Molecular analysis of the hydroxymethylbilane synthase (HMBS) gene in Italian patients with acute intermittent porphyria: report of four novel mutations.

Acute intermittent porphyria (AIP) is an autosomal disorder caused by molecular abnormalities in the hydroxymethylbilane synthase (HMBS) gene coding for the third enzyme in the heme biosynthetic pathway. So far, more than 160 different mutations responsible for AIP have been identified in this gene. We have now identified seven mutations in eight unrelated Italian patients with AIP: two splicing defects (IVS7+2T-->C, 612G-->T), three small deletions (308-309delTG, 730-731delCT, 182delA) and two missense mutations (134C-->A, 541C-->T). The splicing defects were responsible for activation of splicing cryptic sites respectively within intron 7 (15 bp insertion) and exon 10 (9 bp deletion). The small deletions resulted in frameshifts leading to the formation of premature stop codons. The 134C-->A and 541C-->T mutations caused the formation of stop codons likely to be responsible for drastic disruption of the HMBS structure (Ser45Ter, Gln181Ter). This is the first molecular study in AIP patients of Italian origin leading to the identification of four new mutations and three molecular defects that have already been described.

Hereditary coproporphyria: unusual nervous system involvement in two cases.

Two cases of hereditary coproporphyria showed unusual nervous system involvement, one epilepsy with onset in childhood, and the other chronic central and peripheral nervous system damage. The literature is briefly discussed.

Non-alcoholic steatohepatitis induced by carbamazepine and variegate porphyria.

A 42-year-old woman presented with acute bullous skin lesions and angio-oedema that had developed 3 months after initiation of treatment with carbamazepine for epilepsy. Chromatographic analysis of urinary porphyrins was compatible with variegate porphyria. This was manifested initially by neurological symptoms that were mistaken for epilepsy and later by cutaneous symptoms also. Histological findings excluded hepatic porphyria, but revealed severe fatty changes thought to be caused by idiosyncratic metabolism of carbamazepine. While the porphyrinogenicity of carbamazepine is well known, the presence of variegate porphyria has not been reported. The toxic hepatic effects of the drug on hepatic cytochrome P-450, which is involved in haem metabolism, could have aggravated the pre-existent porphyria, provoking the onset of skin lesions.

Incidence of hereditary porphyria cutanea tarda (PCT) in a sample of the Italian population.

The determination of the enzymatic activity of URO-D in erythrocytes is the screening method used for differentiation between hereditary and non-hereditary forms of porphyria cutanea tarda (PCT). The aim of the present work was to establish the relative frequencies of the symptomatic and hereditary forms by the determination of the URO-D enzyme in the PCT patients who were regularly treated at the Centre for Porphyrins in our Institute. In the course of this work we also examined the statistical properties of the distributions of both normal and porphyric subjects, so as to be able to suggest values for discriminating between normal subjects and the various types of porphyric subjects.

Porphyrins in Rotor's syndrome: a study on an Italian family.

Porphyrins in urine, plasma, erythrocytes and feces have been tested in two brothers affected by Rotor's syndrome and in three of their phenotypically normal relatives. In all five subjects normal values of delta-aminolevulinic acid and porphobilinogen in urine, and of prophyrins in plasma, erythrocytes and feces, were found. The two patients showed a marked increase in total urinary coproporphyrin excretion with a high percentage of isomer I. These observations confirm the hypothesis of a different route of the porphyrin excretion in Rotor's syndrome with a shift from the fecal route to the urinary one, and do not agree with the suggestion of an increased hepatic porphyrin production in this type of hyperbilirubinemia.

Hepatitis C virus in patients with porphyria cutanea tarda: relationship to HCV-genotypes.

Porphyria cutanea tarda (PCT) is a rare metabolic disorder characterized by an abnormal porphyrin metabolism and typical cutaneous lesions. Recently a strong association between PCT and hepatitis C virus (HCV) has been proposed. Studies in south Europe have shown high prevalence (53 to 91%) of HCV markers in patients with PCT. We studied HCV genotypes in 72 subjects: 40 with PCT and 32 patients with chronic liver disease. A high rate of HCV-RNA positive PCT patients (84%) was observed, reflecting an active HCV replication, the genotypes study showed a prevalence of genotype 1b in PCT patients (61.2%). These findings implicate HCV in the aetiology of PCT-associated liver disease suggesting that hepatitis C serological and virological testing could be indicated in all patients with PCT.

Recovery from porphyria cutanea tarda with no specific therapy other than avoidance of hepatic toxins.

Little is known of the natural progression of untreated porphyria cutanea tarda. We report sixteen cases (fourteen sporadic and two familial) in which the cutaneous and biochemical abnormalities improved without any specific therapy other than the avoidance of hepatic toxins.

Acquired cutaneous toxoplasmosis.

We examined more than 1,400 dermatologic patients with clinically defined (but having unknown or presumably multiple etiology) affections. The investigation revealed the presence of antitoxoplasma antibodies in more than 50% of the patients, but in only 11% of the cases did the serological analyses give evidence of an active form of disease. It was possible to prove the toxoplasmic etiology of 29 cases of chronic prurigo and of 4 cases of dermatocellulitis. The same infection was involved in a few cases of different dermatoses and in two cases of dermatomyositis-like syndrome. Pseudotumoral granulomatous localizations occurred in immunosuppressed patients. We suggest an 'immunological key' to explain the polymorphism of the cutaneous manifestations. The practical interest of this new knowledge and its importance as a field of interdisciplinary studies are emphasized.

Familial porphyria cutanea tarda with normal erythrocytic urodecarboxylase: an exception to the rule?

The possibility that the differentiation between sporadic and familial porphyria cutanea tarda cannot always be made on the basis of the measurement of the erythrocytic uroporphyrinogen decarboxylase activity has been examined. Two cases of porphyria cutanea tarda, with a normal erythrocytic enzyme activity in a father and son, are described. The authors exclude that these are 2 cases of sporadic or toxic porphyria cutanea tarda within the same family. These 2 cases provide additional evidence for the existence of a form of familial porphyria cutanea tarda in which erythrocytic uroporphyrinogen decarboxylase activity is normal.

Porphyria cutanea tarda in a haemodialysed patient.

A bullous dermatosis, that arose about 2 years after the beginning of haemodialysis treatment, was due to a geniune hereditary porphyria cutanea tarda (PCT). The plasma porphyrins were extraordinarily high. Neither the residual renal function nor the haemodialysis--using different techniques and different materials--succeeded in reducing the plasma porphyrin levels to that usually found in PCT. The serious and rapid evolution of the cutaneous lesions towards a scleroderma-like state might have been due to this level of plasma porphyrins and to their passage into the tissues. The clearance of porphyrins is compared with that of 162 subjects affected by PCT. The porphyrin content in the plasma of seventy-five non-porphyric subjects undergoing maintenance dialysis was also studied.

Iron and porphyria cutanea tarda.

In order to evaluate the pathogenetic role of iron in Porphyria cutanea tarda (PCT), the metabolism of iron was studied in 440 patient with PCT and associated chronic liver disease (CLD) and in 91 nonporphyric CLD patients (used as a control group). The parameters considered were the following: serum iron, ferritin, Total Iron Binding Capacity (TIBC) and percent saturation of transferrin. The statistical analysis showed that the differences between the means, in the two groups, were not significant in any of the parameters examined. To investigate the possible relationships between iron metabolism and other chemico-clinical parameters concerning the porphyric disease, the associated hepatic disease and hemometry, we studied the correlations between iron parameters and total urinary and serum porphyrins, serum copper, serum albumin, hemoglobin, red blood cells, ALT, AST, CHE and GLDH. This investigation was only possible in the last 99 cases. In addition to the obvious correlations between the parameters concerning iron metabolism, the highly significant (p < 0.001) correlation between ferritin and enzyme activities which indicate cytolysis (ALT, AST, GLDH) is extremely interesting. The results seem to point to the tentative conclusion that the alterations of iron metabolism are more related to the hepatocellular necrosis than to the metabolism of porphyrins.