Deficiency Of Uroporphyrinogen Decarboxylase Research Articles

Scleral Necrosis in Porphyria Cutanea Tarda: A Case Report

Scleral necrosis is a rare but well documented ocular manifestation of Porphyria Cutanea Tarda (PCT). The PCT is caused by a deficiency of Uroporphyrinogen Decarboxylase (Uro-D). The typical clinical manifestations of PCT in the form of cutaneous photosensitivity are due to the accumulation of fluorescent polycarboxylated porphyrins. Here, a case of 30-year-old male patient who was referred to the cornea services department for scleral thinning in right eye has been presented. Slit lamp biomicroscopy revealed focal area (5×5 mm2 ) of punched out scleral thinning (>80%) with uveal show in the interpalpebral area, 2 mm temporal to the limbus in right eye and a partial thickness scleral melt in nasal area. The left eye was phthisical. Patient had multiple blisters and pigmented, slightly depressed scars on the skin, especially in the sun-exposed parts such as face, hands and legs. Digital shortening, atrophy and contractures were seen in hands and legs. Based on the clinical, biochemical and dermatological evaluation, the diagnosis of PCT was made. A rare case of scleral necrosis with uveal show in a patient with PCT which was successfully treated with allogenic scleral patch graft has been reported. On follow-up visits scleral patch graft was well taken up.

Porphyria cutanea tarda: a case report

BackgroundThe porphyrias are a rare group of metabolic disorders that can either be inherited or acquired. Along the heme biosynthetic pathway, porphyrias can manifest with neurovisceral and/or cutaneous symptoms, depending on the defective enzyme. Porphyria cutanea tarda, the most common type of porphyria worldwide, is caused by a deficiency of uroporphyrinogen decarboxylase, a crucial enzyme in heme biosynthesis, which results in an accumulation of photosensitive byproducts, such as uroporphyrinogen, which leads to the fragility and blistering of sun-exposed skin.Porphyria cutanea tarda is a condition that affects the liver and skin by reduction and inhibition of uroporphyrinogen decarboxylase enzyme in erythrocytes. Areas of skin that are exposed to the sun can generate blisters, hyperpigmentation, and, sometimes, lesions that heal leaving a scar or keratosis. Liver damage might present in a wide range of ways from liver function test abnormalities to hepatocellular carcinoma. The toxic effect of iron plays a role in liver damage pathogenesis.Case presentationA 59-year-old Turkish man presented with hyperpigmented skin lesions, fatigue, and elevated ferritin level and liver function tests. He was diagnosed as having porphyria cutanea tarda after a clinical investigation and treated with phlebotomy.ConclusionPorphyria cutanea tarda is a rare condition of the liver but it must be remembered in a differential diagnosis of liver disease with typical skin involvement to decrease morbidity and health costs with early treatment.

Hepatitis C virus core protein triggers abnormal porphyrin metabolism in human hepatocellular carcinoma cells.

Porphyria cutanea tarda (PCT), the most common of the human porphyrias, arises from a deficiency of uroporphyrinogen decarboxylase. Studies have shown a high prevalence of hepatitis C virus (HCV) infection in patients with PCT. While these observations implicate HCV infection as a risk factor for PCT pathogenesis, the mechanism of interaction between the virus and porphyrin metabolism is unknown. This study aimed to assess the effect of HCV core protein on intracellular porphyrin metabolism to elucidate the link between HCV infection and PCT. The accumulation and excretion of porphyrins after treatment with 5-aminolevulinic acid, a porphyrin precursor, were compared between cells stably expressing HCV core protein and controls. Cells expressing HCV core protein had lower amounts of intracellular protoporphyrin IX and heme and had higher amounts of excreted coproporphyrin III, the oxidized form of coproporphyrinogen III, compared with controls. These observations suggest that HCV core protein affects porphyrin metabolism and facilitates the export of excess coproporphyrinogen III and/or coproporphyrin III, possibly via porphyrin transporters. Real-time PCR analysis revealed that the presence of HCV core protein increased the mRNA expression of porphyrin exporters ABCG2 and FLVCR1. Western blot analysis showed a higher expression level of FLVCR1, but not ABCG2, as well as a higher expression level of mature ALAS1, which is the rate-limiting enzyme in the heme synthesis pathway, in HCV core protein-expressing cells compared with controls. The data indicate that HCV core protein induced abnormal intracellular porphyrin metabolism, with an over-excretion of coproporphyrin III. These findings may partially account for the susceptibility of HCV-infected individuals to PCT development.

Hepatitis C virus-associated porphyria cutanea tarda: A case report

Porhyria cutanea tarda (PCT) is a rare, inherited or acquired disorder due to decreased activity or deficiency of uroporphyrinogen decarboxylase (UROD), one of the enzymes in the haem synthetic pathway. It is characterized by cutaneous manifestations such as erosions, blisters and bulae in the dorsum of the hand, forearm, elbows and knees; and painful indolent sores that heal with dyspigmented and scarring lesions. A 25 year old sales man presented with a 7 month history of recurrent blistering of the skin of the extremities- hands, elbows, knees and feet which occurred spontaneously or following trivial trauma. There was no family history of similar skin symptoms. Examination showed broken and fresh blisters of varying sizes with some healed lesions on the dorsum of the hands, over the elbow and knee joints, and toes. Serum ferritin was 360μ/L (40- 340 μ/L), urine uroporphyrinogen was positive (+++) and Hepatitis C antibodies screening was positive. Some improvement of the cutaneous lesion was noticed following commencement of therapeutic phlebotomy. Keywords: Porhyria, blisters, Hepatitis C virus, uroporphyrinogen

Sporadic Porphyria Cutanea Tarda in a Patient with Multiple Sclerosis Treated with Interferon Beta 1-a Therapy: A Case Report

Dear Editor, Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system, and interferon beta-1a (IFN-β1a) is a valuable medication in the treatment of the relapsing-remitting form of MS (RR MS). Porphyria cutanea tarda (PCT), which is the most frequent type of porphyria, is the result of a catalytic deficiency of uroporphyrinogen decarboxylase. In sporadic PCT (sPCT), which represents 75% of cases, the deficiency is limited to the liver.1 Accumulated uroporphyrin and other highly carboxylated porphyrins, which are soluble, diffuse from the plasma into the upper dermis. The clinical picture reflects the phototoxic reaction that subsequently occurs in the upper dermis, in that lesions occur almost exclusively in light-exposed areas.2 The cutaneous findings include increased photosensitivity, skin fragility, blistering, erosions, and crusts.1 In this letter we describe new onset of sPCT in a patient with RR MS who was treated with IFN-β1a. In brief, a 33-year-old man without a family history of PCT was admitted to our department complaining of dizziness and diplopia of 3 weeks duration. Neuroimaging revealed several demyelinating lesions in the subcortical white matter and the periventricular regions. Within 4 months he presented with paresthesia and hyposthenia of the left arm, and repeat MRI revealed additional demyelinating lesions (Fig. 1A). The patient was diagnosed with MS according to McDonald criteria3 and was started on treatment with IFN-β1a, which was administered subcutaneously three times weekly. Fig. 1 A: MRI showing several demyelinating lesions. B: Skin lesions on the back of the patient's hands. In the course of his treatment, the patient exhibited no relevant neurological alterations; however, after 5 years he observed the development of skin lesions that were localized to the back of his hands, appearing as bullae up to 1 cm wide, and sometimes larger. There were also crusts, atrophic scars, and areas of hypopigmentation (Fig. 1B). He was diagnosed with dermatitis bullosa, for which he was prescribed prednisone at 25 mg/day, which had no effect. His levels of transaminases were elevated as follows: glutamic-oxaloacetic transaminase, 47 U/L [normal value (NV), <38 U/L]; and glutamic-pyruvate transaminase, 138 U/L (NV, <41U/L). However, testing for hepatitis, including viral markers, antinuclear antibodies, smooth muscle antibodies, and antibodies to liver and kidney microsomes, alcoholic liver disease, and hemochromatosis yielded negative findings. PCT was suspected because of the blistering skin lesions on the back of his hands and other sun-exposed areas of his skin. Laboratory testing for porphyrin levels yielded the following results: total urine porphyrins, 1.838 mg/24 h (NV, <0.150 mg/24 h);4 total serum porphyrins, 0.069 mg/L (NV, <0.004 mg/L);5 plasmatic fluorimetric peak, 620 nm; and erythrocyte porphyrins, within the normal range. A skin biopsy procedure was performed on the patient's thigh, and a final diagnosis of PCT was confirmed by a dermatologist. Repeated phlebotomy resulted in the almost complete disappearance of the skin lesions. The patient suspended the IFN-β1a, and after 3 months commenced glatiramer acetate therapy. Follow-up examinations demonstrated that this medication switch resulted in the patient not experiencing any recurrence of the skin lesions, and porphyrin and transaminase levels within the normal ranges. Cassiman et al.6 showed that there is a significant association between sPCT and liver disorders, and described the occurrence of sPCT after medication intake in three patients. However, to our knowledge the present case is the first report of sPCT probably induced by IFN-β1a. We speculate that the possible hepatotoxic effect of IFN-β1a can trigger the development of sPCT in certain predisposed patients. Furthermore, this case highlights the importance of monitoring liver function in all patients treated with IFN-β1a.

Improved Drug Modification to Treat Porphyria Cutanea Tarda

Porphyria cutanea tarda (PCT) also known as the “vampire disease” is the most common type of porphyritic diseases. This disease occurs 1 in 50,000 people. Symptoms involve hyperpigmentation (tanning of skin) and hypertrichosis (skin manifestations mainly on top of cheeks). This disease is contributed mainly by deficiency of uroporphyrinogen decarboxylase (UROD), an enzyme that is present in the cytoplasm which aids in the synthesis of heme. The commercial drug available that is used to treat PCT is Plaquenil chemically known as Hydroxychloroquinone. This drug has shown to be effective in patients. But, in many cases it even worsens the condition of PCT in addition to its side effects. Gumweed extract shows antiporphyric activity. Quercertin, a phytochemical present in guweed bestows the wonder to treat porphyria. This experiment is dedicated to make the drug hydroxychloroquinone safer and more efficient in the treatment of porphyria. It is manifested by combining it with a gumweed phytochemical quercertin which is originally a flavinoid. This new modified drug can be used in the treatment of porphyria cutanea tarda and also to reduce the harmful effects of plaquenil in addition to unveiling the health benefits of gumweed.

Porphyria cutanea tarda – When skin meets liver

Porphyria cutanea tarda (PCT) is the most frequent type of porphyria worldwide and results from a catalytic deficiency of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in heme biosynthesis. At least two different types of PCT are currently distinguished: an acquired variant, also referred to as sporadic or type I PCT, in which the enzymatic deficiency is limited to the liver; and an autosomal dominantly inherited form, also known as familial or type II PCT, in which there is a decrease of enzymatic activity in all tissues. The cutaneous findings include increased photosensitivity, skin fragility, blistering, erosions, crusts, and miliae on the sun-exposed areas of the body. Additionally, hyperpigmentation, hypertrichosis, sclerodermoid plaques, and scarring alopecia might be observed. In patients with type I PCT, there is a significant association with liver disease that can be triggered by genetic and environmental factors, such as alcohol abuse, iron overload, haemochromatosis, polychlorinated hydrocarbons, and hepatitis C virus infection. The diagnosis of PCT can be made based on the skin symptoms, a characteristic urinary porphyrin excretion profile, and the detection of isocoproporphyrin in the feces. In red blood cells of individuals with type II PCT, UROD activity is decreased by approximately 50% due to heterozygous mutations in the UROD gene. Here we provide an update on clinical, diagnostic and therapeutic aspects of PCT, a disorder that affects both skin and liver.

Porphyria cutanea tarda

A 68-year-old man with relapsed follicular lymphoma developed redness, fragility, recurrent painful blistering and ulcerating lesions on sun-exposed areas of the skin, especially on the back of the hands (Figures). The appearance of the lesions led us to suspect porphyria cutanea tarda (PCT) which was confirmed by elevated urinary excretion of uroporphyrin, hepta-, hexaand pentacarboxylic porphyrins, as well as coproporphyrin. PCT is the most common type of porphyric disorder, triggered by hepatic uroporphyrinogen decarboxylase deficiency. Clinical manifestations include hypertrichosis and a photosensitive bullous dermatosis, predominantly on the hands, forearms, back of the neck and face. PCT may be caused by hepatic siderosis, alcohol abuse, hepatitis C virus infection or oestrogen therapy. During the course of his disease the patient had received several blood transfusions and his serum ferritin concentration was increased (serum ferritin: 2410 lg/l, normal range: 20–290 lg/l). The patient was treated with chloroquine to facilitate urinary elimination of porphyrins and the underlying lymphoma was treated with chemotherapy. Six months later the skin lesions had completely resolved in parallel with lymphoma remission and markedly decreased ferritin levels (serum ferritin: 1130 lg/l).

Serologic hepatitis B markers in porphyria cutanea tarda (author's transl)

Using several seromarkers for hepatitis B virus the frequency of previous hepatitis B in patients with porphyria cutanea tarda (PCT) as a possible manifestation factor was determined. As chronic hepatitis is frequently associated with an increase of factor VIII-associated antigen, this was included in the investigation. Results make it likely that 28 out of 60 investigated patients (47%) have had hepatitis. In 30% an increase of factor VIII-associated antigen was found. It can be assumed that hepatitis B virus infection as a manifestation factor may be of considerable importance in porphyria cutanea tarda when genetic disposition (uroporphyrinogen-decarboxylase deficiency) is present.

The role of inherited and acquired factors in the development of porphyria cutanea tarda in the Argentinean population

Inherited and environmental factors are implicated in the expression of porphyria cutanea tarda (PCT); the contribution of each factor depends on the population. To provide a review of PCT cases diagnosed in Argentina over 24 years and evaluate the role of different precipitating factors in its pathogenesis. Methods Plasma and urinary porphyrin levels and erythrocyte uroporphyrinogen decarboxylase (URO-D) activity were determined. Potential precipitating factors were identified in each patient. Additional tests for hepatitis C virus (HCV) and hemochromatosis gene mutations were carried out. Several factors (mainly alcohol abuse in men and estrogen ingestion in women), alone or combined were identified in our patients. Prevalence of HCV infection was 35.2%. Inherited URO-D deficiency occurs in 25.0% of cases. H63D was the most common hemochromatosis gene mutation. High incidence of PCT associated with HIV infection was found. PCT is multifactorial. Therefore, knowledge of all risk factors in each patient is important for the management of the disease.

Volatile anaesthetics induce biochemical alterations in the heme pathway in a B-lymphocyte cell line established from hepatoerythropoietic porphyria patients (LBHEP) and in mice inoculated with LBHEP cells

Hepatoerythropoietic porphyria (HEP) is the homozygous form of Porphyria Cutanea Tarda (PCT), characterized by an accumulation of porphyrins due to uroporphyrinogen decarboxylase deficiency. Fluorinated volatile anaesthetics are often used to produce general anaesthesia. Anaesthesia has certainly been implicated in the triggering of acute porphyria crisis. The effects of volatile anaesthetics in a B-lymphocyte cell line established from HEP patients (LBHEP) on heme metabolism have been investigated. LBHEP cells were exposed to sodium phosphate buffer containing dissolved Enflurane, Isoflurane or Sevoflurane (10 mM) during 20 min. Aminolevulinate synthase (ALA-S) activity, the regulatory enzyme of heme synthesis, was 300% induced by the anaesthetics. A 25–30% diminution of porphobilinogenase (PBG-ase) activity was found when Isoflurane or Sevoflurane were added to the cells, while no significant changes were detected after Enflurane treatment. Although some oxidative stress has been induced by the anaesthetics, reflected by the 35% diminution of glutathione (GSH), no alteration in heme oxygenase (HO) activity, the enzyme involved in heme breakdown and frequently induced as a response to stress stimuli, was observed. Studies using animals inoculated with LBHEP cells were also performed. Findings here described mimic biochemical alterations in the heme pathway, which are characteristic of another hepatic porphyria, similar to those previously reported when these anaesthetics were administered to animals, and they also advertise about the possible unsafe use of these drugs in the case of hepatic non-acute porphyrias.

Porphyria cutanea tarda: multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency.

The coexistence of factors considered to contribute to development of porphyria cutanea tarda was studied in 39 consecutive patients. Highly prevalent factors were alcohol intake in 79%, smoking in 86%, hepatitis C virus infection in 74%, estrogen use in 73% of 11 females, and at least one mutation in the HFE (hereditary hemochromatosis) gene in 65%. The C282Y mutation was found in 29%, H63D in 47%, and S65C in 0%. HFE genotypes included C282Y/C282Y in 9%, H63D/H63D in 9%, C282Y/H63D in 12%, C282Y/wild type in 9%, and H63D/wild type in 26%. Less prevalent were HIV infection in 15% (or 25% of those tested, N = 24) and erythrocyte uroporphyrinogen decarboxylase deficiency, which distinguishes familial (type 2) from "sporadic" (type 1) porphyria cutanea tarda, in 19%. Multiple contributing factors coexisted in both types 1 and 2, with 92% of all patients having three or more factors. These observations indicate that this porphyria is multifactorial in the individual patient, and therefore is seldom attributable to a single identifiable cause. Profiling for all potentially contributing factors is important for individualizing management.

Alcohol and porphyrin metabolism.

Alcohol is a porphyrinogenic agent which may cause disturbances in porphyrin metabolism in healthy persons as well as biochemical and clinical manifestations of acute and chronic hepatic porphyrias. After excessive consumption of alcohol, a temporary, clinically asymptomatic secondary hepatic coproporphyrinuria is observable, which can become persistent in cases of alcohol-induced liver damage. Nowadays, the alcohol-liver-porphyrinuria syndrome is the first to be mentioned in secondary hepatic disturbances of porphyrin metabolism. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria) are considered to be molecular regulatory diseases, in contrast to non-acute, chronic hepatic porphyria, clinically appearing as porphyria cutanea tarda (PCT). Porphyrins do not accumulate in the liver in acute porphyrias, whereas in chronic hepatic porphyrias they do. Thus, chronic hepatic porphyria is a porphyrin-accumulation disease, whereas acute hepatic porphyrias are haem-pathway-dysregulation diseases, characterized in general by induction of delta-aminolevulinic acid synthase in the liver and excessive stimulation of the pathway without storage of porphyrins in the liver. The clinical expression of acute hepatic porphyrias can be triggered by alcohol, because alcohol augments the inducibility of delta-aminolevulinic acid synthase. In chronic hepatic porphyrias, however, which are already associated with liver damage, alcohol potentiates the disturbance of the decarboxylation of uro- and heptacarboxyporphyrinogen, which is followed by a hepatic accumulation of uro- and heptacarboxyporphyrin and their sometimes extreme urinary excretion. Especially in persons with a genetic deficiency of uroporphyrinogen decarboxylase, but also in patients with the so-called sporadic variety of PCT, alcohol is able to transform an asymptomatic coproporphyrinuria into PCT. Alcohol has many biochemical and clinical effects on porphyrin and haem synthesis both in humans and laboratory animals. Ethanol suppresses the activity of porphobilinogen synthase (synonym: delta-aminolevulinic acid dehydratase), uroporphyrinogen decarboxylase, coproporphyrinogen oxidase and ferrochelatase, whereas it induces the first and rate-limiting enzyme in the pathway, delta-aminolevulinic acid synthase and also porphobilinogen deaminase. Therefore, teetotalism is a therapeutically and prophylactically important measure in all types of hepatic porphyrias.

Correction of Uroporphyrinogen Decarboxylase Deficiency (Hepatoerythropoietic Porphyria) in Epstein-Barr Virus-Transformed B-Cell Lines by Retrovirus-Mediated Gene Transfer: Fluorescence-Based Selection of Transduced Cells

Hepatoerythropoietic porphyria (HEP) is an inherited metabolic disorder characterized by the accumulation of porphyrins resulting from a deficiency in uroporphyrinogen decarboxylase (UROD). This autosomal recessive disorder is severe, starting early in infancy with no specific treatment. Gene therapy would represent a great therapeutic improvement. Because hematopoietic cells are the target for somatic gene therapy in this porphyria, Epstein-Barr virus-transformed B-cell lines from patients with HEP provide a model system for the disease. Thus, retrovirus-mediated expression of UROD was used to restore enzymatic activity in B-cell lines from 3 HEP patients. The potential of gene therapy for the metabolic correction of the disease was demonstrated by a reduction of porphyrin accumulation to the normal level in deficient transduced cells. Mixed culture experiments demonstrated that there is no metabolic cross-correction of deficient cells by normal cells. However, the observation of cellular expansion in vitro and in vivo in immunodeficient mice suggested that genetically corrected cells have a competitive advantage. Finally, to facilitate future human gene therapy trials, we have developed a selection system based on the expression of the therapeutic gene. Genetically corrected cells are easily separated from deficient ones by the absence of fluorescence when illuminated under UV light.

Correction of Uroporphyrinogen Decarboxylase Deficiency (Hepatoerythropoietic Porphyria) in Epstein-Barr Virus-Transformed B-Cell Lines by Retrovirus-Mediated Gene Transfer: Fluorescence-Based Selection of Transduced Cells

AbstractHepatoerythropoietic porphyria (HEP) is an inherited metabolic disorder characterized by the accumulation of porphyrins resulting from a deficiency in uroporphyrinogen decarboxylase (UROD). This autosomal recessive disorder is severe, starting early in infancy with no specific treatment. Gene therapy would represent a great therapeutic improvement. Because hematopoietic cells are the target for somatic gene therapy in this porphyria, Epstein-Barr virus-transformed B-cell lines from patients with HEP provide a model system for the disease. Thus, retrovirus-mediated expression of UROD was used to restore enzymatic activity in B-cell lines from 3 HEP patients. The potential of gene therapy for the metabolic correction of the disease was demonstrated by a reduction of porphyrin accumulation to the normal level in deficient transduced cells. Mixed culture experiments demonstrated that there is no metabolic cross-correction of deficient cells by normal cells. However, the observation of cellular expansion in vitro and in vivo in immunodeficient mice suggested that genetically corrected cells have a competitive advantage. Finally, to facilitate future human gene therapy trials, we have developed a selection system based on the expression of the therapeutic gene. Genetically corrected cells are easily separated from deficient ones by the absence of fluorescence when illuminated under UV light.

Porphyrins in urine, plasma, erythrocytes, bile and faeces in a case of congenital erythropoietic porphyria (Gunther's disease) treated with blood transfusion and iron chelation: lack of benefit from oral charcoal.

Congenital erythropoietic porphyria is a rare genetic disorder in which deficiency of uroporphyrinogen III synthase results in excessive production of Type I porphyrins. The main clinical features are severe photodestruction of the skin and haemolytic anaemia. Treatment consists of shielding from light, blood transfusions and splenectomy, but is generally unsatisfactory. Previous studies have suggested that oral charcoal may be of benefit by binding porphyrins in the gut. A trial was therefore undertaken to evaluate this possibility. Porphyrins in urine, plasma and erythrocytes were measured by HPLC in a 23-year-old male patient with congenital erythropoietic porphyria, during an 8 week "run-in" period, and for a further 3 weeks when oral charcoal was given. Total urinary porphyrin excretion was 79-283 mumol/24 h consisting of 75% uroporphyrin I, 15% coproporphyrin I and smaller amounts of hepta-, hexa-, and pentacarboxylic porphyrins. Similar proportions were found in plasma and erythrocytes. During the first 24 h of charcoal administration a minor decrease in plasma and erythrocyte porphyrins was detected but this was not maintained during the remainder of the trial. In bile and faeces coproporphyrin I constituted approximately 95% of the porphyrins, with 2-3% coproporphyrin III and smaller amounts of pentaporphyrins I and III, but only trace amounts of uroporphyrin I. Oral charcoal was of no value in this case. Reasons are discussed in the context of biochemical differences between this patient with classical Gunther's disease and the similar clinical syndrome due to deficiency of uroporphyrinogen decarboxylase.

A zebrafish model for hepatoerythropoietic porphyria.

Defects in the enzymes involved in the haem biosynthetic pathway can lead to a group of human diseases known as the porphyrias. yquem (yqe(tp61)) is a zebrafish mutant with a photosensitive porphyria syndrome. Here we show that the porphyric phenotype is due to an inherited homozygous mutation in the gene encoding uroporphyrinogen decarboxylase (UROD); a homozygous deficiency of this enzyme causes hepatoerythropoietic porphyria (HEP) in humans. The zebrafish mutant represents the first genetically 'accurate' animal model of HEP, and should be useful for studying the pathogenesis of UROD deficiency and evaluating gene therapy vectors. We rescued the mutant phenotype by transient and germline expression of the wild-type allele.

Porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) is a skin disease that results from decreased activity of uroporphyrinogen decarboxylase (UROD). About 80% of patients have the sporadic (type I) form in which UROD deficiency is restricted to the liver. Others have familial (type II) PCT in which mutations in the UROD gene are inherited in an autosomal dominant pattern with low clinical penetrance. PCT may also follow exposure to porphyrogenic chemicals. Clinically overt PCT (types I and II) is provoked by liver cell injury, particularly when associated with alcohol abuse, hepatitis C infection, or estrogens. Hepatic iron overload is common, depletion of iron stores produces remission, and their replenishment leads to relapse. In PCT, hepatic UROD is inactivated by a process targeted at its catalytic site, which is iron-dependent, requires a heme precursor, and may be accelerated by induction of cytochrome P450s. Susceptibility to develop PCT in response to common causes of liver injury may be determined by co-inheritance of genes that regulate components of this inactivation process.

A Mutation (G281E) of the Human Uroporphyrinogen Decarboxylase Gene Causes Both Hepatoerythropoietic Porphyria and Overt Familial Porphyria Cutanea Tarda: Biochemical and Genetic Studies on Spanish Patients

Hepatoerythropoietic porphyria is a severe cutaneous porphyria caused by deficiency of uroporphyrinogen decarboxylase and is considered to be the homozygous form of familial (type II) porphyria cutanea tarda. To elucidate further the relation between these conditions, we studied five Spanish families with hepatoerythropoietic porphyria and nine unrelated Spanish patients with familial porphyria cutanea tarda. Immunoreactive and catalytic uroporphyrinogen decarboxylase was decreased by greater than 95% in the five patients with hepatoerythropoietic porphyria. Hepatic uroporphyrinogen decarboxylase activity was decreased to 22% of normal. Four patients were homozygous for a mutation (G281E) originally identified in a Tunisian family; the fifth patient was a compound heterozygote for this mutation. The calculated carrier frequency for G281E in Spain is one in 1800. None of the nine familial porphyria cutanea tarda patients carried the G281E mutation. However, one G281E heterozygote in a family with hepatoerythropoietic porphyria had overt porphyria cutanea tarda. These findings suggest that the G281E mutation is functionally less severe than erythrocyte measurements indicate, that its clinical penetrance is very low in heterozygotes, and that, for this particular mutation, hepatoerythropoietic porphyria is the homozygous form of familial porphyria cutanea tarda.

Hepatoerythropoietic porphyria precipitated by viral hepatitis.

Porphyria cutanea tarda (PCT), the condition resulting from a deficiency of hepatic uroporphyrinogen decarboxylase activity, is the commonest form of porphyria. Both acquired and familial form exist and are commonly associated in adults with liver disease and hepatic iron overload. The condition is extremely rare in children; most cases of childhood PCT are familial and some particularly severe cases have been shown to have a hepatoerythropoietic porphyria or homozygous uroporphyrinogen decarboxylase deficiency. A case is described of hepatoerythropoietic porphyria in which the disease was first precipitated at the age of two by a coincidental hepatitis A infection and improved as the hepatitis cleared. This paper reviews the evidence that viral hepatitis may precipitate overt PCT in children in a manner analogous to the precipitation of PCT in adults by alcohol associated liver disease.