [2,3].…”

Section: Heme Biosynthesismentioning

confidence: 99%

“…AIP is caused by mutations in the HMBS gene which lead to about 50% deficiency of HMBS (EC 4.3.1.8) which catalyzes the condensation of 4 PBG molecules to hydroxymethylbilane [3].…”

Section: Acute Intermittent Porphyriamentioning

confidence: 99%

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Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria

2015

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Porphyrias are diverse disorders that arise from various inherited enzyme defects in the heme biosynthesis pathway, except for porphyria cutanea tarda (PCT), in which the enzyme deficiency in most cases is acquired. The biosynthetic blocks resulting from the defective enzymes are largely expressed either in the liver or bone marrow, the sites where the majority of heme is produced. Although the pathophysiologic mechanisms of the clinical manifestations of the porphyrias are not fully understood, two cardinal features prevail: skin photosensitivity and neurologic symptoms of intermittent autonomic neuropathy, acute neurovisceral attacks, and disorders of the nervous system. The primary diagnosis of the proband is based on biochemical testing, which is not always able to identify acute porphyrias, especially in asymptomatic family carriers when heme precursors and porphyrins excretion is normal, low-normal and high-reduced values of enzyme activity overlap, and hematological diseases responsible for abnormal blood cells distribution coexist. Molecular analysis of gene mutations responsible for each type of porphyria is the best diagnostic approach for symptomatic as well as presymptomatic gene carriers (Adv Clin Exp Med 2016, 25, 2, 361-368).

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Human hereditary hepatic porphyrias

Cited by 69 publications

References 79 publications

Psychosocial Aspects of Predictive Genetic Testing for Acute Intermittent Porphyria in Norwegian Minors

Psychosocial Aspects of Predictive Genetic Testing for Acute Intermittent Porphyria in Norwegian Minors

Structural basis of hereditary coproporphyria

Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria

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