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S Thunell

Publications and source records attributed to S Thunell.

At least 19 recordsLinked to original sources
PubMed2001

Highly heterogeneous nature of delta-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria.

The properties of 9 delta-aminolevulinate dehydratase (ALAD) mutants from patients with ALAD porphyria (ADP) were examined by bacterial expression of their complementary DNAs and by enzymologic and immunologic assays. ALADs were expressed as glutathione-S-transferase (GST) fusion proteins in Escherichia coli and purified by glutathione-affinity column chromatography. The GST-ALAD fusion proteins were recognized by anti-ALAD antibodies and were enzymatically active as ALAD. The enzymatic activities of 3 ALAD mutants, K59N, A274T, and V153M, were 69.9%, 19.3%, and 41.0% of that of the wild-type ALAD, respectively, whereas 6 mutants, G133R, K59N/G133R, F12L, R240W, V275M, and delTC, showed little activity (< 8%). These variations generally reflect the phenotype of ALAD in vivo in patients with ADP and indicate that GST-ALAD fusion protein is indeed useful for predicting of the phenotype of ALAD mutants. The location of F12L mutation in the enzyme's molecular structure indicates that its disturbance of the quaternary contact of the ALAD dimer appears to have a significant influence on the enzymatic activity. Mouse monoclonal antibodies to human ALAD were developed that specifically recognized a carboxy terminal portion of ALAD, or other regions in the enzyme. This study represents the first complete analysis of 9 mutants of ALAD identified in ADP and indicates the highly heterogeneous nature of mutations in this disorder.

Adolescent↗
PubMed2000

Porphyrins, porphyrin metabolism and porphyrias. I. Update.

The biosynthesis of porphyrins is one of the most conserved parthways known, about the same sequence of reactions taking place in all species. By associating different metals, porphyrins give rise to the "pigments of life": chlorophyll, haem and cobalamin. The unique tetrapyrrolic structure enables it to function in an array of reactions as a single electron carrier and as a catalyst for redox reactions. In this capacity, it constitutes the prosthetic group of enzymes participating in cellular respiration, in conversion reactions involving steroids and lipophilic xenobiotics, in protective mechanisms directed against oxidative stress and in pathways providing central messenger molecules. The formation of haem is accomplished by a sequence of eight dedicated enzymes encoded by different genes, some being active in ubiquitous as well as in erythroid isoforms. Large differences between the participating enzymes with regard to catalytic power, with low capacity steps positioned early in the catalytic chain, constitute a bar against substrate overloading of enzymes processing porphyrins, thus preventing accumulation in the body of these phototoxic compounds under physiological conditions. Most of the haem in the body is produced by the liver and bone marrow, but the mechanisms applied for the control of the synthesis differ between the two organs. The extremely potent hemeprotein enzymes formed in the liver are rapidly turned over in response to current metabolic needs. They have half-lives in the order of minutes or hours and are restored by fast-acting mechanisms for the de novo synthesis, when needed. Uninterrupted and instant availability of the compound is secured by acute deinhibition of the initial enzyme of the synthetic chain, ubiquitous 5-aminolevulinate synthase (ALAS-1), in response to drain of the free cellular haem pool caused by prevailing demands for hemeproteins or by increased catabolism of the compound. In contrast, in the erythroid progenitor cell the haem synthetic machinery is designed for uninterrupted production of huge amounts of haem for combination with globin chains to form hemoglobin at a steady rate. In the erythron the synthesis of the enzymes participating in the formation of haem is under control of erythropoietin, formed under hypoxic conditions. In the absence of iron, to be incorporated in the porphyrin formed in the last step of the synthesis, the mRNA of erythroid 5-aminolevulinate synthase (ALAS-2) is blocked by attachment of an iron-responsive element (IRE) binding cytosolic protein, and transcription of this key enzyme is inhibited. In humans, the genes for each of the haem synthetic enzymes may become the target of mutations that give rise to impaired cellular enzyme activity. Seven of the enzyme deficiencies are associated with accumulation of toxic intermediaries and with disease entities termed porphyrias. The acute porphyrias are characterized by attacks of neuropsychiatric symptoms, which may be due to a toxic surplus of the porphyrin presursor 5-aminolevulinic acid, or a consequence of a deficit of vital hemeproteins resulting from impaired synthesis of haem. In the cutaneous porphyrias, impairment of enzymatic steps where porphyrins are processed gives rise to solar hypersensitivity due to accumulation of phototoxic porphyrins in the skin. Early diagnosis, information to the patient regarding the nature of the illness and counselling aimed at avoidance of triggering factors are cornerstones in the handling of the porphyric diseases. Gene analysis is of incomparable diagnostic reliability in carrier detection, but biochemical methods must be applied in the important task of monitoring porphyric disease activity. In most forms of porphyria the gene carriers run the risk of development of associated diseases in liver or kidneys, a circumstance that prompts application of well-structured surveillance programs.

Humans↗
PubMed2000

Porphyrins, porphyrin metabolism and porphyrias. II. Diagnosis and monitoring in the acute porphyrias.

The acute porphyrias constitute a group of metabolic disorders engaging enzymes in the haem synthetic chain and generally following dominant inheritance patterns. Some gene carriers are vulnerable to a range of exogenous and endogenous factors, which may trigger neuropsychiatric symptoms. Early diagnosis is of prime importance since it makes way for counselling with the aim to block the development of acute, as well as late, disease. The medical and psycho-social consequences of a porphyria diagnosis are considerable and the freedom for maldiagnosis correspondingly small. The strain imposed upon the diagnostic process makes management in specialized laboratories necessary. Inadvertent handling of the diagnostic procedures in laboratories lacking in knowledge, experience and technical competence is repeatedly the reason for harmful underdiagnosis and overdiagnosis. Gene diagnosis of the carrier condition, principally within reach in all types of acute porphyria, is of incomparable versatility and accuracy. However, despite recent great achievements in the molecular biology of porphyric disease, genomic procedures cannot replace biochemical methods in monitoring the activity and progress of the disease, or the effects of therapy. The classical methods are also useful when it comes to screening for the associated disease states. In these tasks, professional handling of the methods and skillful interpretation of the results are of paramount importance. Knowledge of the limitations and pitfalls of the procedures is a guard against maldiagnosis, which may be fatal. In the article the main diagnostic challenges are discussed; the strategy for early detection of the gene carrier state, the recognition and surveillance of the acute porphyric crisis, the evaluation of subacute/subchronic symptoms, the differential diagnoses of the cutaneous porphyrias and the monitoring of late complications.

Acute Disease↗
PubMed2000

Porphyrins, porphyrin metabolism, porphyrias. III. Diagnosis, care and monitoring in porphyria cutanea tarda--suggestions for a handling programme.

Deficiency of the fifth enzyme in haem synthesis, uroporphyrinogen decarboxylase (UPGD), may give rise to accumulation and excretion of poly-carboxylated porphyrins, as well as to clinical manifestations in the form of a phototoxic skin reaction and liver engagement leading to cirrhosis and hepatocellular cancer. The cutaneous reaction, presenting as skin fragility and blisters on areas exposed to sun--porphyria cutanea tarda (PCT)--develops only in individuals with a remaining hepatic UPGD activity less than 20% of normal. Experimental results and clinical observation give evidence that PCT is a multifactorial disease. In some individuals a 50%, decrease in UPGD activity is a consequence of inheritance of an allele with a mutation in the gene programming for the enzyme, but in these gene carriers, as well as in the other patients with overt PCT, the activity of the hepatic enzyme is reduced below the critical level by the action of specific inhibitors. In the generation of the enzyme inhibitors, iron plays a central role by promoting the formation of reactive oxygen species, a process where a specific class of cytochrome enzymes; cytochrome P450 1A (CYP4501A), participates. The varying individual susceptibility to development of the disease can be discussed in terms of differences in a spectrum of factors that affect the availability of the free form of this element in the liver, or its pathogenic action. In the article the roles of chronic viral infection, alcohol abuse and exposition to polyhalogenated cyclic hydrocarbons are considered in the light of effects on the availability of iron in the liver. Some genetic prerequisites for susceptibility to PCT-inducing agents are included in a tentative model for the disease, i.e. mutations in the UPGD gene and in the HFE gene affected in haemochromatosis, as well as genetically steered inducibilities of the genes programming for CYP4501A and the rate-limiting enzyme in haem synthesis, 5-aminolevulinate synthase. With the pathogenic model as a basis the different therapeutic strategies that can be applied are discussed, and suggestions for a handling programme for the patient presenting with PCT put forward.

Humans↗
PubMed2000

Porphyrins, porphyrin metabolism and porphyrias. IV. Pathophysiology of erythyropoietic protoporphyria--diagnosis, care and monitoring of the patient.

An extremely painful cutaneous condition with no or only slight visible skin changes, presenting in a child or an adult as an acute reaction to sun light, is probably a manifestation of the porphyrin metabolic disorder erythropoietic protoporphyria (EPP). The disease is the result of a genetically determined condition where a mutation in the gene for the final enzyme in the haem synthetic chain, ferrochelatase, results in impaired activity of the enzyme. In some predisposed individuals, the condition is accompanied by heavy accumulation of the substrate for the deficient enzyme, i.e. of protoporphyrin. Distributing to the skin, and there absorbing light of certain wavelengths, the metabolite generates free radicals that give rise to photodynamic cell injury. The primary event takes place in the endothelial cells of the superficial skin capillaries, but complement activation and mast cell degranulation in the surrounding tissue follow in the process. Even if the disease is primarily dermatological the hepatic and psychosocial complications are features requiring close attention by the physician. In order to provide a basis for suggestions regarding lege artis protocols for the diagnosis, treatment and monitoring of the patient with EPP, the pathophysiology of the cutaneous and hepatic manifestations are discussed in some detail in the article.

Humans↗
PubMed1998

[Paranoid psychosis in acute intermittent porphyria treated with perphenazine].

Several drugs may induce or exacerbate symptoms in acute porphyria. This includes most psychotropic drugs, which makes the treatment of psychiatric symptoms in the porphyric patient difficult. A patient with a paranoid psychotic condition related to acute intermittent porphyria was treated with perphenazine. The use of this drug has not previously been reported in acute intermittent porphyria. Therefore, the treatment was closely monitored clinically and biochemically. No deterioration in the porphyric state was observed. However, further experience is needed before perphenazine may be considered as a drug that can be used safely in acute intermittent porphyria.

Adult↗
PubMed1998

[Porphyria cutanea tarda is the most common type of porphyria. Medical control is a team work].

Porphyria cutanea tarda (PCT) is probably the most common of the porphyrias. The development of skin fragility and blisters are the symptoms that generally bring the patient to the notice of the dermatologist. During the past decade the disease has been recognised as being of heterogeneous aetiology, and a pathogenetic classification has been proposed. The significance of subtyping for the choice of management strategy is currently appreciated, as is the need of close monitoring owing to the risk of the common PCT-associated liver conditions. Preferably the PCT patient should be managed by a dermatologist and a hepatologist working in concert and supported by a specialised porphyria laboratory. The use of a structured management protocol should be considered.

Diagnosis, Differential↗
PubMed1998

[Prevention of acute intermittent porphyria is the best solution. Most important are early diagnosis and counseling].

Recent mapping of acute intermittent porphyria (AIP) in Sweden has confirmed its very high prevalence in northern districts, though about fifty per cent of the gene carriers are to be found in the central and southern parts of the country. More than eighteen different AIP mutations are currently recognised in the Swedish kindreds. One mutations, evidently originating in northern Sweden, is predominant. As AIP is a pharmacogenetic disease, more than 200 substances being currently known to precipitate the neuropsychiatric symptoms, the greatest care is required in prescribing drugs to carriers of genetic predisposition to the disease. Guidelines are provided in the booklet. Drugs contraindicated in acute porphyria (Läkemedel farliga vid akut porfyri), jointly issued by the Swedish Porphyria Association and the Corporation of Swedish Pharmacists (Apoteksbolaget). Where doubt exists, specialists should be consulted since there are a number of factors that may contribute to an adverse reaction. Early diagnosis, preferably before puberty, and counselling are the cornerstones of management, and genetic analysis the diagnostic tool of choice, applicable in most families. In the symptomatic phase, glucose or haem arginate is effective in reversing the metabolic processes responsible for the exacerbation. Recently, the hepatic and late renal manifestations of the disease have been recognised, and early detection of the associated conditions is recommended. This includes monitoring for paraneoplastic prodromes of hepatocellular cancer.

Genetic Counseling↗
PubMed1998

[Risk of liver failure in erythropoietic protoporphyria. Be alert for sings of cholestatic development!].

Erythropoietic protoporphyria (EPP) presents clinically as a painful skin reaction to sun-light exposure. The profoundly disabling psychosocial consequences of the disease often go unnoticed by the physician, and the need to monitor the patient for hepatic complications is not generally recognised. The article describes the clinical and biochemical course in a 51-year-old man with EPP, who within a few days developed signs of acute hepatic failure. The case emphasises the importance of a well designed monitoring programme that allows close evaluation of the patient's current porphyrin metabolism, and indicates what measures should be considered.

Cholestasis, Intrahepatic↗
PubMed1998

[Porphyria--a metabolic mine field].

The porphyrias, uncommon conditions often eluding diagnosis, extremely susceptible to inappropriate treatment and associated with severe late manifestations, are representative of the small groups of scarce and complex diseases that are difficult to manage without specialised resources. A network of offices with diagnostic and consultative support from a national specialist centre is probably the most cost effective way of meeting the patients' demands in terms of highly specialised medical experience coupled with close contact and continuity This approach, adopted by the Swedish Porphyria Centre, is based on well structured and regularly updated programmes for the management of porphyria patients.

Counseling↗
PubMed1997

Large phlebotomy in variegate porphyria.

There are no reports on effects of large blood losses in acute hepatic porphyria. In the present study we report the experiences of repeated large therapeutic phlebotomies in a patients with porphyria cutanea tarda coexisting with variegate porphyria. Neither a series of 12 phlebotomies, 300 mL each, resulting in a 17% decrease in blood haemoglobin, nor a single 400 mL phlebotomy activated the acute porphyric condition. It is concluded that the increased bone marrow metabolic throughput resulting from blood loss, in acute types of porphyria does not overload the normoblast or leukocyte precursor haem synthetic pathways in a way which will increase porphyrin precursor excretion or trigger acute porphyric symptoms.

Female↗
PubMed1997

Effects of administration of antioxidants in acute intermittent porphyria.

In order to elucidate the question of free radical involvement in acute porphyric crisis, antioxidants were administered to two acute intermittent porphyria patients with long-standing recurrent attacks. Clinical condition and urinary excretion of porphyrins and porphyrin precursors were monitored before, during and after an eight week therapy with daily doses of vitamin E, beta-carotene, ascorbic acid, selenium, vitamin Q, acetylcysteine, mannitol and carnitine. Blood cell trace element profiles were followed. The administration of the compound antioxidant formula was found not to further impair the clinical or biochemical conditions of the patients but the incidence of the recurrent crises or the severity of the symptoms were not positively affected. Aberrant blood cell trace element profiles with increased granulocyte manganese were normalized during treatment, on cessation of the therapy again resuming the abnormal pretreatment patterns, which may suggest an origin in oxidative stress. No correlation was observed between the concentration of granulocyte manganese and the excretion of 5-aminolaevulinic acid. Indications for participation of this porphyrin precursor in a radical generating process leading to generalized mitochondrial superoxide dismutase induction, as conceivably signalled by increased intracellular manganese, were thus not obtained. The failure to note a clinical response to antioxidant therapy may be due to factors dependent upon dosage of, or interaction between, the antioxidant compounds given, or on restricted bioavailability of the antioxidants at critical anatomical sites, and does not per se invalidate the model of acute porphyria as a hyperoxidative condition.

Adult↗
PubMed1997

Pathogenic mechanisms of the acute porphyric attack: speculative roles of manganese associated enzymes.

The significantly increased concentrations of granulocyte manganese in subjects with AIP may be an indication of overexpression of manganese-associated enzymes. In this study we present further observations related to this phenomenon and speculate that this may provide a rational basis for hypotheses attempting to explain the pathogenesis of the acute attack of porphyria. Such hypotheses are advanced with regard to pyruvate carboxylase, mitochondrial superoxide dismutase and glutamine synthetase, three manganese-dependent enzymes associated with either ALA-generating or ALA-dependent processes. The metabolic impacts in acute porphyria of these enzymes would be functions of the current energy charge of the organism, and would thus explain the protecting and ameliorating effects of glucose in these conditions. Although granulocytes from AIP subjects have elevated manganese concentrations, this did not appear to be associated with increased activities of two enzymes assayed, pyruvate carboxylase or mitochondrial superoxide dismutase. However, enzyme activities in white blood cells do not necessarily represent the levels of catalytic activity in cell types involved in the phenotypic expression of porphyria. Thus it proposed that hypotheses along these new lines of thinking are not flawed by the apparently missing correlations, and should not be therefore discarded. The possible roles of manganese-associated enzymes in the mechanisms behind the acute porphyric attack are discussed in some detail in the paper.

Adult↗
PubMed1995

Diagnosis of acute intermittent porphyria in northern Sweden: an evaluation of mutation analysis and biochemical methods.

OBJECTIVE: To validate the use of a recently observed guanine to adenine mutation in exon 10 in the porphobilinogen deaminase (PBGD) gene as a diagnostic marker of acute intermittent porphyria (AIP). To evaluate the efficiency of the traditional biochemical diagnostic methods. DESIGN: Matched and blinded case-control study (1:4). SETTING: A primary health care centre in Arjeplog, the National Porphyria Research Unit and a department of clinical genetics in Stockholm. SUBJECTS: A total of 48/49 (98%) patients over the age of 15 years living in Arjeplog with AIP, diagnosed according to standard clinical and biochemical criteria. For each AIP patient, four controls were matched for age, sex and geographical area and 164/196 (86%) participated. In the validity study, 35 patients were selected as indisputable AIP gene carriers, according to strict biochemical criteria, and 92 matched controls were selected with strict exclusion criteria. MAIN OUTCOME MEASURES: Validity, specificity and sensitivity of DNA diagnosis for this AIP mutation. Specificity and sensitivity of traditional biochemical methods. RESULTS: Validity study: the mutation was found in all 35 individuals classified as carriers of AIP. None of the 92 controls had the mutation. Evaluation study: all 48 AIP gene carriers, diagnosed by traditional methods, had the mutation, as had one of the control persons. In an inconclusive group of five persons with heredity for AIP, two had a positive DNA test. CONCLUSIONS: The PBGD mutation analysis was found to have full specificity and sensitivity and can be used as the sole diagnostic method in the family complex studied, representing the major AIP mutation in Sweden. The traditional diagnostic methods, used in optimal combinations, work in most cases, but they do not show high precision. However, they must be used when the specific mutation in the PBGD gene is not known.

Adolescent↗
PubMed1995

Erythrocyte porphobilinogen deaminase activity and primary liver cancer.

OBJECTIVES: To study whether primary liver cancer (PLC) could be associated with acute intermittent porphyria (AIP) carriership and whether the activity of erythrocyte porphobilinogen deaminase (PBGD) could be used as a tumour marker for PLC. DESIGN: Prospective study. SETTING: Medical and surgical wards in two general hospitals in Göteborg, Sweden. SUBJECTS: All patients with a strong suspicion of PLC (n = 109) who came to the authors' attention. MAIN OUTCOME MEASURES: Measurement of PBGD activity in erythrocytes. Comparison of the PBGD activity in groups with various final diagnoses-hepatocellular carcinoma (n = 58), cholangiocellular carcinoma (n = 2), malignancy other than PLC (n = 18), benign liver disorders (n = 11)--and according to presence of cirrhosis. RESULTS: None of the patients had a clinical or family history of AIP. Four cases with low PBGD activity, suggesting AIP gene carriership, were found, which is more than expected. However, the cases were evenly distributed amongst the groups. The mean activity of PBGD was higher in cirrhotic patients, irrespective of the presence of PLC, than in others. CONCLUSIONS: (i) Acute intermittent porphyria gene carriership might be associated with an increased risk not only for PLC but also for secondary malignancies and benign tumours in the liver. (ii) High activity of PBGD is not unusual in liver cirrhosis and the reason for this needs to be elucidated, but it seems to be of no clinical value as a tumour marker for PLC.

Adult↗
PubMed1995

Four mutations in the porphobilinogen deaminase gene in patients with acute intermittent porphyria.

We have detected four different mutations in the porphobilinogen deaminase (PBGD) gene in acute intermittent porphyria (AIP) families from England, Norway, and Sweden. A splicing mutation in the first position of intron 8 (Int8 + 1) was found in a family from England and a missense mutation in exon 12 (Glu250) was detected in a Norwegian family. Two mutations were identified in Swedish families, one splicing mutation in the first position of intron 3 (Int3 + 1) and one missense mutation in exon 8 (Pro119).

Acute Disease↗
PubMed1995

Markers for vulnerability in acute porphyria. A hypothesis paper.

Previously symptomatic and permanently asymptomatic carriers of a gene mutation for acute intermittent porphyria as well as matched controls were screened with regard to a series of variables of possible relevance to the development of porphyric symptoms. The basis for the study was a concept of acute porphyria as a condition of a permanent system overload of oxidative stress, with long term effects on hepatic and renal tissue, and with instances of periodic overload of free radicals giving rise to acute neurologic involvement. Leukocyte concentrations of manganese, calcium, iron and zinc, as well as erythrocyte calcium differed between the groups, acute intermittent porphyria gene carriers, irrespective of previous porphyric illness, showing significantly higher levels than the controls. Manganese was found to be the most discriminative component of all the 78 variables investigated, accounting for about 98 per cent of the variance between the groups. An increment, by a factor of four, in cellular manganese is suggestive of an increase, in acute intermittent porphyria, of a manganese associated enzyme, e.g. glutamine synthetase, pyruvate carboxylase or mitochondrial superoxide dismutase. The best fit into the model considered is provided by a theory focused on superoxide dismutase, induced in response to superoxide anion radical produced from aminolaevulinic acid. In porphyria gene carriers seemingly resistant to porphyric manifestations, an increase in potentially prooxidant cellular iron is matched by a proportional increment in manganese, i.e. presumably by a corresponding mitochondrial superoxide dismutase induction. This mechanism is not operative in porphyric individuals prone to development of neuropsychiatric symptoms. In acute intermittent porphyria with a history of porphyric illness there is a positive correlation between erythrocyte manganese and serum folate and a negative correlation between leukocyte ferrochelatase activity and serum cobalamin concentration. This may mirror a role of the cobalamin-folate system in the acute porphyric process.

Adult↗