ABSTRACT
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.
Subject(s)
Genetic Variation , Hydroxymethylbilane Synthase/genetics , Liver/pathology , Porphyria, Acute Intermittent/diagnosis , Porphyria, Acute Intermittent/genetics , Acute Disease , Adult , Base Sequence , DNA Mutational Analysis , Female , Heterozygote , Humans , Hydroxymethylbilane Synthase/metabolism , Liver/metabolism , Molecular Sequence Data , Mutation , Porphyria, Acute Intermittent/blood , Porphyria, Acute Intermittent/urine , Porphyrins/blood , Porphyrins/urine , Uroporphyrinogen III Synthetase/genetics , Uroporphyrinogen III Synthetase/metabolismABSTRACT
Stress, an important aspect of modern life, has long been associated with an altered homeostatic state. Little is known about the effect of the life stress on the outcome of diabetes mellitus, especially related to the higher risk of infections. Here, we evaluate the effects of chronic mild stress (CMS) exposure on the evolution of type I diabetes induced by streptozotocin administration in BALB/c mice. Exposure of diabetic mice to CMS resulted in a significant reduction of survival and a sustained increase in blood glucose values. Concerning the immune response, chronic stress had a differential effect in mice with diabetes with respect to controls, showing a marked decrease in both T- and B-cell proliferation. No correlation was found between splenic catecholamine or circulating corticosterone levels and the proliferative response. However, a significant negative correlation was found between glucose levels and concanavalin A- and lipopolysaccharide-stimulated proliferative responses of T and B cells. A positive correlation between blood glucose and splenic catecholamine concentrations was found in diabetic mice but not in controls subjected to CMS. Hence, the present report shows that diabetic mice show a worse performance in immune function after stress exposure, pointing to the importance of considering life stress as a risk factor for patients with diabetes.
Subject(s)
Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/psychology , Hormones/physiology , Hyperglycemia/blood , Stress, Psychological/immunology , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Blood Glucose/metabolism , Catecholamines/blood , Cells, Cultured , Chronic Disease , Corticosterone/blood , Female , Food Deprivation , Mice , Mice, Inbred BALB C , Mitogens/pharmacology , Survival Analysis , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Water Deprivation/physiologyABSTRACT
1. The effect of in vitro glycation on delta-aminolevulinic dehydratase (ALA-D) under several experimental conditions was investigated. When preincubated with 500 mM glucose at 37 degrees C for 20 hr, ALA-D was 80% inactivated and glycated hemoglobin levels were increased more than fourfold. 2. Thiobarbituric acid species were not modified during glycation; therefore ALA-D inactivation cannot be attributed to glucose autoxidation. 3. Acetyl salicylic acid was effective in preventing both hemoglobin glycation and ALA-D inactivation by glucose. 4. A method has been developed for measuring protein glycation in vitro, in a crude preparation of red blood cells, which can also be applied to sugars other than glucose.
Subject(s)
Aspirin/pharmacology , Glucose/metabolism , Porphobilinogen Synthase/metabolism , Carbohydrate Metabolism , Carbohydrates/pharmacology , Glucose/pharmacology , Glycated Hemoglobin/metabolism , Glycosylation/drug effects , Humans , In Vitro Techniques , Lipid Peroxidation/drug effects , Porphobilinogen Synthase/antagonists & inhibitors , Temperature , Time FactorsABSTRACT
A frequent coexistence of diabetes and porphyria disease has been reported. Under normal conditions, porphyrin biosynthesis is well regulated to only form the amount of heme required for the synthesis of the various hemoproteins. The activity of some heme enzymes and rhodanese in streptozotocin (STZ) induced diabetic mice and in allylisopropylacetamide (AIA) induced experimental acute porphyria mice has been examined. The role of alpha-tocopherol (alpha-T), reported to prevent protein glycation in vitro, has also been investigated. AIA induced hepatic delta-aminolevulinic acid synthetase (ALA-S) activity in control animals but was ineffective in the diabetic group. alpha-Tocopherol did not modify ALA-S activity in either group. delta-Aminolevulinic acid dehydratase (ALA-D) and deaminase activities were significantly diminished both in liver and blood of diabetic animals. alpha-Tocopherol prevented inhibition of ALA-D, deaminase and blood rhodanese activities in diabetic animals but alpha-tocopherol by itself did not affect the basal levels of the enzymes studied. The potential use of alpha-tocopherol to prevent late complications of diabetes, including the onset of a porphyria like syndrome is considered.
