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PubMed2000

Hereditary coproporphyria in Germany: clinical-biochemical studies in 53 patients.

OBJECTIVES: To describe the biochemical and clinical features in hereditary coproporphyria (HCP). DESIGN AND METHOD: Within the last 20 years, we investigated 53 patients (male:female = 1:2.5; age = 8-86 years) suffering from HCP. We describe the characteristic levels of urine, and fecal porphyrins and their precursors in hereditary coproporphyria and present the clinical features. Especially, we measured the coproporphyrin isomers I and III. RESULTS AND CONCLUSION: The group of hereditary coproporphyria patients exhibited a significantly higher (p<0.0001) excretion of urinary porphyrin precursors, delta-aminolevulinic acid (median = 84 micromol/24 h) and porphobilinogen (median = 39 micromol/24 h), as compared to controls (delta-aminolevulinic acid: 22 micromol/24 h, porphobilinogen: 3 micromol/24 h; median, n = 20). The median of coproporphyrin in urine (1315 nmol/24 h) and feces (1855 nmol/g) were enhanced 12- and 168-fold, as compared to healthy subjects (urinary coproporphyrin: 106 nmol/24 h, fecal coproporphyrin: 11 nmol/g; median, n = 20). During therapy on one female patient, with IV application of heme arginate, a considerable decline of porphyrin precursors and porphyrin excretion was observed. The examination of urinary and fecal coproporphyrin isomers I and III revealed an excessive elevation of the coproporphyrin isomer III of 87% in urine and 94% in feces, respectively (normal: urinary isomer III = 69-83% and fecal isomer III = 25-40%). In feces the increase of isomer III caused an inversion of the physiologic coproporphyrin isomer III:I ratio that could be recognized in all various stages in hereditary coproporphyria and in children. Acute attacks of hereditary coproporphyria are accompanied by an acute polysymptomatic clinical syndrome, and this is associated with high levels of urinary porphyrin precursors. On review of our patients, the highest percentage had abdominal pain (89%), followed by neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

Adolescent↗
PubMed1993

Hereditary coproporphyria: a case report.

A case of hereditary coproporphyria was reported, he was a 21-year-old farmer, presenting with abdominal pain and fever. His manifestations were composed of all classical symptoms of acute hepatic porphyrias i.e. convulsions, psychosis, hypertension and respiratory failure as well as dark red urine with positive Watson-Schwartz test. Because of lack of cutaneous photosensitivity and strikingly increased urinary coproporphyrin, diagnosis of hereditary coproporphyria was most likely. Precipitating factor could not be identified. He responded well to glucose and other symptomatic treatment during the first admission but not in the second. He died from respiratory failure.

Adult↗
PubMed2002

[Coexistence of hereditary coproporphyria and porphyria cutanea tarda: a new form of dual porphyria].

BACKGROUND: Dual porphyrias are characterized by two independent disturbances of porphyrin metabolism. PATIENT AND METHODS: At first a porphyria cutanea tarda was diagnosed in a 26-year-old female with back pain and red urine. Later a hereditary coproporphyria was ascertained by additional examinations. The metabolites of porphyrin metabolism were analyzed chromatographically. The activities of coproporphyrinogen oxidase and uroporphyrinogen decarboxylase were determined in blood cells. Molecular analysis was carried out by denaturing gradient gel electrophoresis followed by direct sequencing. RESULTS: Excessive porphyrinuria of 3,128 nmol/24 h (normal < 165 nmol/24 h) with dominance of uro- and heptacarboxyporphyrin (75% of total porphyrins) indicated that the patient suffered from porphyria cutanea tarda. The course of the examination showed an alteration of the constellation with dominance of urinary and fecal coproporphyrin isomer III, which is characteristic for hereditary coproporphyria. Porphyrin precursors and porphyrins increased under the application of ethinylestradiol-cyproteronacetat. The dominance of coproporphyrin III stayed constant in feces besides enhanced urinary uro- and heptacarboxyporphyrin. The activity of the coproporphyrinogen oxidase was diminished to 35%. The uroporphyrinogen decarboxylase in erythrocytes was normal. The mother and both sisters were recognized as heterozygous gene carriers of hereditary coproporphyria in the latent phase by enhanced coproporphyrin with isomer I/III inversion in feces and decrease of the coproporphyrinogen oxidase activity to about 50%. Molecular analyses resulted in a point mutation at exon 4 (854C-->T), which revealed in an amino acid exchange (P258L) in the coproporphyrinogen oxidase protein. CONCLUSION: The hereditary coproporphyria is caused by a new mutation in the coproporphyrinogen oxidase gene in the case of a dual porphyria with co-existence of porphyria cutanea tarda and hereditary coproporphyria. The sporadic, hepatic porphyria cutanea tarda Type I is induced by estrogens. The large excretory variations reflect the influence of hormonal factors on the porphyria process of hereditary coproporphyria and porphyria cutanea tarda.

Adult↗
PubMed1997

Hereditary coproporphyria: exon screening by heteroduplex analysis detects three novel mutations in the coproporphyrinogen oxidase gene.

Hereditary coproporphyria is a dominantly inherited disorder of porphyrin metabolism caused by a partial deficiency of coproporphyrinogen oxidase, the sixth enzyme in the heme synthetic pathway. We investigated the molecular basis of hereditary coproporphyria in three unrelated patients, amplifying each exon of the coproporphyrinogen oxidase gene and performing heteroduplex analysis to look for mutations. Unique heteroduplex patterns were noted in exons 2, 3, and 6. Sequencing revealed different mutations in each patient: a G-->A point mutation encoding a glutamic acid to lysine substitution at codon 101 (E101K), a C-->T point mutation encoding a proline to serine substitution at codon 149 (P149S), and a one base-pair insertion in exon 6 (968insT). No other mutations were found on sequencing the remaining exons and their intron-exon junctions. The two point mutations affect amino acids that are conserved in all species studied to date. The one base-pair insertion in exon 6 is the first frameshift mutation to be described in the coproporphyrinogen oxidase gene. This study adds three new mutations to those that have been previously reported, and all have been restricted to single families. These results indicate that hereditary coproporphyria is a genetically heterogeneous disease.

Amino Acid Sequence↗
PubMed2005

Hereditary coproporphyria: comparison of molecular and biochemical investigations in a large family.

Hereditary coproporphyria (HCP) is the least common of the three autosomal dominant acute porphyrias. To compare the sensitivity of metabolite measurements for the identification of asymptomatic HCP, we carried out a molecular and biochemical investigation of a large family in which HCP is caused by a previously unreported frameshift mutation (c.119delA). Thirteen of 19 asymptomatic family members, aged 10-72 years, were shown by mutational analysis to have HCP. The faecal coproporphyrin isomer III:I ratio was increased in all of these 13 family members; faecal total porphyrin concentration and urinary porphyrin excretion were increased in 11 and 8 of them, respectively. Plasma porphyrin concentrations were marginally increased in three individuals and plasma fluorescence emission scanning showed a porphyrin peak at 618 nm in two of these. Our results add to the evidence that an increased faecal porphyrin coproporphyrin III:I ratio is a highly sensitive test for the detection of clinically latent HCP in individuals over the age of 10 years; its sensitivity below this age remains uncertain. They also show that plasma fluorescence emission scanning is not useful for the investigation of families with HCP.

Adolescent↗
PubMed1977

Hereditary coproporphyria. Demonstration of the abnormalities in haem biosynthesis in peripheral blood.

Hereditary coproporphyria is biochemically distinct from the other porphyrias and is characterized by excessive excretion of coproporphyrin in faeces and usually in urine. The laboratory findings in 28 patients with this disease are presented and the clinical details of eight patients who have been in attack summarised. The remaining 20 patients were latent for the disease. In all patients studied the activity of delta-aminolaevulinic acid synthase was raised and coproporphyrinogen oxidase depressed in the leucocyte. This indicates the partial enzyme block in the haem biosynthetic pathway in this disease. The activities of the other enzymes in the pathway, leucocyte ferrochelatase and erythrocyte delta-aminolaevulinic acid dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase showed no consistent change. On review of 111 cases, 35 per cent presented in acute attack: 80 per cent had abdominal pain, 34 per cent vomiting, 29 per cent solar sensitivity, 23 per cent neurological involvement, 23 per cent psychiatric symptoms and 20 per cent severe constipation. Only two fatalities have been published, both from respiratory failure. There was a female preponderance of cases in attack of 2-5:1 and in the latent cases of 1-5:1 suggesting hormonal provocation in the uncovering of the disease. Drugs were implicated as precipitating 54 per cent of acute attacks and in 34 per cent of cases, these were barbiturates. This study demonstrates the reduction in activity of coproporphyrinogen oxidase in the haem biosynthetic pathway and the elevation of delta-aminolaevulinic acid synthase in the peripheral blood. These features, together with the typical abnormal porphyrin excretion pattern, appear to be diagnostic of hereditary coproporphyria whether in attack, remission, or in the latent form.

5-Aminolevulinate Synthetase↗
PubMed2005

Biochemical and genetic characterization of four cases of hereditary coproporphyria in Spain.

We report a biochemical and genetic characterization of four cases of hereditary coproporphyria (HCP) in Spain. All patients showed a typical HCP porphyrin excretion pattern with a high concentration of coproporphyrins in feces and inverted I:III isomer ratio. The porphyrin precursors in urine were found elevated in two patients who showed acute symptoms. The analysis of the CPO gene showed that three cases harboured novel mutations: V135A (404T>C; exon 1); L214R (641T>G; exon 2); and P249R (746C>G; exon 3) and in the fourth, a previously described R426X mutation in exon 6.

Adult↗
PubMed1983

Harderoporphyria: a variant hereditary coproporphyria.

Three siblings with intense jaundice and hemolytic anemia at birth were found to excrete a high level of coproporphyrin in their urine and feces; the pattern of fecal porphyrin excretion was atypical for hereditary coproporphyria because the major porphyrin was harderoporphyrin (greater than 60%; normal value is less than 20%). The lymphocyte coproporphyrinogen III oxidase activity of each patient was 10% of control values, which suggests a homozygous state. Both parents showed only mild abnormalities in porphyrin excretion and lymphocyte coproporphyrinogen III oxidase activity decreased to 50% of normal values, as is expected in heterozygous cases of hereditary coproporphyria. Kinetic parameters of coproporphyrinogen III oxidase from these patients were clearly modified, with a Michaelis constant 15-20-fold higher than normal values when using coproporphyrinogen or harderoporphyrinogen as substrates. Maximal velocity was half the normal value, and we also observed a marked sensitivity to thermal denaturation. The possibility that a mutation affecting the enzyme on the active center which is specifically involved in the second decarboxylation (from harderoporphyrinogen to protoporphyrinogen) was eliminated by experiments on rat liver that showed that coproporphyrinogen and harderoporphyrinogen were metabolized at the same active center. The pattern of porphyrin excretion and the coproporphyrinogen oxidase from the three patients exhibited abnormalities that were different from the abnormalities found in another recently described homozygous case of hereditary coproporphyria. We suggest naming this variant of coproporphyrinogen oxidase defect "harderoporphyria."

Animals↗
PubMed2001

Neonatal-onset hereditary coproporphyria with male pseudohermaphrodism.

The appearance of hereditary coproporphyria (HCP) before puberty is very rare, and all reported cases of early-onset HCP have been in the homozygous or the compound heterozygous state. Some have been identified as harderoporphyria, which is a rare erythropoietic variant form of HCP. These conditions can be differentiated by molecular analysis because the gene abnormality responsible for harderoporphyria seems to be unique (K404E). Early-onset HCP, not harderoporphyria, is reported with a gene mutation in the heterozygous state and male pseudohermaphrodism. It was shown that adrenal gland hypofunction resulted in male pseudohermaphrodism. This case demonstrates the possibility that abnormalities of steroid metabolism influence porphyria.

Adrenal Insufficiency↗
PubMed1975

Urinary excretion of 17-oxosteroids in hereditary coproporphyria.

1. Urinary 17-oxosteroid conjugates were measured by gas-liquid chromatography in five patients with hereditary coproporphyria. 2. Three patients were in an acute attack and showed significantly increased excretion of sulphate or glucuronide conjugates of aetiocholanolone. There was increased excretion of several other related steroids but no consistent pattern was apparent. 3. In the two patients in remission, excretion of urinary 17-oxosteroids was not increased. 4. The ratio of total urinary aetiocholanolone to androsterone (5beta:5alpha) was found to be significantly elevated for the three patients in an acute attack. Serial measurements were made in two of these patients and showed a highly significant linear correaltion between this ratio and the urinary content of delta-aminolaevulic acid and porphobilinogen. 5. These observations suggest the involvement of the 17-oxosteroids, espically aetiocholanolone, in the pathogenesis of hereditary coproporphyria.

17-Ketosteroids↗
PubMed1992

Effects of erythromycin on gut transit in pseudo-obstruction due to hereditary coproporphyria.

We studied gastrointestinal transit in a 57-year-old man with chronic intestinal pseudo-obstruction along with peripheral and autonomic neuropathy due to hereditary coproporphyria and we evaluated the effects of acute and chronic therapy with erythromycin. Noninvasive scintigraphic studies of regional transit of solid residue through the gut were obtained before treatment, during the acute i.v. administration of 500 mg, every-8-h doses of erythromycin for 24 h and after 15 weeks of oral therapy (500 mg, three times daily). During acute i.v. administration, symptoms and transit measurements dramatically improved; however, all parameters and symptoms returned to pretreatment levels during chronic oral therapy. We conclude that hereditary coproporphyria with associated autonomic neuropathy results in significant delay in small bowel and colonic transit; chronic administration of 500 mg three times a day oral erythromycin was not associated with maintenance of the improvement in regional transit and symptoms observed following acute i.v. administration of the drug at the same dose.

Administration, Oral↗
PubMed2004

Identification of monovinyl tripropionic acid porphyrins and metabolites from faeces of patients with hereditary coproporphyria by high-performance liquid chromatography/electrospray ionization quadrupole time-of-flight tandem mass spectrometry.

Harderoporphyrin (2-vinyl-4,6,7-tripropionic acid porphyrin) and its metabolites in faeces of patients with hereditary coproporphyria (HCP) have been separated and characterized by high-performance liquid chromatography/electrospray ionization quadrupole time-of-flight tandem mass spectrometry (HPLC/ESI-Q-TOFMS/MS). The metabolites identified were 2-ethyl-4,6,7-tripropionic acid porphyrin, 2-hydro-4,6,7-tripropionic acid porphyrin, 2-methoxyethyl-4,6,7-tripropionic acid porphyrin and 2-acetyl-4,6,7-tripropionic acid porphyrin. Isomers of harderoporphyrin derived from isomerization of harderoporphyrinogen were also detected.

Chromatography, High Pressure Liquid↗
PubMed1977

Hereditary coproporphyria presenting with photosensitivity induced by the contraceptive pill.

A 26-year-old woman developed photosensitivity and jaundice after starting on an oral contraceptive agent. She was found to have hereditary coproporphyria. Histological examination of two liver biopsies taken during and after the acute attack did not reveal any changes thought to be due to hereditary coproporphyria. Screening of the patient's family revealed a further six latent cases.

Adult↗