Acquired erythropoietic uroporphyria secondary to myelodysplastic syndrome with chromosome 3 alterations: a case report.

Congenital erythropoietic porphyria is a rare autosomal recessive disease caused by a deficiency of uroporphyrinogen III synthase, owing to mutations in UROS in chromosome 10. Occasionally, patients show a mild, late-onset disease, without germline UROS mutations, associated with haematological malignancies. We report a 65-year-old patient with photosensitivity, overexcretion of porphyrins and thrombocytopenia. Bone marrow analysis gave a diagnosis of myelodysplastic syndrome (MDS) with the presence of a derivative chromosome 3, possibly due to an inversion including 3q21 and 3q26 break points. After allogeneic stem-cell transplantation, complete remission of MDS and uroporphyria was achieved. To our knowledge, this is the first reported case of acquired erythropoietic uroporphyria associated with MDS, with chromosome 3 alterations.

Phototherapy-induced blistering reaction and eruptive melanocytic nevi in a child with transient neonatal porphyrinemia.

Neonatal blue-light phototherapy induced a blistering reaction followed by eruption of melanocytic nevi on the exposed skin surface of a child with transient neonatal porphyrinemia. New nevi are still developing 4 years after the triggering event. The role of phototoxicity-induced epidermal injury, that of porphyrins and the influence of neonatal blue-light therapy, in this unique phenomenon are discussed.

[Clinical and metabolic features of nonalcoholic fatty liver disease in men and women]. / Klinicheskie i metabolicheskie osobennosti nealkogol'noi zhirovoi bolezni pecheni u muzhchin i zhenshchin.

AIM: To evaluate clinical features and metabolic disorders in men and women with non-alcoholic fatty liver disease (NAFLD).

Transient Porphyrinemia in a Neonate: A Case Report.

We describe a neonate with anemia, thrombocytopenia, and hyperbilirubinemia secondary to hemolytic disease of the newborn. After phototherapy for hyperbilirubinemia, the neonate developed a photodistributed eruption with high serum and urine porphyrin levels. This transient porphyrinemia resolved at 1 month.

Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria.

Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in massive porphyrin accumulation in blood cells, which is responsible for hemolytic anemia and skin photosensitivity. Among the missense mutations actually described up to now in CEP patients, the C73R and the P248Q mutations lead to a profound UROS deficiency and are usually associated with a severe clinical phenotype. We previously demonstrated that the UROS(C73R) mutant protein conserves intrinsic enzymatic activity but triggers premature degradation in cellular systems that could be prevented by proteasome inhibitors. We show evidence that the reduced kinetic stability of the UROS(P248Q) mutant is also responsible for increased protein turnover in human erythroid cells. Through the analysis of EGFP-tagged versions of UROS enzyme, we demonstrate that both UROS(C73R) and UROS(P248Q) are equally destabilized in mammalian cells and targeted to the proteasomal pathway for degradation. We show that a treatment with proteasomal inhibitors, but not with lysosomal inhibitors, could rescue the expression of both EGFP-UROS mutants. Finally, in CEP mice (Uros(P248Q/P248Q)) treated with bortezomib (Velcade), a clinically approved proteasome inhibitor, we observed reduced porphyrin accumulation in circulating RBCs and urine, as well as reversion of skin photosensitivity on bortezomib treatment. These results of medical importance pave the way for pharmacologic treatment of CEP disease by preventing certain enzymatically active UROS mutants from early degradation by using proteasome inhibitors or chemical chaperones.

Liver failure after Hydroxycut™ use in a patient with undiagnosed hereditary coproporphyria.

We report the case of a young male presenting with cholestatic liver failure. After an extensive workup, the etiology of the liver failure was determined to be due to hereditary coprophorphyria (HCP). The inciting event was the use of Hydroxycut™, an over-the-counter supplement to promote weight loss that has been reported to cause oxidative liver injury in vulnerable populations. Although HCP is a rare cause of cholestatic liver failure, it is treatable if diagnosed correctly and in a timely manner. In this clinical vignette, we discuss a case that highlights the genetic susceptibility to disease that can be unmasked by environmental exposures. We also review the relevant literature on Hydroxycut™ and how it can affect hepatic function.

Congenital erythropoietic porphyria linked to GATA1-R216W mutation: challenges for diagnosis.

Congenital erythropoietic porphyria (CEP) is a rare genetic disease that is characterized by a severe cutaneous photosensitivity causing unrecoverable deformities, chronic hemolytic anemia requiring blood transfusion program, and by fatal systemic complications. A correct and early diagnosis is required to develop a management plan that is appropriate to the patient's needs. Recently only one case of X-linked CEP had been reported, describing the trans-acting GATA1-R216W mutation. Here, we have characterized two novel X-linked CEP patients, both with misleading hematological phenotypes that include dyserythropoietic anemia, thrombocytopenia, and hereditary persistence of fetal hemoglobin. We compare the previously reported case to ours and propose a diagnostic paradigm for this variant of CEP. Finally, a correlation between phenotype variability and the presence of modifier mutations in loci related to disease-causing gene is described.

Pseudoporphyria following self-medication with chlorophyll.

Two cases of pseudoporphyria are described in which the clinical features of porphyria cutanea tarda occurred in the absence of abnormalities in porphyrin metabolism. Both patients presented with skin fragility and bullae on the dorsal aspect of the hands. The patients consumed a commercial liquid chlorophyll drink in which we detected fluorescent compounds with characteristics typical of previously described chlorophyll derived photosensitisers.

pH-Dependent Changes in the Mechanisms of Transport of Chlorine e6 and Its Derivatives in the Blood.

We studied the effects of medium pH on steady-state distribution of chlorine e6 and its derivatives between the main transport proteins of human blood plasma. The decrease in medium pH from weakly alkaline (pH 7.4) to acid (pH 5.0) was followed by an increase in relative affinity of chlorines to lipoproteins and reduced their affinity to serum albumin. pH-Dependent changes in the parameters of distribution of photosensitizers between the plasma and blood cells was revealed. We discussed the role of charge and polarity degree of photosensitizer molecule in the mechanism of binding to serum albumin. A possible role of changes in hydrogen ion activity in the processes of selective accumulation of chlorines by tumor cells is discussed.

Prevalence of photosensitivity in chronic hepatitis C virus patients and its relation to serum and urinary porphyrins.

BACKGROUND & AIMS: HCV is a major cause of chronic liver disease in Egypt. The aim was to study the prevalence of photosensitivity among asymptomatic HCV-infected patients and its possible relation to porphyrins levels and whether it can be considered an alarm for early diagnosis of the disease, which is the most important goal in the management. METHODS: This study included 100 accidentally discovered HCV positive cases and 100 HCV negative healthy controls. All patients and controls were subjected to: Detailed history and clinical examination, dermatological examination including evaluation of reaction to solar exposure, measurement of serum AST, ALT, albumin, bilirubin, serum and urinary porphyrins levels. RESULTS: The prevalence of photosensitivity among HCV-positive cases (33%) was significantly higher compared to 10% in the control group. Serum porphyrins were positive in 46 cases (46%), twenty-three cases (23%) had positive urinary porphyrins, while only four controls (4%) showed positive serum porphyrins and one (1%) showed positive urinary porphyrins, the difference was statistically significant. Cases with photosensitivity showed significantly higher prevalence of serum and urinary porphyrins existence as well as serum porphyrins levels. Levels of viraemia showed statistically significant relation to levels of porphyrins. CONCLUSION: Asymptomatic chronic HCV infection cases showed significantly high prevalence of photosensitivity, which is related to the associated disturbance of porphyrins metabolism. Photosensitivity can thus be considered an early marker of HCV infection. Patients discovered to have recently acquired photosensitivity should be screened for HCV infection especially in endemic areas like Egypt.

Stability of porphyrins and porphyrin precursors in urine and plasma samples: implications for sample handling and storage.

The porphyrias are rare disorders of haem biosynthesis. Diagnosis requires demonstrating increased porphyrins or porphyrin precursors in blood, urine and faeces. Patients may only be investigated once, and therefore, understanding the preanalytical factors affecting the reliability of results is crucial. Guidance for sample handling exists, but published evidence regarding the stability of porphyrins and their precursors is limited. The aim of this study was to evaluate the effect of light exposure and different storage temperatures on analyte stability for measurement of urinary aminolaevulinic acid and porphobilinogen, total urine porphyrin and plasma porphyrin. Our results confirm that all samples should be protected from light. Results from samples exposed to light for greater than 4 hours should be interpreted with caution and repeat samples requested. If transported to a specialist laboratory, samples should be stored at 4°C before transport. Transit time at ambient temperatures should be less than 24 hours.

Multiplexed optical detection of plasma porphyrins using DNA aptamer-functionalized carbon nanotubes.

A novel optical platform based on DNA aptamer-functionalized SWCNTs (a-SWCNTs) is developed for multiplexed detection of plasma porphyrins. We have investigated the interactions of a-SWCNTs with heme (FePP), protoporphyrin (PP), coproporphyrin (CP), and uroporphyrin (UP). Two interaction mechanisms, specific binding, and nonspecific adsorption between porphyrins and a-SWCNTs are proposed based on observed optical signal modulations. The optical transduction signals are used to formulate a multiplexed detection strategy for the four porphyrin species without a laborious separation process. The detection scheme is sensitive, selective, and can readily be used for porphyrin detection in plasma samples when combined with a solvent extraction method. Our optical platform offers novel analytical tools for probing the surface chemistry at the porphyrin/a-SWCNTs interface, showing great promise for both research and clinical applications.

Vemurafenib: an unusual UVA-induced photosensitivity.

Vemurafenib is a new-targeted therapy approved for the treatment of patients with V600E BRAF-mutant metastatic melanoma. Among the cutaneous adverse events reported, the photosensitivity is frequently experienced. We aimed to characterize more deeply the mechanism leading to this photosensitivity as well as the corresponding UV spectrum. Phototests showed that the phototoxicity was UVA-dependent since from normal value prior to vemurafenib treatment, the UVA-minimal erythema dose decreased in 17 of 18 patients (94.4%) while the minimal erythema dose remained unchanged. Furthermore, a vemurafenib-induced erythema appeared quickly during the UVA exposure contrarily to what is observed with a conventional drug-induced phototoxicity showing an erythema 12-24 h after the phototesting. Vitamin PP concentration decreased, and porphyrin level significantly increased after 2 months of vemurafenib. Our study confirms the high risk of vemurafenib-induced photosensitivity and indicates that it is possibly vitamin PP- and porphyrin dependent.

An odd case of heteroallelic acute intermittent porphyria in the Argentinean population.

AIP is an acute liver disorder caused by a deficiency of porphobilinogen deaminase (PBGD) characterized by neuroabdominal symptoms. It is an autosomal dominant disease. However, homozygous dominant AIP (HD-AIP) have been described. In some cases erythrodontia was observed. CEP is an autosomal recessive disease produced by mutations in the uroporphyrinogen III synthase gene (UROS), characterized by severe cutaneous lesions and erythrodontia. The aim of the work was to establish the differential diagnosis of porphyria in a patient with abdominal pain, neurological attacks, skin symptoms and erythrodontia. The PBGD activity was reduced 50% and the genetic analysis indicated the presence of two genetic variants in the PBGD gene, p.G111R and p.E258G, a new genetic variant, revealing a case of heteroallelic HD-AIP. The patient, first diagnosed as a carrier of a dual porphyria: AIP / CEP based on the excretion profile of porphyrins, precursors and her clinical symptoms, would be an atypical case of human HD-AIP. These results would also suggest the presence of a phenocopy of the CEP, induced by an endogenous or exogenous factor. Our findings highlight the importance of genetic studies for a proper diagnosis of porphyria, prevention of its manifestation and its treatment.

Co-existence of hereditary coproporphyria and porphyria cutanea tarda: The importance of genetic testing.

The porphyrias are a group of inherited disorders that result in defects in the enzymes of the haem biosynthetic pathway, causing photosensitive bullous skin eruptions or abdominal and neurological attacks. Enzymatic defects result in specific porphyrin excretory patterns that are diagnosed biochemically and can be confirmed by genetic testing. Defects in the coproporphyrinogen oxidase (CPOX) enzyme result in the autosomal dominant hereditary coproporphyria. Multiple mutations have been identified in the CPOX gene and incomplete penetrance is noted. Latent carriers without clinical evidence of disease are at risk of life-threatening attacks. Porphyria cutanea tarda may be inherited, but is more commonly acquired. Occasionally two forms of porphyria may co-exist. The importance of genetic testing is discussed.