Clinical aspects of acute intermittent porphyria in northern Sweden: A population-based study

The objective of this study was to update the clinical issues of acute intermittent porphyria (AIP), as they have not been in focus for years, and to be aware of potentially associated disorders and social consequences. A total of 356 gene carriers of AIP from northern Sweden participated in this retrospective population-based study. Eight mutations were found with a predominance of W198X (89%). Clinical manifestations of AIP (manifest AIP) were identified in 42%, 65% were women. Women were more severely stricken by AIP attacks concerning number and duration, hospital admission and early onset. Men reporting most attacks were > 40 years of age. In addition to traditional symptoms during attacks, fatigue was commonly described. Chronic AIP symptoms and disability pension due to AIP were reported in about 20% of subjects. Precipitating factors were reported with evident sex differences. Half of the gene carriers who were on medications used drugs considered not safe (in 1999), mainly antihypertensive drugs. Smoking was associated with high AIP attack frequency. Elevated levels of ALT, bile acids, creatinine, U-ALA and U-PBG and decreased levels of creatinine clearance were associated with manifest AIP. The same was true for hypertension and myalgia in the legs. Hepatoma was strikingly overrepresented. The high prevalence of manifest AIP in this study could be explained by a mutation-dependent penetrance. Our results emphasize the importance of early diagnosis, counselling and treatment of attacks, screening and treatment of associated disorders.     

Elevation of hormone-binding globulins in acute intermittent porphyria

Sex hormone-binding globulin (SHBG), thyroxine-binding globulin (TBG) and cortisol-binding globulin (CBG) were measured in plasma of 26 patients with acute intermittent porphyria (AIP). Twelve patients had clinically manifest disease and all had elevated SHBG levels. All but one of 14 patients with latent porphyria had normal SHBG levels. TBG was elevated in 9 of the patients with clinically manifest porphyria and CBG elevated in three. Levels of TBG and CBG were either normal or only slightly elevated in those with latent porphyria. In a prospective study of 30 attacks of AIP in 7 patients, SHBG levels fell between admission and discharge, the fall being significant in the group of 21 attacks treated with haem arginate (p less than 0.001). Our findings suggest that a close correlation exists between elevated SHBG and clinical expression of AIP.     

AAV8-mediated Gene Therapy Prevents Induced Biochemical Attacks of Acute Intermittent Porphyria and Improves Neuromotor Function

Acute intermittent porphyria (AIP), an autosomal dominant hepatic porphyria due to half-normal hydroxymethylbilane synthase (HMB-synthase) activity, is manifested by life-threatening acute neurological attacks that are precipitated by factors that induce heme biosynthesis. The acute attacks are currently treated with intravenous hemin, but a more continuous therapy is needed, particularly for patients experiencing frequent attacks. Thus, a recombinant AAV8-based serotype vector expressing murine HMB-synthase driven by liver-specific regulatory elements was generated and its effectiveness to prevent the biochemical induction of an acute attack was evaluated in an AIP mouse model. Intraperitoneal administration of the adeno-associated viral (AAV) vector resulted in a rapid and dose-dependent increase of HMB-synthase activity that was restricted to the liver. Stable expression of hepatic HMB-synthase was achieved and wild-type or greater levels were sustained for 36 weeks. When heme synthesis was periodically induced by a series of phenobarbital injections, the treated mice did not accumulate urinary δ-aminolevulinic acid (ALA) or porphobilinogen (PBG), indicating that the expressed enzyme was functional in vivo and prevented induction of the acute attack. Further, rotarod performance and footprint analyses improved significantly. Thus, liver-directed gene therapy provided successful long-term correction of the hepatic metabolic abnormalities and improved neuromotor function in the murine model of human AIP.     

Molecular and biochemical studies of acute intermittent porphyria in 196 patients and their families

BACKGROUND: Acute intermittent porphyria (AIP) is a metabolic disease with clinical manifestations that mimic other abdominal, neurologic, or mental crises. We studied the diagnostic accuracy of current laboratory tests during an acute attack and in remission. METHODS: Since 1966, we have studied all known Finnish AIP patients (n = 196) and their families (n = 45) and identified the porphobilinogen deaminase (PBGD) mutation in each family. Diagnoses or exclusions of AIP were based on clinical data (including family history), biochemical tests, and in 239 cases, mutation testing. We retrospectively evaluated the diagnostic accuracy of erythrocyte PBGD activity, urinary excretion of porphobilinogen (PBG) and delta-aminolevulinic acid, and urinary and fecal excretion of porphyrins in these patients. RESULTS: Measurement of urinary PBG identified all 35 AIP patients studied during an acute attack. The mean excretion of PBG was 50-fold above the reference interval, although the intraindividual increases were modest (1.6- to 4.0-fold). In the mutation-screened population, urinary PBG analysis identified only 85% of 81 AIP patients studied during remission, but by ROC curve analysis it was nonetheless the best of the biochemical tests. It was increased 相似文献   

Sustained Enzymatic Correction by rAAV-Mediated Liver Gene Therapy Protects Against Induced Motor Neuropathy in Acute Porphyria Mice

Acute intermittent porphyria (AIP) is characterized by a hereditary deficiency of hepatic porphobilinogen deaminase (PBGD) activity. Clinical features are acute neurovisceral attacks accompanied by overproduction of porphyrin precursors in the liver. Recurrent life-threatening attacks can be cured only by liver transplantation. We developed recombinant adeno-associated virus (rAAV) vectors expressing human PBGD protein driven by a liver-specific promoter to provide sustained protection against induced attacks in a predictive model for AIP. Phenobarbital injections in AIP mice induced porphyrin precursor accumulation, functional block of nerve conduction, and progressive loss of large-caliber axons in the sciatic nerve. Hepatocyte transduction showed no gender variation after rAAV2/8 injection, while rAAV2/5 showed lower transduction efficiency in females than males. Full protection against induced phenobarbital-attacks was achieved in animals showing over 10% of hepatocytes expressing high amounts of PBGD. More importantly, sustained hepatic expression of hPBGD protected against loss of large-caliber axons in the sciatic nerve and disturbances in nerve conduction velocity as induced by recurrent phenobarbital administrations. These data show for the first time that porphyrin precursors generated in the liver interfere with motor function. rAAV2/5-hPBGD vector can be produced in sufficient quantity for an intended gene therapy trial in patients with recurrent life-threatening porphyria attacks.     

New form of dual porphyria: coexistent acute intermittent porphyria and porphyria cutanea tarda

A previously unrecognized form of dual porphyria has been identified in four patients. One male and one female with acute symptoms were diagnosed as having acute intermittent porphyria (AIP), and two males with cutaneous and acute symptoms were diagnosed as having porphyria cutanea tarda (PCT). Biochemically, the excretion of haem precursors showed a complex constellation, with signs characteristic of both AIP and PCT. In one male, a clinical course with both overt PCT and acute manifestations of AIP was observed. Enzyme studies of haem biosynthesis in erythrocytes revealed a dual deficiency, with decreased activity of both porphobilinogen deaminase, as seen in AIP, and uroporphyrinogen decarboxylase, as seen in PCT. A family study showed that the two disorders do not consistently segregate together. These findings suggest that the dual porphyria reflects a double heterozygous condition of coexistent AIP and PCT genes in the same subject.     

Early-Onset Chronic Renal Failure as a Complication of Acute Intermittent Porphyria

In a retrospective survey of patients who have had a provenattack of acute intermittent porphyria (AIP) in the West ofScotland a highly significant association (p < 0·001)was observed between AIP and the development of early-onsetchronic renal failure. Six patients with AIP and chronic renalfailure arising in early middle-age are described. As no othercause could be attributed to the renal failure three possiblecausal links between these two conditions were considered, namely,enhanced susceptibility to analgesic nephropathy, porphyria-inducedhypertension, and nephrotoxic effects of porphyrins and theirprecursors. We suggest that porphyria-induced hypertension isthe most important factor in causing early-onset chronic renalfailure in acute intermittent porphyria     

Estimation and application of biological variation of urinary delta-aminolevulinic acid and porphobilinogen in healthy individuals and in patients with acute intermittent porphyria

BACKGROUND: Diagnosis of an attack of acute intermittent porphyria (AIP) is based on the demonstration of increased concentrations of porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) in urine, but many AIP patients also have high baseline concentrations in remission. The aim of this study was to estimate the biological variations of ALA, PBG, and porphyrins in healthy individuals and AIP patients to improve interpretation of test results. METHODS: Fifteen healthy individuals and 15 AIP patients were included, and biological variations were calculated based on urine samples collected weekly for 10 consecutive weeks. For the AIP patients, long-term variations were also estimated based on 7 samples collected through a 2-year period. RESULTS: The porphyrin variances were inhomogeneously distributed; biological variations of porphyrins were therefore not calculated. The within-subject biological variations of ALA and PBG were 16%-20% in the short-term settings and for PBG, 25% in the long-term setting, giving reference change values of approximately 50% and 70%, respectively. The probability of detecting a 100% real change in PBG was 97% in the short-term setting and 80% in the long-term setting. CONCLUSIONS: In an AIP patient, a 2-fold increase in PBG, independent of the baseline concentration, will be detected with a probability >80% and is most likely related to the patient's disease and not caused only by analytical and biological variation. When PBG is used in the assessment of AIP-related symptoms, both the PBG concentration in remission and the length of time since the previous sample must be considered.     

Early-onset chronic renal failure as a complication of acute intermittent porphyria

In a retrospective survey of patients who have had a proven attack of acute intermittent porphyria (AIP) in the West of Scotland a highly significant association (p less than 0.001) was observed between AIP and the development of early-onset chronic renal failure. Six patients with AIP and chronic renal failure arising in early middle-age are described. As no other cause could be attributed to the renal failure three possible causal links between these two conditions were considered, namely, enhanced susceptibility to analgesic nephropathy, porphyria-induced hypertension, and nephrotoxic effects of porphyrins and their precursors. We suggest that porphyria-induced hypertension is the most important factor in causing early-onset chronic renal failure in acute intermittent porphyria.     

Difficulties in diagnosis of intermittent porphyria

A case of acute intermittent porphyria (AIP) in a woman aged 51 years with a lethal outcome is reported. The diagnosis was made late because of insufficient knowledge of physicians about this disease. The article gives diagnostic criteria and methods of examination in AIP which provide timely diagnosis and adequate treatment.     

Increased activity of porphobilinogen deaminase in erythrocytes during attacks of acute intermittent porphyria

The activity of porphobilinogen deaminase was determined in 25 patients with acute intermittent porphyria during and after fully developed attacks of porphyria. It was found that in most cases (in 20 of 25) it was higher than 24.3 nmoles/ml erythrocytes/hour, a value considered as characteristic for acute intermittent porphyria, and that it decreased during convalescence and remission. In a proportion of these cases the decrease in the activity of the enzyme was parallelled by decreasing urinary excretion of porphobilinogen. A normal activity of porphobilinogen deaminase during an attack of porphyria can be a source of error in the differential diagnosis of porphyria.     

Human hereditary hepatic porphyrias

The human hereditary hepatic porphyrias are diseases due to marked deficiencies of enzymes in the heme biosynthetic pathway. Porphyrias can be classified as either hepatic or erythroid, depending on the major production site of porphyrins or their precursors. The pathogenesis of inherited hepatic porphyrias has now been defined at the molecular level. Some gene carriers are vulnerable to a range of exogenous and endogenous factors, which may trigger neuropsychiatric and/or cutaneous symptoms. Early diagnosis is of prime importance since it makes way for counselling. In this article we present an overview of recent advances on hepatic porphyrias: 5-aminolevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria (AIP), porphyria cutanea tarda (PCT), hereditary coproporphyria (HC), and variegate porphyria (VP).     

Increased delta aminolevulinic acid and decreased pineal melatonin production. A common event in acute porphyria studies in the rat.

Tryptophan (TRP) is the precursor of melatonin, the primary secretory product of the pineal gland. Hepatic heme deficiency decreases the activity of liver tryptophan pyrrolase, leading to increased plasma TRP and serotonin. As a paradox, patients with attacks of acute intermittent porphyria (AIP), exhibit low nocturnal plasma melatonin levels. This study using a rat experimental model was designed to produce a pattern of TRP and melatonin production similar to that in AIP patients. Pineal melatonin production was measured in response to: (a) a heme synthesis inhibitor, succinylacetone, (b) a heme precursor, delta-aminolevulinic acid (Ala), (c) a structural analogue of Ala, gamma-aminobutyric acid. Studies were performed in intact rats, perifused pineal glands, and pinealocyte cultures. Ala, succinylacetone, and gamma-aminobutyric acid significantly decreased plasma melatonin levels independently of blood TRP concentration. In the pineal gland, the key enzyme activities of melatonin synthesis were unchanged for hydroxyindole-O-methyltransferase and decreased for N-acetyltransferase. Our results strongly suggest that Ala overproduced by the liver acts by mimicking the effect of gamma-aminobutyric acid on pineal melatonin in AIP. They also support the view that Ala acts as a toxic element in the pathophysiology of AIP.     

Circulating fluorocytes at the first attack of acute intermittent porphyria: A missing link in the pathogenesis

BackgroundAcute intermittent porphyria (AIP) is an autosomal dominant disorder of the haem biosynthesis resulting from a partial deficiency of hydroxymethylbilane synthase (HMBS) with incomplete penetrance. By conventional means, it is able to identify asymptomatic mutation carrier by molecular diagnosis, but one cannot reliably predict an acute porphyric attack. The presence of fluorescent red cells (fluorocytes) in AIP is probably under-recognized since AIP is a hepatic porphyria and not associated with photosensitivity.MethodsWe used an automatic image acquisition platform to detect the circulating fluorocytes at 700 nm emission in a diabetic AIP patient during acute attack. We screened the patient and her family members for the mutation on HMBS, urine porphobilinogen and circulating fluorocytes.ResultsThe patient was heterozygous for a disease-causing mutation on HMBS and several bright circulating fluorocytes were detected. We showed evidence that protoporphyrin contributed to the erythrocyte auto-fluorescence. Interestingly, asymptomatic mutation carriers with increased urine porphobilinogen did not have circulating fluorocytes. All mutation-negative family members revealed no circulating fluorocytes.ConclusionSudden decrease in plasma glucose concentration might invoke acute attack of AIP and appearance of circulatory fluorocytes. Potential of detecting fluorocytes as screening test or for predicting an acute attack of AIP in diabetes is worth investigating.     

Characterization of the Porphobilinogen Deaminase Deficiency in Acute Intermittent Porphyria: IMMUNOLOGIC EVIDENCE FOR HETEROGENEITY OF THE GENETIC DEFECT

The molecular pathology of the porphobilinogen (PBG)-deaminase deficiency in heterozygotes for acute intermittent porphyria (AIP) was investigated by means of biochemical and immunologic techniques. The stable enzyme-substrate intermediates (A, B, C, D, and E) of PBG-deaminase were separated by anion-exchange chromatography of erythrocyte lysates from heterozygotes for AIP and normal individuals. In normal lysates, the intermediates eluted in a characteristic pattern with decreasing amounts of activity (A > B > C > D > E), the combined A and B intermediates representing >75% of total recovered activity. In contrast, two different profiles were observed in lysates from heterozygotes for AIP. In most heterozygotes, the elution profile was similar to that of normal individuals, but each intermediate was reduced ~50%. A second profile in which the C intermediate had disproportionately higher activity than the A or B intermediates was observed in asymptomatic heterozygotes with high urinary levels of PBG (>5 μg/ml) as well as in heterozygotes during acute attacks. These findings suggested that the C intermediate (the dipyrrole-enzyme intermediate) may be rate limiting in the stepwise conversion of the monopyrrole, PBG, to the linear tetrapyrrole, hydroxymethylbilane. To investigate further the nature of the enzymatic defect in AIP, sensitive immunotitration and immunoelectrophoretic assays were developed with the aid of a rabbit anti-human PBG-deaminase IgG preparation produced against the homogeneous enzyme. Equal amounts of erythrocyte lysate activity from 32 heterozygotes for AIP from 22 unrelated families and 35 normal individuals were immunoelectrophoresed. There were no detectable differences in the amounts of cross-reactive immunologic material (CRIM) in lysates from the normal individuals and 25 heterozygotes from 21 of the 22 unrelated families with AIP. In contrast, when equal enzymatic activities were coimmunoelectrophoresed, all seven heterozygotes from one family had ~ 1.6 times the amount of CRIM compared with that detected in normal lysates. Consistent with these findings, immunotitration studies also demonstrated similar quantities of noncatalytic CRIM in lysates from this AIP family. When equal activities of the individual A, B, C, and D enzyme-substrate intermediates from normal and CRIM-positive erythrocytes were immunoelectrophoresed, increased amounts of immunoreactive protein were observed for each intermediate, B > A C D, from the CRIM-positive AIP variants. On the basis of these findings, it is hypothesized that the enzymatic defect in the CRIM-positive AIP family resulted from a mutation in the structural gene for PBG-deaminase which altered the catalytic as well as a substrate binding site. These studies of the enzymatic defect provide the first demonstration of genetic heterogeneity in AIP.     

Acute intermittent porphyria with atypical neuropathy

The patient we have described had lower extremity numbness, paresthesias, constipation, urinary retention, and sexual dysfunction. Laboratory evaluation confirmed a diagnosis of acute intermittent porphyria (AIP). Vitamin B6 and glucose therapy initiated resolution of symptoms. The sensory neuropathy described here is unusual, and we believe sexual dysfunction is a previously unreported manifestation of AIP.     

Acute intermittent porphyria in the practice of an intensive care specialist]

Acute intermittent porphyria (AIP) is a hereditary disease caused by disordered haem biosynthesis and characterized by paroxysmal exacerbations. It usually manifests in adult women. Provoking factors are pregnancy, alcohol, and "porphyrogenic" drugs. Grave attacks of AIP require urgent hospitalization in intensive care wards, rapid purposeful diagnosis and adequate therapy, determining the prognosis. The number of drugs should be minimized and drugs with a known porphyrogenic effect absolutely ruled out. A 35-year-old patient with the first episode of AIP is described; the disease eventuated in death after 2 months.     

Acute intermittent porphyria in the practice of anesthesiology and intensive care

Acute intermittent porphyria (AIP) is a hereditary disease caused by disordered haem biosynthesis and characterized by paroxysmal exacerbations. It usually manifests in adult women. Provoking factors are pregnancy, alcohol, and "porphyrogenic" drugs. Grave attacks of AIP require urgent hospitalization in intensive care wards, rapid purposeful diagnosis and adequate therapy, determining the prognosis. The number of drugs should be minimized and drugs with a known porphyrogenic effect absolutely ruled out. A 35-year-old patient with the first episode of AIP is described; the disease eventuated in death after 2 months.     

Studies in Porphyria: VII. INDUCTION OF UROPORPHYRINOGEN-I SYNTHASE AND EXPRESSION OF THE GENE DEFECT OF ACUTE INTERMITTENT PORPHYRIA IN MITOGEN-STIMULATED HUMAN LYMPHOCYTES

A 50% reduction in the activity of uroporphyrinogen-I (URO) synthase in liver, erythrocytes, and cultured skin fibroblasts characterizes all patients with clinically active acute intermittent porphyria (AIP). The same enzyme defect has also been demonstrated in the erythrocytes and skin fibroblasts of completely latent gene carriers of this disorder and presumably exists in the liver as well.     

The W198X and R173W mutations in the porphobilinogen deaminase gene in acute intermittent porphyria have higher clinical penetrance than R167W. A population-based study

In northern Sweden, 468 patients with DNA-verified acute intermittent porphyria (AIP) were registered. A higher prevalence of manifest AIP was found in patients with mutations W198X and R173W when separately compared with mutation R167W, indicating higher clinical penetrance. Signs of increased seriousness of the disease were also found in patients with the W198X and R173W mutations in relation to the number and duration of attacks, impaired renal function and chronic disability. One explanation could be lower PBGD enzyme activity resulting from the W198X and R173W mutations than from the R167W mutation, though other factors might also be the cause.