SNOMEDCT: 238056003; ORPHA: 659672;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q11.2 | Harderoporphyria | 618892 | Autosomal recessive | 3 | CPOX | 612732 |
A number sign (#) is used with this entry because of evidence that harderoporphyria (HARPO) is caused by homozygous or compound heterozygous mutation in the CPOX gene (612732) on chromosome 3q12.
Heterozygous mutations in the CPOX gene cause coproporphyria (HCP; 121300).
Harderoporphyria (HARPO) is a rare erythropoietic variant form of hereditary coproporphyria (HCP; 121300) characterized by neonatal hemolytic anemia, sometimes accompanied by skin lesions, and massive excretion of harderoporphyrin in feces. During childhood and adulthood, a mild residual anemia is chronically observed (review by Schmitt et al., 2005).
In 3 sibs (2 boys, 1 girl) with intense jaundice and hemolytic anemia at birth, Nordmann et al. (1983) found a high level of coproporphyrin in the urine and feces. The pattern of fetal porphyrin excretion was atypical because the major porphyrin was harderoporphyrin (more than 60%; normal, less than 20%). Homozygosity was suggested by the fact that the level of lymphocyte coproporphyrinogen III oxidase was 10% of controls in the sibs and 50% of normal in both parents (who showed only mild abnormalities of porphyrin excretion). The mutant enzyme showed abnormal kinetics.
Doss et al. (1984) likewise reported a case of harderoporphyria. The parents were related, and the enzyme level was 7% in the patient and 53% in the mother; thus, homozygosity was suggested. The proband had severe jaundice, hemolytic anemia, and hepatosplenomegaly at birth. At age 10, slight photosensitivity and mild, compensated hemolytic anemia prompted diagnostic search for porphyria.
Schmitt et al. (2005) reported a fifth patient with harderoporphyria. They demonstrated that harderoporphyric patients exhibit iron overload secondary to dyserythropoiesis.
Hasanoglu et al. (2011) reported a Turkish male infant, born of consanguineous parents, with harderoporphyria. He presented with neonatal jaundice, hemolytic anemia, and severe cutaneous photosensitivity. At age 1.5 months, he had an acute porphyric attack characterized by hepatosplenomegaly, elevated liver enzymes, red urine, metabolic acidosis, and severe Coombs-negative hemolytic anemia. The child died at age 5 months. Laboratory studies showed increased urinary porphyrins, increased aminolevulinic acid, and porphobilinogen; fecal porphyrins were not measured.
Schmitt et al. (2005) noted that all 5 reported cases of harderoporphyria have homozygous or compound heterozygous mutations, indicating recessive inheritance.
In the 3 sibs with the harderoporphyria variant reported by Nordmann et al. (1983), Lamoril et al. (1995) demonstrated a K404E missense mutation in exon 6 of the CPO gene (see 612732.0003).
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.
In a Turkish male infant, born of consanguineous parents, with harderoporphyria, Hasanoglu et al. (2011) identified a homozygous H327R mutation in the CPOX gene (612732.0014). The mutation occurred at a highly conserved residue involved in the enzyme's conversion of harderoporphyrinogen to protoporphyrinogen IX. The unaffected parents and an unaffected brother were all heterozygous for the mutation. Functional studies of the variant were not performed, but structural analysis suggested that it would alter the enzyme's structure and affect the second decarboxylation step. The findings expanded the genotype/phenotype correlations for this disease.
Doss, M., von Tiepermann, R., Kopp, W. Harderoporphyrin coproporphyria. (Letter) Lancet 323: 292 only, 1984. Note: Originally Volume I. [PubMed: 6143037] [Full Text: https://doi.org/10.1016/s0140-6736(84)90169-7]
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]
Lamoril, J., Martasek, P., Deybach, J.-C., Da Silva, V., Grandchamp, B., Nordmann, Y. A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria. Hum. Molec. Genet. 4: 275-278, 1995. [PubMed: 7757079] [Full Text: https://doi.org/10.1093/hmg/4.2.275]
Nordmann, Y., Grandchamp, B., de Verneuil, H., Phung, L., Cartigny, B., Fontaine, G. Harderoporphyria: a variant hereditary coproporphyria. J. Clin. Invest. 72: 1139-1149, 1983. [PubMed: 6886003] [Full Text: https://doi.org/10.1172/JCI111039]
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]