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PubMed2005

Acute intermittent porphyria.

Acute intermittent porphyria (AIP) is characterised by neurovisceral crises the most common clinical presentation of which is abdominal pain. It is an autosomal dominant condition with incomplete penetrance and is potentially life-threatening. The key point in management is to suspect and confirm the diagnosis as early as possible in order to treat the attack and to avoid inappropriate treatments which may exacerbate the crisis. In this chapter we briefly outline the haem biosynthetic pathway and how deficiencies in individual enzymes give rise to the different porphyrias. We then describe the clinical features and diagnosis of AIP, followed by a discussion of pathogenesis, highlighting advances in the molecular biology of AIP and introducing the debate as to whether neurovisceral crises might result from porphyrin precursor neurotoxicity or from haem deficiency. Finally we discuss management, including family screening, avoidance of triggering factors, analgesia, maintenance of a high calorie intake, and administration of haem derivatives.

Abdominal Pain↗

PubMed1993

High prevalence of a point mutation in the porphobilinogen deaminase gene in Dutch patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal dominant disease characterized by a deficiency of porphobilinogen deaminase (PBGD). Up to now 14 different mutations have been described. In an effort to investigate the molecular epidemiology of AIP we have undertaken a systematic study of different exons of the PBGD gene from a large number of unrelated patients. Here, exon 8 from 82 unrelated Dutch and French AIP patients was examined using single strand confirmation polymorphism analysis (SSCP) after polymerase chain reaction (PCR) amplification. A single base mutation, C to T, at position 346 of the sequence coding for PBGD was observed in 15 Dutch families but in only 1 French family. A simple PCR assay is described to facilitate the diagnosis of this common mutation at the DNA level.

Base Sequence↗

PubMed2005

Clinical and biochemical characteristics and genotype-phenotype correlation in 143 Finnish and Russian patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP), resulting from a deficiency of porphobilinogen deaminase (PBGD) in heme biosynthesis, is genetically heterogeneous and manifests with variable penetrance. The clinical outcome, prognosis, and correlation between PBGD genotype and phenotype were investigated in 143 Finnish and Russian AIP patients with 10 mutations (33G-->T, 97delA, InsAlu333, R149X, R167W, R173W, R173Q, R225G, R225X, 1073delA). Thirty-eight percent of the patients had experienced 1 or more acute attacks during their lives. The proportion of symptomatic patients has decreased dramatically from 49% to 17% among patients diagnosed before and after 1980, respectively. Patients with the R167W and R225G mutations showed lower penetrance (19% and 11%, respectively) and recurrence rate (33% and 0%, respectively) than patients with other mutations (range, 36%-67% and 0%-66%, respectively). Moreover, urinary excretions of porphyrins and their precursors were significantly lower in these patients (porphobilinogen [PBG], 47 +/- 10 vs. 163 +/- 21 micromol/L, p < 0.001; uroporphyrin, 130 +/- 40 vs. 942 +/- 183 nmol/d, p < 0.001). Erythrocyte PBGD activity did not correlate with PBG excretion in remission or with the clinical severity of the disease. Mutations R167W and R225G resulted in milder biochemical abnormalities and clinical symptoms indicating a milder form of AIP in these patients. In all AIP patients, normal PBG excretion predicted freedom from acute attacks. The risk of symptoms was highest for female patients with markedly increased PBG excretion (>100 micromol/L). Proper counseling contributed to the prevention of subsequent attacks in 60% of previously symptomatic and in 95% of previously symptom-free patients.

Abdominal Pain↗

PubMed1999

New mutations of the hydroxymethylbilane synthase gene in German patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a low-penetrant, autosomal dominant disorder caused by decreased activity of hydroxymethylbilane synthase (HMBS; MIM 176 000), the third enzyme in the heme biosynthetic pathway. We report the first molecular analysis of HMBS gene mutations in classical AIP patients of German origin. The HMBS gene of 5 German AIP patients was analysed by DGGE-screening and direct sequencing of amplified genomic DNA. Five different mutations including four novel mutations were found. Three of them are single base substitutions that affected exon 3 (R16C), exon 10 (V202L), and intron 13 (T to A, IVS13+2) The two remaining mutations are frameshifts which produce a stop codon (del GA in exon 6 and insA in exon 14). These mutations are likely to be responsible for the decrease in HMBS activity found in both erythrocytes and non-erythroid cell lines (lymphocytes). Our results demonstrate the allelic heterogeneity of HMBS mutations in AIP patients of German origin.

Adolescent↗

PubMed2005

Nine mutations including three novel mutations among Russian patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a metabolic disease due to a partial deficiency of hydroxymethylbilane synthase (HMBS) in heme biosynthesis. Direct sequencing of genomic DNA samples of 11 unrelated Russian AIP patients, 32 of their relatives and 50 healthy controls from northwestern Russia including Saint Petersburg revealed nine mutations in the HMBS gene. Three novel mutations, c.825+5G>C, c.825+3_825+6del, and c.770T>C, resulted in varying amounts of abnormal transcripts, r.822_825del and [r.770U>C, r.652_771del, r.613_771del]. Six mutations, c.77G>A (p.R26H), c.517C>T (p.R173W), c.583C>T (p.R195C), c.673C>T (p.R225X), c.739T>C (p.C247R), and c.748G>C (p.E250A), have previously been identified in AIP patients from Western and other Eastern European populations. All mutations expressed in COS-1 cells demonstrated low residual activities (0.1-1%). The majority of the mutations were family-specific and also confirmed allelic heterogeneity among Russian AIP patients. The diversity of mutations may reflect the old international history of Saint Petersburg and immigration of people from other parts of Europe.

Animals↗

PubMed2004

Molecular diagnostics of acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an inherited metabolic disease with an autosomal dominant pattern of inheritance. The disease is caused by a partial deficiency of porphobilinogen deaminase (PBGD) in heme biosynthesis. Since biochemical measurements of patients and their healthy relatives overlap, the diagnosis of AIP may remain undetermined at the symptom-free phase. Mutation detection in AIP, which provides 95% sensitivity and around 100% specificity, has quickly been incorporated into good clinical practice. During an acute attack, which includes various neurovisceral symptoms, measurement of urinary porphobilinogen (PBG) is a method of choice to confirm diagnosis, and DNA testing is unnecessary at that stage. DNA testing has revealed many new patients and excluded AIP from many healthy relatives despite slightly increased excretions of porphyrin precursors and erythrocyte PBGD in the low or borderline zone. Thus, quality-assured DNA testing is accurate enough to confirm or exclude the diagnosis of AIP. The clinical utility of DNA testing is limited for those individuals whose mutation is currently unknown, in which biochemical analyses are essential and the majority of the patients can be identified using urinary PBG and erythrocyte PBGD measurements. The measurement of urinary PBG can be used to evaluate the prognosis for symptom-free individuals. Currently, DNA testing of AIP at the population level is not recommended unless the frequency of gene carriers is locally very high and large-scale population-based mutation screening is reasonable. In the future, the knowledge of gene-gene and gene-environment interactions and protein networks using gene array and proteomics technologies may provide more precise information about pathogenetic mechanisms and novel therapeutic strategies for an acute attack and the long-term complications of AIP. Increasing knowledge of pharmacogenetics may identify the patients who are at high risk for clinical manifestations.

Genetic Testing↗

PubMed2000

Two deletion mutations in the hydroxymethylbilane synthase gene in two unrelated Japanese patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease caused by a decreased activity of hydroxymethylbilane synthase (HMBS). Regarding the abnormalities of the HMBS gene, many different mutations have been reported worldwide; however, few families from Japan have been studied. In this work, we investigated the presence of mutations in two unrelated Japanese patients with AIP. Mutational analysis was performed using the polymerase chain reaction-single strand conformation polymorphism (SSCP) method, followed by DNA sequencing. Reliable restriction enzyme cleavage assays were also established for the pedigree analyses. Unique SSCP patterns were noted in exons 12 and 15 of the HMBS gene. Sequencing revealed different mutations in each patient: a two-base deletion of CT at nucleotide 730-731 (730delCT), and also a two-base deletion of CA at position 982-983 (982delCA). Both of the deletion mutations lead to truncated proteins with an abnormal C-terminus, which would be expected to decrease the stability and/or activity of HMBS. Using the cleavage assays, we were able to definitively identify gene carriers in the family. This study adds a novel mutation to those that have been previously reported, and emphasizes that molecular analysis would be very useful not only for the identification of asymptomatic gene carriers in the family but also for the detection of ancestral founders in porphyria families.

Adult↗

PubMed2002

Molecular study of the hydroxymethylbilane synthase gene (HMBS) among Polish patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP), an autosomal dominant disorder of heme biosynthesis, is due to mutations in hydroxymethylbilane synthase (HMBS; or porphobilinogen deaminase, PBGD) gene. In this study, we analyzed 20 Polish patients affected by AIP and we were able to characterize seven novel mutations. A nonsense mutation (Y46X), two frameshift mutations (315delT and 552delT) and a 131bp deletion (nucleotides 992-1123) give rise to truncated proteins. A donor splice site mutation IVS12+2T>C predicts skipping of exon 12. A missense mutation (D61Y) was identified in two apparently unrelated patients with a clearly clinical indication of AIP. An inframe 3-bp deletion (278-280delTTG) results in the removal of V93 from the enzyme. In addition to the novel mutations, nine previously described HMBS gene mutations-R26H, G111R, IVS7+1G>A, R149X, R173Q, 730-731delCT, R225X, 982-983delCA and G335D-were identified in this cohort. Our results demonstrate that molecular analysis of the PBGD gene is a more reliable method comparing to enzymatic assay in the diagnosis of AIP. Although more than 170 different mutations are known to the HMBS gene so far, over 40% of all mutations identified among the Polish AIP patients of this study are novel mutations, indicating the heterogeneity of molecular defects causing AIP.

Adult↗

PubMed2006

A large deletion on chromosome 11 in acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal disorder caused by molecular abnormalities in the gene coding for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. So far, more than 242 different mutations responsible for AIP have been identified in this gene. In an Italian family with typical clinical and biochemical signs of AIP, no mutation was found by direct sequencing of the entire hydroxymethylbilane synthase gene (HMBS). All the symptomatic patients showed apparent homozygosity and absence of mendelian segregation for eleven common polymorphisms along the gene. Excluding interference of polymorphisms in the primer sites, we assumed the presence of a complete HMBS gene deletion. In order to identify the size of this deletion, single nucleotide polymorphisms (SNPs) analysis was extended to flanking genes, H2A Histone Family member X (H2AFX) and Dolichyl-Phosphate N-Acetylglucosamine Phosphotransferase 1 (DPAGT1), downstream and Vacuolar protein sorting 11 (VPS11), upstream. Heterozygous polymorphisms in the VPS11 and DPAGT1 genes were found. Thus, we performed a Long-PCR with primers situated in regions outside the homozygous polymorphisms and we identified a double deletion with inversion on chromosome 11 (g22516974_22524062del7088, g22524062_22524278inv216, g22524278_22531093del6815). Even if the deletions include the entire HMBS and H2AFX genes and 1463 bp of the final portion of DPAGT1 gene, our patients had no other symptoms than AIP.

Chromosome Deletion↗

PubMed1998

Mutation in the exon 10 (R173W) of the hydroxymethylbilane synthase gene in two unrelated Japanese families with acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an inherited disorder characterized by a deficiency of hydroxymethylbilane synthase (EC 4.3.1.8.; HMBS), the third enzyme in the heme biosynthetic pathway. To date, 113 different HMBS gene mutations have been reported in the world. However, there were a few reports of the gene mutations in the Japanese AIP patients. We studied the gene mutation in two unrelated AIP families in the San-in district, a local area of Western Japan. The overlapping 6 fragments of the HMBS gene, amplified by the reverse transcript-polymerase chain reaction, were analyzed by the single-strand conformation polymorphism with silver staining technique. The abnormal fragment from a member of one family was sequenced to detect the C to T substitution at 517 nucleic acid position of cDNA, which led to a missense mutation of arginine to tryptophan exchange at an amino acid level (R173W). This mutation located in exon 10 created a new site of the MSP 1 restriction endonuclease and was screened by the amplified fragment of exon 10 from genomic DNA with the MSP 1 digestion. The mutation was detected totally in three members of the family and interestingly also in two patients of an unrelated family. This mutation has been reported widely in the world independently, such as in a Swedish, a Canadian, a Finnish, and a French family, but is the first in Japanese patients. The screening method for this mutation is useful for diagnosis in Japanese AIP patients.

Adult↗

PubMed2003

Renal transplantation in a case of acute intermittent porphyria.

Acute intermittent porphyria (AIP) results from a deficiency of the porphobilinogen deaminase enzyme of heme biosynthesis. The disease is exacerbated by a wide variety of drugs. Only steroids and azathioprine (Aza) have so far been considered safe in patients with AIP, and cyclosporine is listed as contraindicated. From the transplantation point of view, it is well known that cyclosporine (CsA) is a superior immunosuppressive agent compared to azathioprine. This case report presents a female patient evaluated for renal transplantation. A test dose of CsA was given, and no symptoms of AIP occurred. Renal transplantation with a cadaveric donor was performed, and the patient was immunosuppressed with CsA, Aza, and prednisolone. Following three acute rejections, Aza was replaced by mycophenolate mofetil. Nevertheless, graft function deteriorated slowly, necessitating return to dialysis 3 years after transplantation. No symptoms of AIP were observed while the patient was on cyclosporine and/or mycophenolate mofetil therapy, and the authors conclude that these drugs can be safely administered to at least some patients with AIP.

Aminolevulinic Acid↗

PubMed2006

Proteasomal degradation regulates expression of porphobilinogen deaminase (PBGD) mutants of acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a neuropathic disease caused by a dominant inherited deficiency in porphobilinogen deaminase (PBGD). We investigated the expression and the degradation of the human PBGD-mutations G748A, G748C and 887insA following transfection into human SH-SY5Y neuroblastoma cells. Mutant proteins exhibited reduced protein expression compared to transfected wild-type (wt) PBGD as revealed by Western blotting. The transcription levels assessed by real-time PCR of these mutant species were identical to those of the wild type. Immuno-fluorescence microscopy revealed reduced cellular distribution of the mutated PBGDs in the cytosol and the nucleus in comparison to the wild-type PBGD. Enhanced cellular accumulation of the mutated and wild-type PBGDs was detected following inhibition of the proteasome by the inhibitors CLBL and hemin. Elevated expression of wt and mutated PBGD protein levels was either achieved by hemin or heme-arginate treatment. On the other hand, enhanced PBGD degradation was achieved by lead poisoning of ALAD in the SH-SY5Y cells concomitant with acceleration of proteasomal activity, most probably by ALAD participation in proteasomal regulation [G.G. Guo, M. Gu, J.D. Etlinger, 240-kDa proteasome inhibitor (CF-2) is identical to delta-aminolevulinic acid dehydratase. J Biol Chem 1994; 269:12399-402.] Our results suggest that the difference in expression between the wild-type and mutant proteins appears to be regulated on the level of protein degradation. In conclusion, we demonstrate that the PBGD cellular pool is controlled by the proteasome activity, which in turn is down regulated by hemin or up-regulated by Pb-ALAD.

Aminolevulinic Acid↗

PubMed1998

Exon 1 donor splice site mutations in the porphobilinogen deaminase gene in the non-erythroid variant form of acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial defect of the heme biosynthesis enzyme, porphobilinogen deaminase (PBGD). PBGD is encoded by two distinct mRNA species expressed in a tissue-specific manner from a single gene. One transcript is expressed in erythroid tissues, while the housekeeping transcript is expressed in all tissues. In classical AIP (95% of cases) the housekeeping and the erythroid-specific enzymes both have half-normal activity in erythroid and non-erythroid tissues, whereas in the variant non-erythroid form of the disease the enzymatic defect is present only in non-erythroid cells. A large allelic heterogeneity of mutations (n>135) has been demonstrated in classical AIP, but to date only three different mutations have been characterized in the non-erythroid variant form of AIP. We describe the molecular abnormalities responsible for the non-erythroid variant form of AIP in two French and two German unrelated AIP patients with normal PBGD activity in the erythrocytes. Three different splicing defects located in the intron 1 donor splice site were identified: a 33+1 g-->a mutation, previously described in a Dutch family, was found in two patients; two novel mutations (33+2 t-->a, 33+5 c-->g) affected the two remaining patients. All the mutations resulted in the activation of a cryptic splice site 67 bp downstream in intron 1, leading to a frameshift and a premature stop codon in exon 4. Mutations in the exon 1 donor splice site are involved in eight of the nine non-erythroid variant AIP families reported in the literature. These data show that most mutations causing the non-erythroid variant AIP are exon 1 splice defects, in contrast with classical AIP, where missense mutations are chiefly involved. Moreover, the allelic heterogeneity of PBGD gene defects causing the non-erythroid variant AIP is demonstrated, with five different mutations identified. These mutations could be easily detected by a single denaturing gradient gel electrophoresis which also allows the presymptomatic detection of gene carriers in the affected families.

Adult↗

PubMed1983

[Acute intermittent porphyria].

Acute intermittent porphyria (AIP) is a congenital disease which as its name suggests, runs intermittently. Biochemically it is characterised by over-production of hepatic ALA synthetase (ALA-s), inducible mitochondrial enzyme and an increase in prophyrinic precursors (PBG, ac S-ALA). Clinically it is characterised by an abdominal nervous symptomatology. The primary metabolic error has been identified as a deficiency in enzyme activity which partially blocks haem biosynthesis. During the appearance of clinical manifestations, certain factors are present which have the capacity of inducing hepatic ALA-s production in vitro. Apart from some preventive measures treatment is mainly of symptomatology and complications. More recently the use of ALA-s inhibitors has been introduced.

Acute Disease↗

PubMed1981

Respiratory insufficiency associated with acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a disease that may present with gastrointestinal, psychiatric, or neurologic symptoms. We describe two patients in whom AIP was first diagnosed during episodes of acute respiratory insufficiency. The biochemical defects, clinical presentations, pathophysiology, diagnostic criteria, and treatment of AIP are reviewed. We emphasize that AIP should be considered in the differential diagnosis of every patient with unexplained respiratory failure. Once considered, AIP is relatively simple to diagnose and specific therapeutic measures can be instituted.

Acute Disease↗

PubMed1979

Danazol administration to females with menses-associated exacerbations of acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a disorder of porphyrin metabolism in which the basic defect is a partial deficiency of uroporphyrinogen I synthase. The clinical disorder is more common in women, and some experience acute attacks before menstrual periods. Oral contraceptives have prevented menstrual-associated attacks in some cases, but exogenous estrogens and progestins are otherwise contraindicated in this disease. Danazol, a new synthetic steroid with weak androgenic activity, was thought to be of potential therapeutic benefit in AIP because of its effect of decreasing gonadotropin secretion without exposure to estrogen or progesterone. The drug was administered at a dosage of 200 mg t.i.d. to two adult females with AIP who were experiencing frequent exacerbations of their disease in association with their menstrual periods. Symptomatic and chemical evidence for exacerbation of porphyria occurred within 10 days of commencing danazol treatment in both patients.

Adult↗

PubMed1994

Varied psychiatric manifestations of acute intermittent porphyria.

Acute Intermittent Porphyria (AIP) is an autosomal dominant metabolic disorder that has various psychiatric manifestations. This is a report of a case who had six brief psychotic episodes of varying nature within a 2-month period. The psychotic manifestations included catatonic stupor, hypomania, and delirium in different episodes. The management aspects of the case have been highlighted.

Acute Disease↗

PubMed1992

High frequency of mutations in exon 10 of the porphobilinogen deaminase gene in patients with a CRIM-positive subtype of acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal dominant disease characterized by a partial deficiency of porphobilinogen (PBG) deaminase. Different subtypes of the disease have been defined, and more than 10 different mutations have been described. We focused our study on exon 10, since we previously found that three different mutations were located in this exon and that two of them seemed to be relatively common. We used denaturing gradient gel electrophoresis (DGGE) after in vitro amplification to detect all possible mutations in exon 10 in 41 unrelated AIP patients. In about one-fourth of these patients we could distinguish three abnormal migration patterns, indicating the presence of various mutations. Additional sequencing demonstrated the presence of three different single-base substitutions. Two of these mutations had already been described. A third one consisted of a C-to-T transition located at position 499 of the PBG deaminase mRNA and resulted in an Arg-to-Trp substitution. All three mutations were found in patients with cross-reacting immunological material (CRIM)-positive forms of AIP. The high frequency of these mutations make DGGE analysis of exon 10 a useful approach allowing the direct direction of the DNA abnormality in most of the families with the CRIM-positive subtype of AIP.

Acute Disease↗