Gunther's disease
Porphyrias

Author: chiara burzio
Date: 20/10/2007

Description

Introduction

This disease is extremely rare and is autosomal recessive.
The deficient enzyme is uroporphyrinogen III cosynthase
Various mutations in the gene for this enzyme have been identified in different families. As is characteristic of the erythropoietic porphyrias, symptoms begin during infancy. Sometimes CEP is recognized as a cause of anemia in a fetus before birth. In less severe cases symptoms may begin during adult life. Porphyrins are markedly increased in bone marrow, red blood cells, plasma, urine and feces. Porphyrins are also deposited in the teeth and bones.

Pathogenesis

Different kind of mutation of the gene for uroporphyrinogen III human cosynthetasis have been identified.The big part of patients has got parents not related and has ereditated a different mutation from everybody. Even in the worst cases persist a certain rest activity of cosynthetasis. The heme production is actually increased in answer to an haemolytic anaemy, but that happens to disadvantage of a considerable accumulation of HMB, the deficient enzyme substrate. The HMB in exess is converted without enzyme in uroporphyrinogen I and then with the enzyme in coproporphyrinogen I. The porphyrinogenes type I are not precursors of heme and when they pile up they are oxydated spontaneously in the correspondent porphyrines. The excess of porphyrines pile up in the bone marrow mostly at the maturative stage of erithroide cells, when the haemoglobin synthesis is more active. Red blood cells have a shortened life-span, and anaemia often results. Synthesis of home and haemoglobin is actually increased to compensate for the shortened red blood cell survival.

Signs and sinthoms

The coetaneous bladder formation is usually severe; it starts precociously after the birth ad is accompanied by anaemy and red urines. Some cases are soft with the manifestation in adult age. The severe expression depends on some mutations present in each patient ad on the entity of the enzymatic deficit. Cases especially graves had got a manifestation like a prenatal not autoimmunitary hydrope, a condition that needs intra-uterine transfusion and (if the disease has been not recognised before or immediately after the birth) as a pronounced photosensitivity which develops at the beginning of the phototherapy for the prenatal citrus. These cases can take advantage of the intra-uterine diagnosis. The amniotic liquid can be red because of the high content of porphyries. Skin photosensitivity may be extreme and lead to blistering, severe scarring and increased hair growth. Bacteria may infect the damaged skin. Facial features and fingers may be lost through phototoxic damage as well as infection. Ipertricosis and alteration of pigmentation are common. The corneal blistering can be graves. Porphyries settle on teeth (which determines a brown-reddish coloration called eritrodontia and in the bone.

The bone demineralisation can be heavy. Almost always there are haemolytic anaemy and splenomegaly; the splenomegaly can contribute to anaemy and to cause leucopoenia and thrombocytopenia (ipersplenism). Anaemy stimulating bone marrow to produce more quantity of erithroid cells rich in porphyrines, increasing the production of porphyrines and perpetuating hemolysis and photosensitivity. Drugs, hormones (different from endogen erythropoietin) and nutritional factors (different from vitaminic lack which can damage the bone marrow) have got scarce influence on the disease. There are not neurologic manifestations.

Diagnosis

This type of porphyria is diagnosticated as the other porphyrias.
The diagnosis of CEP is also suggested from the presence of pink/red/brown urines and/or the appearance of a photosensitivity during the childhood (or, rarely, in adult age). It also appear in womb as a non autoimmunitary hydrope. . 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. Another possibility is a generic test to find the mutation responsible of the disease
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 looking for that mutation in fetal DNA. The same method can be done on umbilical cord blood to individuate from the birth if the child is carrier of the type of porphyria which is afflicted one of his parents.

Therapy and prevention

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. It is important to give to the patient a diet rich in carbohydrates and against the photosensitivity the patients have to repair themselves from the light using adapt creams and wearing specific induments. A subministration of beta-carotene (systemic way) is also important.
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-50s, 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.

Outline of therapy

• Beta-carotene is sometimes useful
• Blood transfusions sometimes can origine a too great quantity of iron in blood
• Splenectomy allows sometimes a reduction of hemolysis and of transfusion
• Sunlight protection
• Protection against skin traumas
Transplantation of bone marrow
• Genetic therapy
Stem cells transplantation

congenital erythropoietic porphyria in two siblings

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