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K Timonen

Publications and source records attributed to K Timonen.

14 recordsLinked to original sources
PubMed2001

Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect.

The long-term follow-up of a homozygous variegate porphyria patient revealed severe photosensitivity accompanied by mild sensory neuropathy and IgA nephropathy. A 35T to C transition in exon 2 (I12T) and a 767C to G transversion in exon 7 (P256R) of the protoporphyrinogen oxidase gene were identified from both alleles of the patient's cDNA and genomic DNA samples. Both prokaryotic and eukaryotic expression studies showed that the first mutation in the evolutionary conserved region resulted in a decrease in the protoporphyrinogen oxidase activity in contrast to the polymorphic substitution in exon 7, which affected the function of the enzyme assayed in Escherichia coli but not COS-1 cells.

Base Sequence↗
PubMed2000

Fixed drug eruption due to fluconazole.

We report a case of fixed drug eruption caused by fluconazole. A local provocation with 10% fluconazole test in petrolatum applied at the site of a previous lesion of fixed drug eruption reproduced the eruption clinically and histopathologically.

Adult↗
PubMed2000

Vascular changes in erythropoietic protoporphyria: histopathologic and immunohistochemical study.

BACKGROUND: Erythropoietic protoporphyria (EPP) is an inherited disease caused by deficient activity of ferrochelatase in the heme biosynthetic pathway. Accumulation of protoporphyrins and light exposure results in acute phototoxic skin reactions. The histopathologic findings of the light-exposed skin are thickening of the superficial dermal vessel walls and amorphous deposits around the vessels, but the origin and detailed composition of the perivascular material have been unclear. OBJECTIVE: The vascular morphology and composition of the perivascular material were studied in the skin samples of patients with EPP. METHODS: Skin biopsy specimens of 8 patients with EPP representing 7 Finnish EPP families with different genotypes were studied by means of light and electron microscopy and immunohistochemical methods. RESULTS: The characteristic finding was thickened, periodic acid-Schiff-positive vessel walls caused by concentric reduplication of basal lamina and excess of fine granular material at the basal membrane zone in the superficial dermis. The perivascular deposits in the vicinity of vessel walls had a homogeneous or fine granular appearance without filaments. Direct immunofluorescence showed constant IgG deposits together with IgA, IgM, and C3 in the vessel walls. In immunohistochemistry, collagen IV and laminin could be demonstrated at the vascular basal membrane together with serum amyloid P protein, kappa and lambda light chains, and a 90-kd glycoprotein. CONCLUSION: The vascular involvement indicates that the blood vessel walls in the papillary dermis are the primary tissues affected during an acute photoreaction. The repeated acute damage and repair processes in the basement membrane zone result in thickening of the vessel walls. Perivascular deposits are a secondary and irreversible phenomenon resulting from the leakage and accumulation of different serum components. These changes were not found in the nonexposed skin, indicating that an increased level of erythrocyte protoporphyrin per se is not responsible for the cutaneous manifestations, but the interaction of solar radiation is mandatory. Amorphous deposits distinguish EPP from variegate porphyria and porphyria cutanea tarda; a histopathologic examination may be a helpful tool in differentiating porphyric and nonporphyric photosensitivity.

Adolescent↗
PubMed1996

Four novel mutations in the ferrochelatase gene among erythropoietic protoporphyria patients.

A novel mutation was identified by direct sequencing of genomic polymerase chain reaction products in each of four Finnish erythropoietic protoporphyria families. All four mutations, including two deletions (751delGAGAA and the first de novo mutation, 1122delT) and two point mutations (286C-->T and 343C-->T), resulted in a dramatically decreased steady-state level of the allelic transcript, since none of the mutations could be demonstrated by direct sequencing of the amplified cDNAs synthesized from total RNA extracted from patients' lymphoblast cell lines. Because the assays of the ferrochelatase activity and erythrocyte protoporphyrin identify asymptomatic patients poorly, the DNA-based demonstration of a mutation is the only reliable way to screen individuals for the disease-associated mutation.

Base Sequence↗
PubMed1994

Treatment of the porphyrias.

There are seven porphyrias which are caused by defective functions of the enzymes in the haem biosynthesis. Pathogenic mechanisms and symptoms differ greatly in individual porphyrias and, consequently, most of them require a specific therapy. Clinically, the three most important entities are acute porphyric attack, porphyria cutanea tarda and protoporphyria. For an acute porphyric attack the treatment of choice is administration of haem; the other measures are elimination of precipitating factors and symptomatic therapy for many associated symptoms. Porphyria cutanea tarda is controlled by removal of iron by phlebotomies or with low-dose chloroquine. Skin symptoms in protoporphyria can be alleviated with betacaroten but there is no effective procedure to normalize disturbed porphyrin metabolism; hepatic failure seen in some patients may need a liver transplantation. The only effective treatment in congenital erythropoietic porphyria is probably a bone marrow transplantation. No satisfactory treatment is available for very rare delta-aminolevulinic acid dehydrase deficiency porphyria.

Acute Disease↗
PubMed1992

Sustained high plasma 5-aminolaevulinic acid concentration in a volunteer: no porphyric symptoms.

The pathogenesis of the acute porphyric attack is not known. One hypothesis is that porphyrin precursors, especially 5-aminolaevulinic acid (ALA), are toxic for neuronal tissue. This was tested by infusing ALA in a male volunteer after a loading dose at a rate of 50-80 mg h-1 for 92.5 h. During the experiment plasma ALA concentration was 9-11 mumol 1-l and porphobilinogen concentration 3-6 mumol 1-l which are the levels seen during acute attacks. Urinary excretion of these porphyrin precursors was also markedly increased. ALA infusion caused no subjective symptoms and no change in pulse rate, blood pressure, or autonomic nerve function or conduction velocity of peripheral nerves. Photosensitivity was not demonstrable. It is concluded that sustained high plasma ALA concentration does not cause porphyria-like symptoms.

Aminolevulinic Acid↗
PubMed1991

Skin morphology in porphyria cutanea tarda does not improve despite clinical remission.

Five patients with porphyria cutanea tarda (PCT) were treated with a prolonged, low-dose chloroquine regimen (250 mg twice weekly). Their skin symptoms disappeared, and the abnormal urinary porphyrin excretion normalized during treatment periods ranging from 6 to 17 (mean 11.8) months. The morphology of the skin was studied by light and electron microscopy methods before treatment, at the onset of remission, and 6-12 months later. In samples taken during remission, the PAS-positive thickening of the superficial dermal vessels was comparable to that before treatment. In electron microscopy, the vessels showed thickening because of reduplication of the basal lamina and perivascular deposition of amorphous material; no consistent changes were found during remission. The results show that the histopathological changes of the skin in PCT are of chronic nature, and are probably irreversible.

Adult↗
PubMed1990

Skin changes in variegate porphyria. Clinical, histopathological, and ultrastructural study.

The skin of 20 patients with variegate porphyria (VP) was studied using light, fluorescent, and electron microscopy. Twelve patients had skin symptoms and markedly increased fecal protoporphyrin excretion. Their sun-exposed skin was characterized by homogeneous PAS-positive thickening and IgG deposition in the vessel walls. The basic ultrastructural change was thickening of the vascular walls caused by reduplication of the basal lamina and perivascular deposition of amorphous material. Qualitatively similar but less prominent histopathological changes occurred in sun-protected skin in some of the patients. Six patients had no skin symptoms but an increased porphyrin excretion. The light microscopical changes were comparable to those in the patients with skin symptoms, but the ultrastructural changes were less severe. No abnormal histopathological changes occurred in two symptomless patients who had low lymphocyte protoporphyrinogen oxidase activity but normal fecal porphyrin excretion. These results show that the primary site of skin damage in VP is the vessel wall, and that histopathological changes of the skin also occur in porphyric patients who have never had skin symptoms. Factors determining the occurrence of skin symptoms in VP are discussed.

Adult↗
PubMed1990

Effects of haem arginate on variegate porphyria.

Four patients with variegate porphyria (VP) were treated with repeated haem arginate infusions daily for 4 days and then weekly for 4 weeks. After the initial four daily doses of haem arginate (haem 3 mg/kg), the excretion of faecal protoporphyrin (mean 579 nmol/g dry wt) fell to an almost normal level (mean 123 nmol/g dry wt), and that of coproporphyrin (mean 162 nmol/g dry wt) to the normal level (mean 21 nmol/g dry wt) in all patients. However, during the period of the four weekly infusions of haem the excretion of porphyrins increased almost to the pretreatment level. Phototesting showed no changes in the photoreactivity of the skin, and no improvement in skin lesions was seen during the treatment. Except for one case of thrombophlebitis no side-effects occurred. In a child with homozygous VP, four daily infusions of haem arginate (2 mg/kg) normalized the faecal protoporphyrin content, but had no effect on the increased erythrocyte protoporphyrin concentration.

Adult↗
PubMed1984

Localized heat urticaria associated with a decrease in serum complement factor B (C3 proactivator).

A case of localized heat urticaria is reported in a 51-year-old woman who within a few minutes of contact with warm water developed erythema and swelling sharply localized to the heated area. After a hot bath urticarial lesions appeared over large areas of her body, accompanied by a feeling of weakness, but no other systemic symptoms. After challenge with heat by immersing her left arm in water heated to 42 degrees C, a rapid decrease of her serum complement level of factor B was demonstrated, suggesting that activation of an alternative complement pathway plays a role in this form of urticaria. Biopsies for immunofluorescent study of complement and immunoglobulins were negative at 30 and 180 min after heat challenge. The dermal fibres and endothelial cells of dermal vessels were capable, in vitro, of complement binding before and after exposure to heat.

Complement Factor B↗