Alternative titles; symbols
SNOMEDCT: 190913009, 22935002, 67312003; ICD10CM: E80.0; ORPHA: 79277; DO: 13271;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q26.2 | Porphyria, congenital erythropoietic | 263700 | Autosomal recessive | 3 | UROS | 606938 |
A number sign (#) is used with this entry because congenital erythropoietic porphyria (CEP) is caused by homozygous or compound heterozygous mutation in the uroporphyrinogen III synthase gene (UROS; 606938) on chromosome 10q26.
The porphyrias are diseases caused by defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver (Gross et al., 2000).
Desnick and Astrin (2002) provided a comprehensive review of congenital erythropoietic porphyria pathogenesis and treatment.
One patient with a phenotype suggestive of congenital erythropoietic anemia was found to have a mutation in the GATA1 gene (305371.0010) that affected UROS expression (see XLTT, 314050).
The most dramatic form of genetic porphyria is that which was early recognized as an inborn error of metabolism by Gunther (Dean, 1972). It is associated with lifelong overproduction of series I porphyrins which circulate and are deposited in many tissues, causing light-sensitization and severe damage to skin beginning in childhood. Blistering and scarring of exposed areas may lead to mutilating deformity. Hypertrichosis is sometimes severe. Uroporphyrin I and coproporphyrin I are found in plasma, red blood cells, urine, and feces. Red urine may be observed from infancy, and the teeth become stained red. Hemolytic anemia, an additional complication, may be helped by splenectomy (Meyer and Schmid, 1978). Gunther called this condition congenital haematoporphyria. Watson et al. (1958) renamed it erythropoietic porphyria.
Nordmann et al. (1990) described an infant girl who had inherited Gunther disease from both parents and coproporphyria (121300) from her mother. In the newborn period the patient developed intense jaundice with hepatosplenomegaly associated with diffuse bleeding and thrombocytopenia. On the tenth day of life the baby showed a rash with blisters on the backs of the hands and red discoloration of the urine. Porphyria was established by high levels of porphyrins in the urine, feces, and blood. During the next 2 years transfusions were required because of hemolysis. Skin photosensitivity with blistering, fragility, hypertrichosis of the face, and erythrodontia developed. Somatic and mental development were poor. Each of the 2 forms of porphyria was established by enzymatic study. The biologic features of coproporphyria predominated during the first days of life.
Adult-Onset Form
Deybach et al. (1981) described a mild form of congenital erythropoietic porphyria with onset in adulthood. Rank et al. (1990) reported what they stated to be the sixth report of adult onset of congenital erythropoietic porphyria. A beneficial effect of hematin therapy was observed. Murphy et al. (1995) described a man who developed cutaneous signs of congenital erythropoietic porphyria at the age of 65 years, 5 years after the onset of symptomatic thrombocytopenia. Persistent thrombocytopenia unresponsive to corticosteroids and immunoglobulin necessitated a splenectomy. Photosensitivity, hemolytic anemia, and hypersplenism are prominent features of adult-onset Gunther disease and thrombocytopenia had been documented in several cases. In the patient reported by Murphy et al. (1995), platelet sequestration studies implicated the spleen as the major site of platelet consumption; however, platelet-associated IgG antibodies were also present. Four weeks following splenectomy, the platelet count rose and stabilized and remained stable 1 year later.
Congenital erythropoietic porphyria is an autosomal recessive condition. Most other forms of genetic porphyria are dominantly inherited (121300, 176000, 176100, 176200). Acute hepatic porphyria is apparently recessive (see 125270).
As would be expected for an enzyme deficiency, autosomal recessive inheritance of congenital erythropoietic porphyria is well documented, with multiple sib cases and increased consanguinity in parents; obligate heterozygotes have intermediate levels of uroporphyrinogen III cosynthetase activity (Romeo et al., 1970). The patient described by Nordmann et al. (1990) was an Algerian girl, born to first-cousin parents. The patient described by Pollack and Rosenthal (1994) was the offspring of first-cousin parents and showed organomegaly, hemolytic anemia, thrombocytopenia, and cutaneous blisters.
Tsai et al. (1987) described an enzymatic method for the diagnosis of heterozygotes and homozygotes. Pollack and Rosenthal (1994) illustrated the diagnosis of this disorder in a neonate by examining a urine-soaked diaper under Wood's light. Urine and feces of patients contain increased levels of uroporphyrinogen I and coproporphyrinogen I (Gross et al., 2000).
Prenatal Diagnosis
Uroporphyrinogen III cosynthetase is expressed in cultured amniotic cells so that prenatal diagnosis is possible (Deybach et al., 1980). Since the chromosomal assignment and molecular genetics of congenital erythropoietic porphyria have been determined, prenatal diagnosis by genetic analysis is possible (Lim and Cohen, 1999).
Piomelli et al. (1986) showed that by suppressing erythropoiesis with high-level transfusions, one can prevent symptoms of this disorder. As their patient grew older, transfusion requirements to keep the hematocrit above the desired 39% increased, but the requirement was reduced by splenectomy, indicating that the spleen is a factor in the hemolytic anemia. Iron overload was mitigated by slow infusions of deferoxamine.
Pimstone et al. (1987) reviewed the various forms of therapy that have been used in this disorder: splenectomy, hypertransfusion, and orally administered sorbents such as charcoal and cholestyramine, which bind porphyrins and retard intestinal absorption of endogenous porphyrins excreted into the gut lumen. In a man in his mid-fifties, Pimstone et al. (1987) found that charcoal was more effective than cholestyramine and that treatment with charcoal for 9 months lowered porphyrin levels in plasma and skin and resulted in a complete clinical remission. Measurements of subnormal red cell uroporphyrinogen decarboxylase activity and urinary, fecal, and plasma porphyrin analyses in this patient and his 7 children indicated classic features of familial porphyria cutanea tarda (176100). They concluded that their patient had an atypical form of congenital erythropoietic porphyria similar to that described by Eriksen and Eriksen (1977). The authors pointed out that the usefulness of charcoal therapy in photocutaneous porphyrias other than this form and in reversing the hepatic lesion in patients with protoporphyric liver disease remains to be explored. Subtle complications of long-term charcoal ingestion, such as nutrient malabsorption or systemic absorption of charcoal, require further evaluation.
Tezcan et al. (1998) stated that allogeneic bone marrow transplantation (BMT) had been performed in 3 patients with CEP. They demonstrated long-term biochemical and clinical effectiveness of BMT performed in a severely affected, transfusion-dependent 18-month-old female with CEP. Three years post-BMT, the recipient had normal hemoglobin, markedly reduced urinary uroporphyrin excretion, and no cutaneous lesions despite unlimited exposure to sunlight. The patient was homoallelic for a novel UROS missense mutation, G188R (606938.0010), that expressed less than 5% of mean normal activity of the enzyme in E. coli, consistent with her transfusion dependency. Tezcan et al. (1998) emphasized that because the clinical severity of CEP is highly variable, ranging from nonimmune hydrops fetalis to milder, later-onset forms with only cutaneous lesions, it is important to genotype newly diagnosed infants to select severely affected patients for BMT. The long-term effectiveness of BMT in their patient provided the rationale for future hematopoietic stem cell gene therapy in severely affected patients.
Deficiency of the enzyme uroporphyrinogen III cosynthetase was demonstrated in peripheral blood (Levin, 1968; Romeo and Levin, 1969) and cultured fibroblasts (Romeo et al., 1970). Kappas et al. (1983) stated that the mechanism of the hemolytic anemia in CEP was poorly understood; it obviously creates a vicious cycle by leading to exaggerated erythropoiesis. Petry, the famous CEP patient studied by Gunther and by Hans Fischer (pictured by Kappas et al., 1983), was thought to have died of pernicious anemia and splenomegaly but the published autopsy findings were said to be more suggestive of hemolytic anemia.
In a patient with Gunther disease, Deybach et al. (1990) and Warner et al. (1990) found a mutation in codon 73 of the uroporphyrinogen III synthase gene (606938.0001). Xu et al. (1996) stated that 17 mutations in the UROS gene had been reported as the basis of CEP: 11 missense, 1 nonsense, 2 mRNA splicing defects, 1 deletion, and 2 coding region insertions.
Congenital erythropoietic porphyria is exceedingly rare; as of 1997, about 130 cases had been reported (Fritsch et al., 1997).
An analogous disorder has been described in several animal species; the best-delineated animal model is in cattle, in which autosomal recessive inheritance is well demonstrated (Watson et al., 1958; Levin, 1968), but congenital erythropoietic porphyria is said to be dominant in swine and in cats (Glenn et al., 1968).
All fox squirrels (Sciurus niger) exhibit a species characteristic resembling congenital erythropoietic porphyria in humans (Levin and Flyger (1971, 1973)). Flyger and Levin (1977) noted that this appears to be the only mammalian species that possesses this characteristic except as a rare pathologic condition. However, the condition in fox squirrels is accompanied by neither skin lesions nor hemolytic anemia.
Bishop et al. (2006) generated knockin mice with 3 missense mutations in the Uros gene. Mice homozygous for all 3 mutations were fetal lethals, except for those homozygous for a spontaneous recombinant allele. Mice homozygous for the recombinant allele had 20% of wildtype URO-synthase activity in erythrocytes, apparently sufficient for fetal development and survival. The mice showed marked porphyrin I isomer accumulation in erythrocytes, bone, tissues, and excreta and had fluorescent erythrodontia, hemolytic anemia with reticulocytosis and extramedullary erythropoiesis, and, notably, the characteristic light-induced cutaneous involvement. These mice provided insight into why congenital erythropoietic porphyria is an erythroid porphyria and should facilitate studies of the disease pathogenesis and therapeutic endeavors.
Robert-Richard et al. (2008) studied the feasibility of gene therapy in a murine model of congenital erythropoietic porphyria. Lentivirus-mediated transfer of the human UROS cDNA into hematopoietic stem cells (HSCs) from the mouse model Uros(mut248) resulted in a complete and long-term enzymatic, metabolic, and phenotypic correction of the disease, favored by a survival advantage of corrected red blood cells. The results demonstrated the cure of this mouse model of CEP at a moderate transduction level, thus providing proof of concept of a gene therapy in this disease by transplanting genetically modified hematopoietic stem cells.
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