Porphyrias are inherited defects in the biosynthesis of heme. Acute intermittent porphyria, the most common form of porphyria, is an autosomal dominant disorder characterized by recurrent attacks of abdominal pain, gastrointestinal dysfunction, and neurologic disturbances. In the classic ... Porphyrias are inherited defects in the biosynthesis of heme. Acute intermittent porphyria, the most common form of porphyria, is an autosomal dominant disorder characterized by recurrent attacks of abdominal pain, gastrointestinal dysfunction, and neurologic disturbances. In the classic form of AIP, both the ubiquitous 'nonerythroid' housekeeping HMBS isoform and the 'erythroid' HMBS isoform are deficient. However, about 5% of families have the 'nonerythroid variant' of AIP, with a defect only in the ubiquitous nonerythroid HMBS isoform and normal levels of the erythroid HMBS isoform. Clinical characteristics in the 2 forms are identical; diagnostic methods based on the level of enzyme in erythrocytes is ineffective (Puy et al., 1998; Petrides, 1998; Whatley et al., 2000). There are several other forms of porphyria: see porphyria cutanea tarda (176100), variegata porphyria (176200), coproporphyria (121300), acute hepatic porphyria (125270), and congenital erythropoietic porphyria (263700).
Sassa et al. (1975) noted that the enzyme defect in AIP is expressed in cultured fibroblasts and amniotic cells, so that prenatal diagnosis is possible. The enzyme can be induced and the defect demonstrated in mitogen-stimulated lymphocytes (Sassa ... Sassa et al. (1975) noted that the enzyme defect in AIP is expressed in cultured fibroblasts and amniotic cells, so that prenatal diagnosis is possible. The enzyme can be induced and the defect demonstrated in mitogen-stimulated lymphocytes (Sassa et al., 1978). Puy et al. (1997) found that the standard PBGD enzymatic screening method for gene-carrier detection had 95% concordancy with the molecular-based diagnosis.
Acute intermittent porphyria is characterized clinically by acute episodes of a variety of gastrointestinal and neuropathic symptoms; between episodes, the patient is healthy. Abdominal pain is the most common symptom, sometimes with constipation and urinary retention; paraesthesias and ... Acute intermittent porphyria is characterized clinically by acute episodes of a variety of gastrointestinal and neuropathic symptoms; between episodes, the patient is healthy. Abdominal pain is the most common symptom, sometimes with constipation and urinary retention; paraesthesias and paralysis also occur, and death may result from respiratory paralysis (Goldberg, 1959; Stein and Tschudy, 1970; Becker and Kramer, 1977). Many other phenomena, including seizures, psychotic episodes, and hypertension, may occur in acute attacks. Acute attacks rarely occur before puberty; they may be precipitated by porphyrinogenic drugs such as barbiturates and sulfonamides (for list, see Tschudy et al., 1975), some of which are known to induce the earlier rate-controlling step in heme synthesis, delta-aminolevulinic acid (ALA) synthesis. Other known precipitants are alcohol, infection, starvation, and hormonal changes; attacks are more common in women. Only about 10 to 20% of AIP gene carriers become symptomatic during their lifetime (Petrides, 1998). From a survey of AIP cases in the west of Scotland, Yeung Laiwah et al. (1983) observed an association with early-onset chronic renal failure. Porphyria-induced hypertension was considered the most likely causal factor, but enhanced susceptibility to analgesic nephropathy and nephrotoxic effects of porphyrins and their precursors were mentioned as possibilities. Beukeveld et al. (1990) reported a rare case of a child with presumed homozygous AIP who demonstrated porencephaly and severe developmental retardation. The child consistently excreted excessive amounts of delta-aminolevulinic acid, porphobilinogen, and uroporphyrin in her urine from early childhood. She died at age 8 years. Her mother suffered from AIP. Although the father never had attacks, blood and urine studies showed that he too was affected. Using allele-specific oligonucleotides, Picat et al. (1990) demonstrated that the proband reported by Beukeveld et al. (1990) was compound heterozygous for 2 mutations in the HMBS gene (609806.0005; 609806.0006). Each parent was heterozygous for 1 of the mutations. Hessels et al. (2004) described a 7-year-old boy with homozygous AIP who demonstrated hepatosplenomegaly, mild anemia, mild mental retardation, yellow-brown teeth, and dark red urine and who had excessively elevated levels of urinary delta-aminolevulinic acid, porphobilinogen, and uroporphyrin. Further hepta-, hexa-, penta- and copro(I)porphyrins were highly increased in urine. This pattern of porphyrin precursor and metabolite excretion is characteristic of acute intermittent porphyria. The porphobilinogen deaminase activity in red cells was decreased to 2 to 4%. The parents were unaffected. - Chester Type Porphyria McColl et al. (1985) identified a form of acute porphyria in a large family in Chester, U.K. Patients presented with attacks of neurovisceral dysfunction; none had cutaneous photosensitivity. Biochemically, the pattern of excretion of heme precursors varied between individuals. Some had a pattern of acute intermittent porphyria, others showed that of variegate porphyria, and some showed an intermediate pattern. A dual enzyme deficiency was found in peripheral blood cells; reduced activity was found in both PBGD, as in AIP, and protoporphyrinogen oxidase (PPOX; 600923), as in variegate porphyria. McColl et al. (1985) initially thought that this was a new form of porphyria. In the family with Chester type porphyria, Norton et al. (1991, 1993) identified a multipoint maximum lod score of 7.33 at a distance less than 1 cM proximal to D11S351. In affected members of the original family reported by McColl et al. (1985), Poblete-Gutierrez et al. (2006) identified a heterozygous truncating mutation in the HMBS gene (609806.0046). No mutations were found in the PPOX gene. These findings confirmed that Chester type porphyria is a variant of AIP. Poblete-Gutierrez et al. (2006) suggested that the original biochemical studies indicating PPOX deficiency may have been erroneous or misinterpreted.
In a large Dutch family with the nonerythroid variant of AIP, Grandchamp et al. (1989) identified a heterozygous splice site mutation in intron 1 of the PBGD gene (609806.0001). The mutation interrupted the sequence coding for the nonerythroid ... In a large Dutch family with the nonerythroid variant of AIP, Grandchamp et al. (1989) identified a heterozygous splice site mutation in intron 1 of the PBGD gene (609806.0001). The mutation interrupted the sequence coding for the nonerythroid isoform of PBGD; thus, expression of the erythroid isoform was unaffected. In a patient with CRM-positive AIP, Grandchamp et al. (1989) identified a mutation in the HMBS gene, resulting in the skipping of exon 12 (609806.0002). In affected members of 11 different families with either CRM-negative or CRM-positive AIP, Grandchamp et al. (1990) identified 7 different point mutations in the PBGD gene. Astrin and Desnick (1994) reviewed the 26 mutations in the HMBS identified to that time. Puy et al. (1997) performed molecular analysis of the PBGD gene by denaturing gradient gel electrophoresis followed by direct sequencing in 405 subjects from 121 unrelated French-Caucasian AIP families. PBGD mutations were identified in 109 families, but only 78 were of different type, and each of these had a prevalence rate of less than 5%. Among these mutations, 33 had not previously been published. Sixty percent of the 78 mutations were located in 3 exons (exons 10, 12, and 14); 44% were missense, 18% were splice defect, 19% were frameshift, and 16% were nonsense. Whatley et al. (1999) reported a prospective comparison of direct automated sequencing of cDNA (in 29 patients) or genomic DNA (in 28 patients) to identify HMBS mutations in 57 patients referred consecutively for mutation analysis; 39 different mutations were identified in 54 patients. The sensitivity of the cDNA and genomic DNA methods was 69% and 95%, respectively, indicating that analysis of genomic DNA provides a higher mutation detection rate. The mutations included 6 missense, 8 splice defects, 10 frameshifts, and 1 nonsense; 25 had not previously been reported. The results defined the extent of allelic heterogeneity and the types (41% missense, 59% truncating) and distribution (35% in exons 10, 12, and 14) of HMBS mutations for AIP in the United Kingdom.
High prevalence of AIP is known in northern Sweden where Waldenstrom's classic observations were made (Waldenstrom, 1956).
AIP occurs with very low prevalence, perhaps 1 in 50,000, probably in all ethnic groups (Tschudy et al., 1975), ... High prevalence of AIP is known in northern Sweden where Waldenstrom's classic observations were made (Waldenstrom, 1956). AIP occurs with very low prevalence, perhaps 1 in 50,000, probably in all ethnic groups (Tschudy et al., 1975), including blacks (Kreimer-Birnbaum et al., 1980), but figures for prevalence based on manifest AIP, i.e., acute attacks, greatly underestimate the number of persons with latent AIP. Lee et al. (1991) stated that the prevalence of AIP in Lappland, northern Sweden was 1 in 1,500. They identified 3 different disease haplotypes among 28 Swedish AIP families. The haplotype designated 2/1/1/2 was the most frequent, segregating with AIP in 10 of 28 families. Lee and Anvret (1991) identified a mutation in the HMBS gene (W198X; 609806.0012) in 15 of 33 AIP families from Lappland, Sweden. Genealogic data showed that 12 of the 15 were related, suggesting a founder effect. In 28 Finnish families representing 72% of all AIP families in the Finnish population of 5 million, Kauppinen et al. (1995) found 19 separate mutations in HMBS: 13 novel mutations, including 1 de novo event, and 6 previously characterized mutations. Floderus et al. (2002) stated that the prevalence of AIP in Sweden is about 1 in 10,000. Among Swedish AIP kindreds, they identified 27 novel HMBS mutations, bringing the total number of known mutations in Sweden to 39.
Individuals with acute intermittent porphyria (AIP) can be divided into two categories:...
DiagnosisClinical DiagnosisIndividuals with acute intermittent porphyria (AIP) can be divided into two categories:Clinically manifest (or overt) AIP. Individuals who are currently symptomatic or who are in remission following an acute attack. Persons in remission often continue to excrete excess PBG in their urine long after symptoms have resolved. Latent (or presymptomatic) AIP. Individuals often detected by cascade screening (i.e., screening of at-risk family members) who have never had symptoms of AIP. Up to 50% of adults with latent AIP have increased urinary PBG excretion. The risk that an individual with latent AIP will later develop symptoms depends on age, sex, exposure to provoking agents, and other factors; however, the majority will remain asymptomatic throughout their lives. An acute attack of AIP should be suspected in individuals with:Otherwise unexplained severe, acute abdominal pain without physical signs (see Note). The pain, which occasionally may be more severe in the back or thighs, usually requires opiate analgesia. Nausea, vomiting, constipation, tachycardia, and hypertension are common. Muscle weakness, convulsions, mental changes, and hyponatremia are all features that may be present alone or in combination and that heighten the probability of acute porphyria [Hift & Meissner 2005, Puy et al 2010]. The urine may be reddish-brown or red; however, this is not a constant finding especially if the sample is fresh. The color is enhanced by exposure to air and light and reflects increased urinary concentrations of porphyrins and porphobilins formed from the porphyrin precursor porphobilinogen (PBG). Note: Abdominal pain is present in almost all acute attacks; atypical presentations are rare [Hift & Meissner 2005, Puy et al 2010]. Clinically indistinguishable acute attacks occur in other acute porphyrias. See Differential Diagnosis.A family history consistent with autosomal dominant inheritance of an acute porphyria; however, is often absent given the low penetrance of clinical manifestations of AIP (see Penetrance). TestingClinically manifest AIP. Evidence of an increased concentration of PBG in urine, using a specific quantitative assay, is essential to establish an unequivocal diagnosis of acute porphyria in a symptomatic individual.Confirmation that the increased urinary PBG is caused by AIP (Table 1) requires evidence that:Total fecal porphyrin concentration or coproporphyrin isomer ratio is normal; Plasma porphyrin fluorescence emission scan either shows a peak around 619 nm or is normal. Table 1. Biochemical Characteristics of Clinically Manifest AIPView in own windowEnzyme DefectEnzyme ActivityErythrocytesUrineStoolPlasmaHydroxymethylbilane synthase (HMBS) (EC 2.5.1.61)HMBS ~50% of normal 1, 2Erythrocyte porphyrins: normal PBG 3 and ALA 4: increased Porphyrins: increased 5Total porphyrin: normal or small increase 6 Coproporphyrin isomer III/I ratio: normal 7Plasma porphyrins: increased fluorescence emission peak ~619 nm 81. Activity is decreased in all tissues, except in the 3% of individuals with the non-erythroid variant of AIP in which erythrocyte HMBS activity is normal.2. Measurement of erythrocyte HMBS activity is not required for the diagnosis of an acute attack of AIP. Mean erythrocyte HMBS activity is 50% of normal but overlap between AIP and reference ranges diminishes its sensitivity and specificity as a diagnostic test for AIP, even when persons with the non-erythroid variant are excluded [Kauppinen & Fraunberg 2002].3. PBG (porphobilinogen) is increased more than ALA (5-aminolevulinic acid). A normal PBG concentration in a symptomatic individual excludes the diagnosis of AIP. PBG concentrations decrease during remission but may remain increased for months or years.4. ALA is often measured with PBG by specialist laboratories but does not appear to provide any significant additional diagnostic information in uncomplicated AIP (see Differential Diagnosis).5. Increase mainly indicates in vitro condensation of PBG to uroporphyrins. Total urinary porphyrin, but not PBG, concentration may be increased in various disorders, including alcohol abuse and liver disease [Badminton et al 2012].6. The increase may be large if an analytic method that includes ether-insoluble porphyrins, e.g., uroporphyrin, is used [Rossi 1999].7. Excludes hereditary coproporphyria (see Differential Diagnosis).8. Plasma porphyrin concentration is usually increased during an acute attack. Plasma porphyrin fluorescence emission scanning excludes variegate porphyria if the peak is at less than 622 nm (see Differential Diagnosis).Determination of PBG in urine. Testing is best performed on a random urine sample, protected from light prior to analysis. Note: (1) 24-hour urine collection needlessly delays analysis and can lead to degradation of PBG; (2) very dilute urine may produce false negative results. Specific quantitative tests. In the most widely used methods, PBG (and ALA) are separated from other chromogens in urine by ion-exchange column chromatography and PBG is measured by spectrophotometry after reaction with modified Ehrlich’s reagent [Badminton et al 2012]. Note: Urinary (and plasma) concentrations of PBG and ALA can also be quantified by high-performance liquid chromatography - mass spectrometry [Floderus et al 2006, Zhang et al 2011]. Results should be corrected for urine concentration by expression as the ratio of PBG to creatinine. Qualitative/semi-quantitative screening tests for PBG. The Watson-Schwartz test or the Hoescht test is easy to perform; however, both have problems with sensitivity and specificity. They are positive about 50% of the time when urinary concentrations of PBG are five times the upper limit of normal and are consistently positive when urinary concentrations of PBG are more than ten to 20 times normal, as would be typically found in an acute attack of AIP. A rapid, semi-quantitative assay for PBG is available in some countries (Trace PBG kit, Thermo Trace/DMA, Arlington, Texas). The sensitivity compared to the Watson-Schwartz test was 95% vs 38% and specificity was 99% vs 82% [Deacon & Peters 1998]. Note: (1) All positive qualitative and semi-quantitative tests must be confirmed by a specific quantitative measurement to avoid false-positives. (2) If clinical suspicion of acute porphyria persists, negative tests should also be confirmed in the same way in order to detect false negatives and PBG concentrations below the sensitivity of screening tests.Interpretation. A normal urinary PBG concentration in an individual with symptoms consistent with AIP excludes the diagnosis. The concentration of PBG in urine is invariably increased in individuals with symptoms of AIP. During an acute attack, PBG concentration is often more than 10-20 times the upper reference limit [Kauppinen & Fraunberg 2002, Anderson et al 2005, Elder et al 2012]. Adults with latent AIP and persons in remission following an acute attack may excrete increased amounts of PBG. Thus, increased urinary PBG excretion does not necessarily confirm that symptoms are the result of porphyria. Note that a minimum two-fold increase in urinary PBG concentration above the baseline for that individual is consistent with symptoms due to AIP [Aarsand et al 2006]; however, in practice, baseline information is rarely available.Latent (presymptomatic) AIP. See Related Genetic Counseling Issues, Testing of at-risk asymptomatic family members.Molecular Genetic TestingGene. HMBS is the only gene in which mutation is known to cause AIP. Clinical testing Table 2. Summary of Molecular Genetic Testing Used in Acute Intermittent PorphyriaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency 1Test AvailabilityHMBSSequence analysis Sequence variants 298% 4Clinical Deletion / duplication analysis 3Exonic or whole-gene deletions / duplications1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.4. Detection frequency for sequence analysis supplemented by deletion/duplication analysis is 98.1% (95% confidence interval: 95.6%-99.2%) [Whatley et al 2009].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm the diagnosis in a proband. The diagnosis of AIP in a symptomatic individual is based on increased PBG in a random urine sample (protected from light prior to analysis), together with evidence of a normal total fecal porphyrin or normal coproporphyrin isomer ratio, and plasma porphyrin fluorescence emission scan that is either normal or shows a peak emission around 619 nm. Molecular genetic testing is not required to confirm the diagnosis in a symptomatic individual but may help to confirm or refute a previous diagnosis of overt AIP in an individual who is in full clinical and biochemical remission [Whatley et al 2009]. In addition, molecular genetic testing of an index patient may be indicated if clinical features and/or biochemical findings suggest the presence of homozygous HMBS mutations or dual porphyria (heterozygous mutations in two separate porphyria-related genes) or are otherwise atypical.The main use of molecular genetic testing of an individual with biochemically proven AIP is to identify a mutation for the molecular investigation of the individual’s family (i.e., cascade screening).When used, molecular genetic testing usually begins with sequence analysis of HMBS followed by deletion/duplication analysis if a mutation is not identified.Molecular genetic testing is not useful for assessing prognosis. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo phenotypes other than those discussed in this GeneReview are known to be associated with mutations in HMBS.
Symptoms are present in only a minority of those with a genetic change that predisposes to acute intermittent porphyria (AIP). Symptoms are more common in women than men and very rare before puberty. Onset typically occurs in the third or fourth decade [Anderson et al 2001, Elder et al 2012]. ...
Natural HistorySymptoms are present in only a minority of those with a genetic change that predisposes to acute intermittent porphyria (AIP). Symptoms are more common in women than men and very rare before puberty. Onset typically occurs in the third or fourth decade [Anderson et al 2001, Elder et al 2012]. Acute Intermittent Porphyria (AIP)In AIP, the visceral, peripheral, autonomic, and/or central nervous systems may be affected, leading to a range of findings that are usually intermittent and sometimes life threatening. The course of acute attacks is highly variable within and between individuals. Affected individuals may recover from acute AIP attacks within days, but recovery from severe attacks that are not promptly recognized and treated may take weeks or months. Clinical expression of AIP is typically caused by exposure to certain endogenous or exogenous factors in most individuals, but it is not uncommon for individuals to have acute attacks in which no precipitating factor can be identified.Acute attack. Severe abdominal pain, which may be generalized or localized and not accompanied by muscle guarding, is the most common symptom and is often the initial sign of an acute attack. Back, buttock, or limb pain may be a feature. Gastrointestinal features including nausea, vomiting, constipation or diarrhea, abdominal distention, and ileus are also common. Tachycardia and hypertension are frequent, while fever, sweating, restlessness, and tremor are seen less frequently. Urinary retention, incontinence, and dysuria may be present.Peripheral neuropathy is predominantly motor and is less common now than in the past. Muscle weakness often begins proximally in the legs but may involve the arms or legs distally and can progress to include respiratory muscles resulting in complete paralysis with respiratory failure. Bilateral axonal motor neuropathy may also involve the distal radial nerves [King et al 2002]. Motor neuropathy may also affect the cranial nerves or lead to bulbar paralysis. Patchy sensory neuropathy may also occur [Wikberg et al 2000]. Mental changes are present in up to 30% of symptomatic individuals but are only very rarely the dominant feature of the disease [Hift & Meissner 2005, Puy et al 2010]. Changes include insomnia, anxiety, depression, hallucinations, confusion, paranoia, amnesia, and/or altered consciousness ranging from somnolence to coma. These symptoms resolve after the attack, though anxiety may persist. Seizures may occur in acute attacks, especially in individuals with hyponatremia which may be worsened by vomiting and/or inappropriate fluid therapy. The cause of hyponatremia is not clear; both SIADH (syndrome of inappropriate antidiuretic hormone release) and renal salt wasting have been proposed as mechanisms. Seizures may also occur as a manifestation of central nervous system involvement of the acute attack. MRI findings. MRI changes were observed in two out of seven individuals with signs of CNS involvement. The main finding is posterior reversible encephalopathy syndrome [Celik et al 2002, Bylesjö et al 2004, Pischik & Kauppinen 2009]. Some MRI findings may result from rapid correction of hyponatremia rather than AIP [Susa et al 1999]. Cutaneous manifestations of porphyria do not occur in AIP. Precipitating factors. Attacks of acute porphyria may be precipitated by endogenous or exogenous factors [Anderson et al 2001]. These include: Prescribed and illicit drugs which are detoxified in the liver by cytochrome P450 and/or result in induction of ALA synthase and heme biosynthesis. Prescription drugs that can precipitate an attack include, for example, barbiturates, sulfa-containing antibiotics, some antiepileptic drugs, progestagens, and synthetic estrogens (see Agents/Circumstances to Avoid).Endocrine factors. Reproductive hormones play an important role in the clinical expression of AIP. In women, acute neurovisceral attacks related to the menstrual cycle, usually the luteal phase, are common [Andersson et al 2003, Hift & Meissner 2005]. However, the majority of women with AIP fare well during pregnancy, despite massive increases in the serum concentration of various steroid hormones [Andersson et al 2003, Marsden & Rees 2010]. Fasting. A recognized precipitating factor is inadequate caloric intake [Anderson et al 2005] in connection with, for example, dieting or heavy exercise schedules.Stress. Psychosocial and other stresses, including intercurrent illnesses, infections, alcoholic excess, and surgery, can precipitate an attack.Chronic complicationsHepatocellular carcinoma (HCC). Individuals with AIP, whether clinically manifest or latent, appear to be at increased risk of developing primary HCC [Linet et al 1999, Innala & Andersson 2011], usually after age 54 years. The highest risk has been reported from Sweden; at present, it is unclear why the risk appears to be lower in other populations [Deybach & Puy 2011]. Renal involvement. Some individuals, especially those with long-standing repeated attacks, have renal insufficiency without another apparent cause. Although many have hypertension, others are normotensive despite renal insufficiency [Andersson et al 2000b]. Renal histopathology typically shows diffuse glomerulosclerosis, interstitial changes, and ischemic lesions. Protracted vasospasm in attacks of AIP is a possible cause [Andersson et al 2000b].Recurrent acute attacks. Approximately 3%-5% of individuals with AIP, mainly women, experience repeat attacks (usually defined as >4/year) for a prolonged period, often many years [Elder et al 2012]. Mortality. Mortality directly related to acute attacks is now very rare in most countries as a result of improved treatment (use of human hemin) and identification and counseling of presymptomatic relatives. Deaths may occur as a complication of HCC or liver transplantation. Homozygous HMBS DeficiencyTo date, five children with homozygous HMBS disease-causing mutations have been described. All had less than 3% of the HMBS enzyme activity found in controls. Four had mutations in exon 10. Symptoms started early in childhood and included severe ataxia, dysarthria, severe psychomotor delay, and central and peripheral neurologic manifestations. MRI studies in one showed white matter abnormalities that suggested selective postnatal involvement of cerebral oligodendrocytes [Solis et al 2004]. One was homozygous for a mutation in exon 6 and was less severely affected than the four described above [Hessels et al 2004].
Genotype-phenotype correlations are not evident in AIP, apart from some evidence that mutations that retain about 10% of normal activity may be less penetrant than those that retain less than 10% of normal activity [Andersson et al 2000a, Fraunberg et al 2005]. ...
Genotype-Phenotype CorrelationsGenotype-phenotype correlations are not evident in AIP, apart from some evidence that mutations that retain about 10% of normal activity may be less penetrant than those that retain less than 10% of normal activity [Andersson et al 2000a, Fraunberg et al 2005].
Clinically indistinguishable acute neurovisceral attacks occur in acute intermittent porphyria (AIP) and the three other acute porphyrias: hereditary coproporphyria (HCP), variegate porphyria (VP), and ALAD deficiency porphyria (ADP), and may complicate hereditary tyrosinemia type 1 (Table 3) [Puy et al 2010]. ...
Differential DiagnosisClinically indistinguishable acute neurovisceral attacks occur in acute intermittent porphyria (AIP) and the three other acute porphyrias: hereditary coproporphyria (HCP), variegate porphyria (VP), and ALAD deficiency porphyria (ADP), and may complicate hereditary tyrosinemia type 1 (Table 3) [Puy et al 2010]. Lead poisoning may also mimic the symptoms and disturb heme biosynthesis; however, anemia, a feature of lead poisoning, is not a feature of AIP.Table 3. Disorders to Consider in the Differential Diagnosis of Clinically Manifest AIPView in own windowDisorderClinical featuresUrineStoolPlasmaErythrocytesHereditary coproporphyria (HCP)Acute attack ± skin lesions 1Increased PBG, ALA 2, porphyrins 3Increased coproporphyrin IIIIncreased plasma porphyrins; fluorescence emission peak ~620 nm 4Variegate porphyria (VP)Acute attack ± skin lesions 1Increased PBG, ALA 2, porphyrins 3Increased protoporphyrin 5Increased plasma porphyrins; fluorescence emission peak ~626 nm 6ALAD deficiency porphyriaAcute attackIncreased ALA, coproporphyrin III, normal PBGIncreased zinc-protoporphyrin; decreased ALAD activity Hereditary tyrosinemia type 1Acute attackIncreased ALADecreased ALAD activity Lead poisoningAbdominal pain, anemiaIncreased ALA; normal coproporphyrin III, PBG Increased zinc-protoporphyrin; decreased ALAD activity Diagnostic abnormalities are shown. See Table 1 for biochemical characteristics of clinically manifest AIP.ALA = 5-aminolevulinic acidALAD = 5-aminolevulinate dehydratase1. Acute neurovisceral attacks are accompanied by porphyric skin lesions (bullae, fragile skin) in about 15% of persons with HCP and about 60% of persons with VP.2. PBG increased more than ALA; both may decrease rapidly as symptoms resolve.3. Uroporphyrin from in vitro polymerization of PBG and coproporphyrin; measurement is not required for diagnosis and may mislead.4. Plasma porphyrin concentration may occasionally be normal; fluorescence emission spectroscopy does not distinguish between HCP and AIP.5. Protoporphyrin is the main stool porphyrin, but a small increase in coproporphyrin III is also observed 6. Plasma porphyrin concentration is always increased and fluorescence emission spectroscopy distinguishes VP from all other porphyrias.Hematuria, ingestion of beetroot, some drugs and food additives, and porphyrin excretion in other porphyrias (e.g., porphyria cutanea tarda, congenital erythropoietic porphyria) may produce similar red discoloration of the urine. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with acute intermittent porphyria (AIP) the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with acute intermittent porphyria (AIP) the following evaluations are recommended:Full clinical history and examination, including neurologic evaluation if symptomaticReview of medications to assess risk versus benefit (see Agents/Circumstances to Avoid) Quantitation of urine porphobilinogen excretion to establish a baseline for comparison with future measurements taken during symptoms suggestive of active porphyriaReferral to a porphyria specialist for more detailed clinical advice on AIPReferral to medical genetics for counselingTreatment of ManifestationsAcute Neurovisceral Attack Immediate treatment of an acute neurovisceral attack does not require confirmation of the specific type of acute porphyria. Clinical assessment should include a full neurologic evaluation. In persons known to have AIP consider other causes of abdominal pain in addition to porphyria. Investigations should include: Full blood count (FBC);Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes;Serum and urine osmolality;Urine sodium concentration if hyponatremic;Other blood tests as indicated by the patient’s condition and possible cause of the attack, e.g., CRP, blood cultures, CK, magnesium. MRI should be considered if CNS symptoms are present.General measuresReview all medications and discontinue any that can exacerbate acute porphyria [Elder & Hift 2001]. See Agents/Circumstances to Avoid. Restore energy balance using an enteral route if possible. When required, intravenous fluid should contain a minimum of 5% dextrose; however, hypotonic dextrose-water solutions should be avoided because of the risk of hyponatremia. Treat intercurrent infections and other diseases promptly. Supportive treatmentPain relief. Effective analgesia should be provided as soon as possible, usually in the form of parenteral opiates (morphine, diamorphine, and fentanyl are safe). Very large quantities may be required in a severe acute attack. Consider patient-controlled analgesia and support from a pain team.Nausea and vomiting. Prochloperazine, promazine or ondansetron are considered safe.Hypertension. Beta blockers are considered safe.Convulsions can be terminated with intravenous diazepam, clonazepam, or magnesium sulphate.Fluid balance and electrolytes. Dextrose saline is preferred. Severe hyponatremia should be treated with intravenous saline rather than fluid restriction [Hift & Meissner 2005].Specific treatmentFor mild acute neurovisceral attacks, a high carbohydrate intake, preferably oral and together with other supportive measures (see Acute Neurovisceral Attack), may be used for up to 48 hours. If improvement is unsatisfactory or if additional and progressive neurologic features present, intravenous administration of hemin preparations is recommended.Intravenous human hemin is the most effective treatment for acute neurovisceral attacks. Intravenous administration of hemin preparations may be life-saving when employed early when neuronal damage is still reversible, and may help to avoid paresis or prevent its progression.The recommended dose for hemin is 3-4 mg/kg IV, given once daily for four days. Treatment may be extended, depending on the clinical course.Panhematin™ (Ovation Pharmaceuticals, Deerfield, IL) is approved for treatment of acute attacks in the US. This product is supplied as a dried powder, which must be reconstituted with sterile water immediately before intravenous injection and administered over 10-15 minutes. Because the administration of Panhematin™ reconstituted with sterile water is associated with transient, mild coagulopathy, concurrent anticoagulant therapy should be avoided.Heme arginate (Normosang Orphan Europe, Paris) is an arginine-stabilized form of human hemin available in most other countries, including Europe, Africa, the Middle East, and South America. It is infused over at least 30 minutes. It has the same advantage as hemin in treating an acute neurovisceral attack, but has fewer reported side-effects [Hift & Meissner 2005, Puy et al 2010].Note: (1) Phlebitis after intravenous injection can be minimized by reconstituting hematin in 20% human serum albumin solution and/or by using a large vein or a central catheter for infusion. Peripheral cannulas used to administer hematin should be replaced after each use. (2) An infusion set with an in-line filter is recommended to remove any undissolved particulate matter. (3) Rigorous flushing of venous catheters with boluses of saline totaling 100 mL is recommended. Recurrent Acute AttacksRecurrent acute attacks are best managed with support and advice from a porphyria specialist. See information and contact details of specialist porphyria centers at www.porphyria-europe.org. Medical therapy aims to reduce the frequency and or severity of acute attacks by the following measures:Ovulation suppression with gonadorelin analogues for patients with recurrent menstrual cycle-related acute neurovisceral attacks [Innala et al 2010]. Long acting analogues can be used to prevent ovulation and should be administered during the first few days of the menstrual cycle to minimize the early stimulation effect on hormone release which can trigger an attack. Side effects can be minimized by administering estrogen, preferably by patch. Gynecological review and bone density monitoring are recommended. Prophylactic hemin infusion. The minimum effective infusion frequency should be employed, usually a weekly dose of hemin infused via an in-dwelling venous catheter. Problems include those associated with a venous access device (infection, blockage) and iron overload (see Prevention of Primary Manifestations, Prevention of Secondary Complications). Other TreatmentsLiver transplantation is curative and reported from several centers [Soonawalla et al 2004, Wahlin et al 2010, Dowman et al 2012]. Indications include repeated life-threatening acute attacks, failure of medical therapy, and poor quality of life [Seth et al 2007]. Combined liver and kidney transplantation, which has been successful, can be considered in those with AIP with repeated severe attacks and renal failure [Wahlin et al 2010]. Kidney transplantation has been performed for renal failure in persons with overt and latent AIP [Nunez et al 1987, Warholm & Wilczek 2003]. Cimetidine has been suggested as an alternative treatment [Rogers 1997]; however, evidence for clinical efficacy remains elusive. No recent formal study has been performed, but informal feedback from experienced clinicians at international porphyria meetings indicates that few patients have benefited from this treatment. OtherPatients should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert® or similar). Patients should be advised about support available from national patient associations where available. Good-quality information is now widely available from patient or professional organizations either in paper form or from the Internet; see Resources.Advice on safe treatment of persons with porphyria in some specific clinical situations (e.g., epilepsy, HIV, malaria, tuberculosis, hyperlipidemia, and hypertension) is available on the European Porphyria Network Web site and/or Porphyria South Africa Web site. Prevention of Primary Manifestations To prevent acute attacks patients are advised on the potential triggers as follows:Assure that adequate nutrition is provided by a normal balanced diet. Avoid unsupervised calorie restriction diets, particularly those that exclude carbohydrate completely. Avoid drugs and chemicals known to exacerbate porphyria, particularly prescribed medication and over the counter medication. See Agents/Circumstances to Avoid. Seek timely treatment of systemic illness or infection.Avoid excessive alcohol consumption and smoking. Prevention of Secondary ComplicationsEnd-stage renal disease, which is thought to result from chronic systemic arterial hypertension, may be delayed through effective blood pressure control [Andersson et al 2000b]. Because 100 mg of hemin contains 8 mg of iron, frequent administration of hemin may increase the risk for iron overload. Periodic monitoring of serum ferritin concentration and/or transferrin saturation is therefore appropriate in individuals treated repeatedly with hemin.Surveillance In view of the high risk for HCC in individuals with AIP in Sweden, annual hepatic imaging is offered after age 50 years. It has been shown to improve survival [Innala & Andersson 2011]. A few other countries have also initiated screening. It is not yet clear whether similar testing should be offered more widely, since the risk appears to be low in some countries [Deybach & Puy 2011, Stewart 2012]. Note: Serum α-fetoprotein measurement is not helpful.Agents/Circumstances to AvoidExcessive alcohol consumption and smoking should be avoided.Knowledge about the safety of many drugs and other over-the-counter preparations in acute porphyrias is incomplete; however, evidence-based guidelines for assessment of drug porphyrogenicity have been published [Thunell et al 2007, Hift et al 2011]. Searchable drug safety databases are available at the following Web sites: The Drug Database for Acute Porphyria The American Porphyria Foundation Porphyria South AfricaSafe drug lists are available at the following Web sites:European Porphyria Network Welsh Medicines Information Centre - Porphyria Information Service Unsafe drug lists are available at the following Web sites: European Porphyria NetworkBritish National Formulary Evaluation of Relatives at Risk If the HMBS mutation is known in a family, at-risk relatives can benefit from molecular genetic testing to clarify their genetic status, so that those at increased risk of developing acute attacks of AIP can be identified early and counseled about preventive measures. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management The majority of women with AIP have completely normal pregnancies with no clinical problems relating to the porphyria [Marsden & Rees 2010]. However, there is a small chance that pregnancy could initiate or worsen porphyria symptoms.When a woman with AIP experiences abdominal pain, hypertension, and tachycardia during pregnancy, complications of pregnancy should be excluded before the findings are attributed to an acute attack.Symptomatic treatment of an acute attack that occurs during pregnancy should take into account drug safety with respect to teratogenicity and precipitating/exacerbating an acute attack of porphyria.Intravenous human hemin (both available preparations) has been used for the treatment of acute attacks in pregnancy and appears to be safe [Anderson et al 2005, Marsden & Rees 2010]. Several women in the UK and France have received regular heme arginate infusions during pregnancy without any obvious adverse effects on mother or child [Badminton & Deybach 2006].Prolonged fasting should be avoided during labor and delivery as should the use of unsafe drugs, for example, ergometrine. Note: In an obstetric emergency, no drug should be restricted if it is likely to be of major clinical benefit or is required in a life-threatening situation. Stress should be minimized by providing good analgesia. Regional anesthesia, in the form of spinal or epidural anesthesia using bupivacaine, has been safely used. Therapies Under InvestigationA clinical trial of adeno-associated virus (AAV)-based gene therapy for AIP is underway in Europe (see www.aipgene.org for details).Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Acute Intermittent Porphyria: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDHMBS11q23.3Porphobilinogen deaminaseHMBS homepage - Mendelian genesHMBSData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Acute Intermittent Porphyria (View All in OMIM) View in own window 176000PORPHYRIA, ACUTE INTERMITTENT 609806HYDROXYMETHYLBILANE SYNTHASE; HMBSAcute intermittent porphyria (AIP) is caused by a defect in HMBS [Grandchamp 1998]. Normal allelic variants. The gene consists of 15 exons distributed over 10 kb that encode a ubiquitous HMBS isoform (exons 1 and 3-15) that is expressed in all tissues [Puy et al 1998] and an erythroid isoform (exons 2-15) that is restricted to erythroid cells [Grandchamp et al 1989]. However, exon 2 encodes only RNA for the 5’ untranslated region of the erythroid specific isoform. The erythroid-specific and housekeeping mRNAs are produced by alternative splicing under the control of two promoters (reference sequence of longest transcript variant NM_000190.3). The upstream promoter is active in all tissues, while the other promoter, located 3 kb downstream, is active only in erythroid cells. The erythroid promoter displays some structural characteristics of other erythroid-specific promoters, including a CACCC motif, two GATA-1 sites, and one NF-E2 binding site. This finding suggests that common trans-acting factors may co-regulate the transcription of the HMBS enzyme activity of these genes. Pathologic allelic variants. More than 386 mutations have been identified in HMBS (see Table A, HGMD). Most HMBS mutations are missense/nonsense or small deletions/insertions in the protein-coding regions. Variants in splice consensus regions flanking each exon are common. Larger deletions/duplications/insertions and even whole-gene deletions have been reported.Normal gene product. HMBS (porphobilinogen deaminase) is the third enzyme in the heme biosynthetic pathway. It functions as a monomer localized within the cytoplasm where it catalyzes the synthesis of the linear tetrapyrrole hydroxymethlbilane from four molecules of porphobilinogen [Anderson et al 2001]. Abnormal gene product. A large proportion of mutations (~85%) are associated with a 50% reduction in enzyme protein in all tissues (previously referred to as CRIM-negative mutations) as a consequence of mutations that render the protein unstable or absent. The remainder, mainly due to missense mutations (previously known as CRIM positive), result in effects on protein stability and folding, cofactor assembly and the catalytic process. Modeling studies based on the crystallographic structure have provided important insight into these mechanisms [Gill et al 2009].