Alternative titles; symbols
SNOMEDCT: 7425008; ICD10CM: E80.29; ORPHA: 79273; DO: 13269;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q11.2 | Coproporphyria | 121300 | Autosomal dominant; Autosomal recessive | 3 | CPOX | 612732 |
A number sign (#) is used with this entry because hereditary coproporphyria (HCP) is caused by heterozygous mutation in the CPOX gene (612732) on chromosome 3q12. Rare cases of homozygous mutation have been reported.
Biallelic mutation in the CPOX gene can cause harderoporphyria (HARPO; 618892), a variant form of coproporphyria.
Hereditary coproporphyria (HCP), an acute hepatic porphyria, is characterized by acute attacks of neurologic dysfunction often provoked by drugs, fasting, menstrual cycle, or infectious diseases. Skin photosensitivity may also be present. Inheritance is usually autosomal dominant, but autosomal recessive inheritance can also occur. Excretion of large amounts of coproporphyrin III, mostly in feces and urine, is observed (review by Schmitt et al., 2005).
The first case of coproporphyria, reported by Berger and Goldberg (1955), was the offspring of first-cousin parents, both of whom showed excessive excretion of coproporphyrin III. The authors suggested that the disorder is autosomal dominant and that their proband was homozygous.
Barnes and Whittaker (1965) described 4 of 5 sibs who were affected. The parents were not tested. Marked elevation of coproporphyria in the feces differentiated the condition from acute intermittent porphyria (AIP; 176000) in which stool porphyrins are usually normal and from variegate porphyria (VP; 176200) in which both coproporphyrin and protoporphyrin fractions are increased in the stool. The proband experienced typical acute porphyria. Constipation and abdominal colic were striking features in these patients.
Goldberg et al. (1967) added 20 new cases. A massive excretion of coproporphyrin III in the urine and predominantly in the feces was demonstrated. Attacks resembling those of AIP were precipitated by drugs, and during attacks porphobilinogen and delta-aminolevulinic acid were excreted in the urine in excess. Photosensitivity is occasionally present and the only manifestations may be psychiatric. About half of cases are asymptomatic. This is an hepatic form of porphyria.
In the family of Haeger-Aronsen et al. (1968), 13 persons in 5 sibships of 2 generations showed latent coproporphyria, in addition to the symptomatic proband.
Cripps and Peters (1970) found that tranquilizers, including meprobamate and chlorpromazine, precipitated attacks.
McIntyre et al. (1971) noted that increased hepatic delta-aminolevulinic acid synthetase has been demonstrated in 3 forms of hereditary porphyria: AIP, VP, and coproporphyria.
In cultured skin fibroblasts, Elder et al. (1976) found that the activity of coproporphyrinogen oxidase was about half normal. Similar findings were reported for leukocytes (Brodie et al., 1977). In the homozygous patient reported by Grandchamp et al. (1977), activity of coproporphyrinogen oxidase was only 2% of control values.
Andrews et al. (1984) found 27 cases of coproporphyria in a kindred in which 135 members were screened for fecal porphyrins. Of the 135, 6 females and 1 male had probably suffered clinical attacks; the M:F ratio of cases revealed by screening was 13:14. The proband had her first attack at age 84 years; diazepam and nitrazepam were incriminated in her attack, and other drugs in the other patients. The late manifestation is indicated by the fact that this report was from a department of geriatric medicine. The earliest attack in an affected person was at age 14 years.
Barohn et al. (1994) described acute peripheral neuropathy with hereditary coproporphyria. This is a common feature of AIP but is rare with this form of porphyria.
Gross et al. (2002) reported the molecular, enzymatic, and clinical study of a family with hereditary coproporphyria in which the proband was a 30-year-old woman suffering from acute crises with abdominal, neurologic, and psychiatric complaints. The proband's father, 1 brother, and a sister were found to be new carriers. The patient was treated with intravenous interval therapy with heme arginate for 10 months, with good clinical and metabolic response.
Dominant inheritance of coproporphyria seems adequately established (Goldberg et al. (1967)). The disorder shows incomplete penetrance (Hasanoglu et al., 2011).
Rare cases of coproporphyria are homozygous (see, e.g., Grandchamp et al., 1977 and Martasek et al., 1994).
In a study of a large family with genetically confirmed HCP, Allen et al. (2005) found that measurement of fecal coproporphyrin III:I ratio is a highly sensitive test for the detection of asymptomatic HCP. The proband was a 35-year-old man who presented with unexplained severe abdominal pain and was found to have an increased fecal coproporphyrin III:I ratio of 12.7. Total urine porphyrins were also elevated. There were 13 asymptomatic mutation carriers; all had an increased fecal coproporphyrin III:I ratio (mean 14.0, normal less than 1.0), and 11 (85%) had increased fecal total porphyrin. Eight (62%) of the 13 asymptomatic carriers had increased urinary total porphyrin (up to 3-fold) due to excess coproporphyrin III. All individuals studied were older than 10 years of age; the sensitivity of the test for those under 10 years of age was uncertain. Plasma fluorescence emission scanning for porphyrin was not a useful indicator.
In the homozygous patient with coproporphyria reported by Grandchamp et al. (1977), Martasek et al. (1994) demonstrated an arg231-to-trp mutation in the CPO gene (612732.0001).
Lamoril et al. (2001) studied 17 unrelated British patients with HCP. They identified 10 novel and 4 previously reported CPO mutations in 15 of the 17 patients. All but 1 mutation were restricted to a single family, with a predominance of missense mutations. Both patients in whom mutations were not identified had an unequivocal diagnosis of HCP. Complete deletions of the CPO gene were excluded by showing that both patients were heterozygous for at least 1 intragenic SNP. It is probable that the causative mutations either lie outside the regions that were sequenced or were partial deletions or insertions not detected by the PCR-based methods. The findings of this study demonstrated that single copies of CPO mutations that are known or predicted to cause 'homozygous' HCP or harderoporphyria can produce typical HCP in adults and demonstrated that the severity of the phenotype does not correlate with the degree of inactivation by mutation of the coproporphyrinogen oxidase enzyme.
In 5 of 9 Swedish families with HCP, Wiman et al. (2002) identified heterozygous mutations in the CPO gene. In each of 2 of the families, a novel mutation was identified: ser208 to phe (S208F; 612732.0010) and arg328 to cys (R328C; 612732.0011). In the affected members of the other 3 families, 2 previously reported mutations, R331W (612732.0001) and R447C (612732.0009), were shown to coexist on 1 allele. This was the first report of patients carrying 2 HCP-related mutations on the same allele.
Schmitt et al. (2005) noted that all 5 reported patients (from 3 families) with harderoporphyria had a K404E mutation (612732.0003) in the CPOX gene in homozygosity or compound heterozygosity with a null mutation. Biochemical and expression studies revealed that only a few missense mutations, restricted to 5 amino acids encoded by exon 6 (D400-K404), may accumulate significant amounts of harderoporphyrin. All types of mutations occurring elsewhere throughout the CPOX gene resulted in coproporphyrin accumulation and subsequently typical HCP. They stated that this was the first metabolic disorder in which clinical expression of overt disease depended on the location and type of mutation, resulting either in acute hepatic or in erythropoietic porphyria.
Allen, K. R., Whatley, S. D., Degg, T. J., Barth, J. H. Hereditary coproporphyria: comparison of molecular and biochemical investigations in a large family. J. Inherit. Metab. Dis. 28: 779-785, 2005. [PubMed: 16151909] [Full Text: https://doi.org/10.1007/s10545-005-0092-z]
Andrews, J., Erdjument, H., Nicholson, D. C. Hereditary coproporphyria: incidence in a large English family. J. Med. Genet. 21: 341-349, 1984. [PubMed: 6502649] [Full Text: https://doi.org/10.1136/jmg.21.5.341]
Barnes, H. D., Whittaker, N. Hereditary coproporphyria with acute intermittent manifestations. Brit. Med. J. 2: 1102-1104, 1965. [PubMed: 5838412] [Full Text: https://doi.org/10.1136/bmj.2.5470.1102]
Barohn, R. J., Sanchez, J. A., Anderson, K. E. Acute peripheral neuropathy due to hereditary coproporphyria. Muscle Nerve 17: 793-799, 1994. [PubMed: 8008008] [Full Text: https://doi.org/10.1002/mus.880170715]
Berger, H., Goldberg, A. Hereditary coproporphyria. Brit. Med. J. 2: 85-88, 1955. [PubMed: 14378650] [Full Text: https://doi.org/10.1136/bmj.2.4931.85]
Brodie, M. J., Thompson, G. G., Moore, M. R., Beattie, A. D., Goldberg, A. Hereditary coproporphyria: demonstration of the abnormalities in haem biosynthesis in peripheral blood. Quart. J. Med. 46: 229-241, 1977. [PubMed: 866576]
Connon, J. J., Turkington, V. Hereditary coproporphyria. Lancet 292: 263-264, 1968. Note: Originally Volume II. [PubMed: 4173691] [Full Text: https://doi.org/10.1016/s0140-6736(68)92359-3]
Cripps, D. J., Peters, H. A. Stool porphyrins in acute intermittent and hereditary coproporphyria: adverse effects of tranquilizers. Arch. Neurol. 23: 80-84, 1970. [PubMed: 4393048] [Full Text: https://doi.org/10.1001/archneur.1970.00480250084012]
Elder, G. H., Evans, J. O., Thomas, N., Cox, R., Brodie, M. J., Moore, M. R., Goldberg, A., Nicholson, D. C. The primary enzyme defect in hereditary coproporphyria. Lancet 308: 1217-1219, 1976. Note: Originally Volume II. [PubMed: 63041] [Full Text: https://doi.org/10.1016/s0140-6736(76)91143-0]
Goldberg, A., Rimington, C., Lochhead, A. C. Hereditary coproporphyria. Lancet 289: 632-636, 1967. Note: Originally Volume I. [PubMed: 4163920] [Full Text: https://doi.org/10.1016/s0140-6736(67)92538-x]
Grandchamp, B., Phung, N., Nordmann, Y. Homozygous case of hereditary coproporphyria. (Letter) Lancet 310: 1348-1349, 1977. Note: Originally Volume II. [PubMed: 74745] [Full Text: https://doi.org/10.1016/s0140-6736(77)90386-5]
Gross, U., Puy, H., Meissauer, U., Lamoril, J., Deybach, J. C., Doss, M., Nordmann, Y., Doss, M. O. A molecular, enzymatic and clinical study in a family with hereditary coproporphyria. J. Inherit. Metab. Dis. 25: 279-286, 2002. [PubMed: 12227458] [Full Text: https://doi.org/10.1023/a:1016598207397]
Haeger-Aronsen, B., Stathers, G., Swahn, G. Hereditary coproporphyria: study of a Swedish family. Ann. Intern. Med. 69: 221-227, 1968. [PubMed: 5667765] [Full Text: https://doi.org/10.7326/0003-4819-69-2-221]
Hasanoglu, A., Balwani, M., Kasapkara, C. S., Ezgu, F. S., Okur, I., Tumer, L., Cakmak, A., Nazarenko, I., Yu, C., Clavero, S., Bishop, D. F., Desnick, R. J. Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R. J. Inherit. Metab. Dis. 34: 225-231, 2011. [PubMed: 21103937] [Full Text: https://doi.org/10.1007/s10545-010-9237-9]
Hunter, J. A. A., Khan, S. A., Hope, E., Beattie, A. D., Beveridge, G. W., Smith, A. W. M., Goldberg, A. Hereditary coproporphyria. Photosensitivity, jaundice and neuropsychiatric manifestations associated with pregnancy. Brit. J. Derm. 84: 301-310, 1971. [PubMed: 5575195] [Full Text: https://doi.org/10.1111/j.1365-2133.1971.tb14223.x]
Kohno, H., Furukawa, T., Yoshinaga, T., Tokunaga, R., Taketani, S. Coproporphyrinogen oxidase: purification, molecular cloning, and induction of mRNA during erythroid differentiation. J. Biol. Chem. 268: 21359-21363, 1993. [PubMed: 8407975]
Lamoril, J., Puy, H., Gouya, L., Rosipal, R., Da Silva, V., Grandchamp, B., Foint, T., Bader-Meunier, B., Dommergues, J. P., Deybach, J. C., Nordmann, Y. Neonatal hemolytic anemia due to inherited harderoporphyria: clinical characteristics and molecular basis. Blood 91: 1453-1457, 1998. [PubMed: 9454777]
Lamoril, J., Puy, H., Whatley, S. D., Martin, C., Woolf, J. R., Da Silva, V., Deybach, J.-C., Elder, G. H. Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria. Am. J. Hum. Genet. 68: 1130-1138, 2001. [PubMed: 11309681] [Full Text: https://doi.org/10.1086/320118]
Lomholt, J. C., With, T. K. Hereditary coproporphyria: a family with unusually few and mild symptoms. Acta Med. Scand. 186: 83-85, 1969. [PubMed: 5807649]
Martasek, P., Nordmann, Y., Grandchamp, B. Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms. Hum. Molec. Genet. 3: 477-480, 1994. [PubMed: 8012360] [Full Text: https://doi.org/10.1093/hmg/3.3.477]
McIntyre, N., Pearson, A. J. G., Allan, D. J., Craske, S., West, G. M. L., Moore, M. R., Beattie, A. D., Paxton, J., Goldberg, A. Hepatic delta-aminolaevulinic acid synthetase in an attack of hereditary coproporphyria and during remission. Lancet 297: 560-564, 1971. Note: Originally Volume I. [PubMed: 4100900] [Full Text: https://doi.org/10.1016/s0140-6736(71)91161-5]
Roberts, D. T., Brodie, M. J., Moore, M. R., Thompson, G. G. G., Goldberg, A., MacSween, R. N. M. Hereditary coproporphyria presenting with photosensitivity induced by the contraceptive pill. Brit. J. Derm. 96: 549-554, 1977. [PubMed: 871392] [Full Text: https://doi.org/10.1111/j.1365-2133.1977.tb07161.x]
Schmitt, C., Gouya, L., Malonova, E., Lamoril, J., Camadro, J.-M., Flamme, M., Rose, C., Lyoumi, S., Da Silva, V., Boileau, C., Grandchamp, B., Beaumont, C., Deybach, J.-C., Puy, H. Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria. Hum. Molec. Genet. 14: 3089-3098, 2005. [PubMed: 16159891] [Full Text: https://doi.org/10.1093/hmg/ddi342]
Wiman, A., Floderus, Y., Harper, P. Two novel mutations and coexistence of the 991C-T and the 1339C-T mutation on a single allele in the coproporphyrinogen oxidase gene in Swedish patients with hereditary coproporphyria. J. Hum. Genet. 47: 407-412, 2002. [PubMed: 12181641] [Full Text: https://doi.org/10.1007/s100380200059]