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Acute intermittent porphyria(AIP)

MedGen UID:
56452
Concept ID:
C0162565
Disease or Syndrome
Synonyms: Acute Porphyria; AIP; HMBS deficiency; Hydroxymethylbilane Synthase Deficiency; Porphobilinogen deaminase deficiency; Porphyria, Swedish type; UPS deficiency; Uroporphyrinogen synthase deficiency
SNOMED CT: Acute intermittent porphyria (234422006); AIP - Acute intermittent porphyria (234422006); Pyrroloporphyria (234422006); Acute porphyria (234422006); Intermittent acute porphyria (234422006); Swedish porphyria (234422006); Intermittent acute porphyria syndrome (234422006)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): HMBS (11q23.3)
 
Monarch Initiative: MONDO:0008294
OMIM®: 176000
Orphanet: ORPHA79276

Disease characteristics

Excerpted from the GeneReview: Acute Intermittent Porphyria
An acute porphyria attack is characterized by a urine porphobilinogen (PBG)-to-creatinine ratio ≥10 times the upper limit of normal (ULN) and the presence of ≥2 porphyria manifestations (involving the visceral, peripheral, autonomic, and/or central nervous systems) persisting for >24 hours in the absence of other likely explanations. Onset of acute attacks typically occurs in the second or third decade of life. Acute attacks are more common in women than men. Although attacks in most individuals are typically caused by exposure to certain endogenous or exogenous factors, often no precipitating factor can be identified. The course of acute porphyria attacks is highly variable in an individual and between individuals. Recovery from acute porphyria attacks may occur within days; however, recovery from severe attacks that are not promptly recognized and treated may take weeks or months. The five categories of acute intermittent porphyria (AIP), caused by a heterozygous HMBS pathogenic variant, are based on the urine PBG-to-creatinine ratio and occurrence of acute attacks. Active (symptomatic) AIP: An individual who has experienced at least one acute attack within the last two years. Symptomatic high excreter: Urine PBG-to-creatinine ratio ≥4 times ULN and no acute attacks in the last two years but chronic long-standing manifestations of acute porphyria. Asymptomatic high excreter: Urine PBG-to-creatinine ratio ≥4 times ULN and no acute attacks in the last two years and no porphyria-related manifestations. Asymptomatic AIP: Urine PBG-to-creatinine ratio <4 times ULN and no acute attacks in the last two years but has had ≥1 acute attack in the past. Latent (inactive) AIP: Urine PBG-to-creatinine ratio <4 times ULN and no acute porphyria-related manifestations to date. [from GeneReviews]
Authors:
Eliane Sardh  |  Michela Barbaro   view full author information

Additional descriptions

From OMIM
Porphyrias are inherited defects in the biosynthesis of heme. Acute intermittent porphyria (AIP), the most common form of porphyria, is an autosomal dominant disorder characterized by recurrent attacks of abdominal pain, gastrointestinal dysfunction, and neurologic disturbances. The disorder is notably incompletely penetrant: fewer than 10% of heterozygous mutation carriers actually develop acute porphyric 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. The precipitants cause increased ALAS1 (125290) activity and increased levels of the porphyrin precursors ALA and PBG. The half-normal hepatic HMBS activity in heterozygous AIP patients is insufficient to prevent pathologic accumulation of these precursors, which are most likely responsible for the symptoms (Petrides, 1998; Solis et al., 2004; Kevelam et al., 2016). 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 are 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).  http://www.omim.org/entry/176000
From MedlinePlus Genetics
Porphyria is a group of disorders caused by abnormalities in the chemical steps that lead to heme production. Heme is a vital molecule for all of the body's organs, although it is most abundant in the blood, bone marrow, and liver. Heme is a component of several iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood).

Researchers have identified several types of porphyria, which are distinguished by their genetic cause and their signs and symptoms. Some types of porphyria, called cutaneous porphyrias, primarily affect the skin. Areas of skin exposed to the sun become fragile and blistered, which can lead to infection, scarring, changes in skin coloring (pigmentation), and increased hair growth. Cutaneous porphyrias include congenital erythropoietic porphyria, erythropoietic protoporphyria, hepatoerythropoietic porphyria, and porphyria cutanea tarda.

Other types of porphyria, called acute porphyrias, primarily affect the nervous system. These disorders are described as "acute" because their signs and symptoms appear quickly and usually last a short time. Episodes of acute porphyria can cause abdominal pain, vomiting, constipation, and diarrhea. During an episode, a person may also experience muscle weakness, seizures, fever, and mental changes such as anxiety and hallucinations. These signs and symptoms can be life-threatening, especially if the muscles that control breathing become paralyzed. Acute porphyrias include acute intermittent porphyria and ALAD deficiency porphyria. Two other forms of porphyria, hereditary coproporphyria and variegate porphyria, can have both acute and cutaneous symptoms.

The porphyrias can also be split into erythropoietic and hepatic types, depending on where damaging compounds called porphyrins and porphyrin precursors first build up in the body. In erythropoietic porphyrias, these compounds originate in the bone marrow. Erythropoietic porphyrias include erythropoietic protoporphyria and congenital erythropoietic porphyria. Health problems associated with erythropoietic porphyrias include a low number of red blood cells (anemia) and enlargement of the spleen (splenomegaly). The other types of porphyrias are considered hepatic porphyrias. In these disorders, porphyrins and porphyrin precursors originate primarily in the liver, leading to abnormal liver function and an increased risk of developing liver cancer.

Environmental factors can strongly influence the occurrence and severity of signs and symptoms of porphyria. Alcohol, smoking, certain drugs, hormones, other illnesses, stress, and dieting or periods without food (fasting) can all trigger the signs and symptoms of some forms of the disorder. Additionally, exposure to sunlight worsens the skin damage in people with cutaneous porphyrias.  https://medlineplus.gov/genetics/condition/porphyria

Clinical features

From HPO
Abdominal pain
MedGen UID:
7803
Concept ID:
C0000737
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) and perceived to originate in the abdomen.
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Loss of the ability to control the urinary bladder leading to involuntary urination.
Dysuria
MedGen UID:
3943
Concept ID:
C0013428
Sign or Symptom
Painful or difficult urination.
Urinary retention
MedGen UID:
38289
Concept ID:
C0080274
Functional Concept
Inability to completely empty the urinary bladder during the process of urination.
Elevated urinary delta-aminolevulinic acid
MedGen UID:
341286
Concept ID:
C1848702
Finding
An increased concentration of 5-aminolevulinic acid (CHEBI:17549) in the urine.
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Tachycardia
MedGen UID:
21453
Concept ID:
C0039231
Finding
A rapid heartrate that exceeds the range of the normal resting heartrate for age.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Nausea
MedGen UID:
10196
Concept ID:
C0027497
Sign or Symptom
A sensation of unease in the stomach together with an urge to vomit.
Paralytic ileus
MedGen UID:
18293
Concept ID:
C0030446
Disease or Syndrome
An ileus caused by abdominal or pelvic surgery, infections, disorders that affect the muscles and nerves, and medications. Signs and symptoms include those of intestinal obstruction.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Hepatocellular carcinoma
MedGen UID:
389187
Concept ID:
C2239176
Neoplastic Process
Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (Taniguchi et al., 2002).
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
Paresthesia
MedGen UID:
14619
Concept ID:
C0030554
Disease or Syndrome
Abnormal sensations such as tingling, pricking, or numbness of the skin with no apparent physical cause.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Psychotic episodes
MedGen UID:
90930
Concept ID:
C0338614
Mental or Behavioral Dysfunction
Periods of time during which an individual experiences significant disturbances in their thoughts, perceptions, emotions, and behavior, resulting in a loss of touch with reality. These episodes are hallmark features of psychotic disorders such as schizophrenia, schizoaffective disorder, and certain forms of bipolar disorder.
Paralysis
MedGen UID:
105510
Concept ID:
C0522224
Finding
Paralysis of voluntary muscles means loss of contraction due to interruption of one or more motor pathways from the brain to the muscle fibers. Although the word paralysis is often used interchangeably to mean either complete or partial loss of muscle strength, it is preferable to use paralysis or plegia for complete or severe loss of muscle strength, and paresis for partial or slight loss. Motor paralysis results from deficits of the upper motor neurons (corticospinal, corticobulbar, or subcorticospinal). Motor paralysis is often accompanied by an impairment in the facility of movement.
Acute episodes of neuropathic symptoms
MedGen UID:
401350
Concept ID:
C1867971
Finding
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Respiratory paralysis
MedGen UID:
19748
Concept ID:
C0035232
Finding
Inability to move the muscles of respiration.
Reduced erythrocyte porphobilinogen deaminase activity
MedGen UID:
1051078
Concept ID:
CN375670
Finding
Activity or concentration of in the level of porphobilinogen deaminase (EC 4.3.1.8) in erythrocytes below the lower limit of normal.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAcute intermittent porphyria
Follow this link to review classifications for Acute intermittent porphyria in Orphanet.

Professional guidelines

PubMed

Wang B, Bonkovsky HL, Lim JK, Balwani M
Gastroenterology 2023 Mar;164(3):484-491. Epub 2023 Jan 13 doi: 10.1053/j.gastro.2022.11.034. PMID: 36642627Free PMC Article
Ricci A, Ventura P
Expert Rev Clin Pharmacol 2022 Apr;15(4):383-393. Epub 2022 May 11 doi: 10.1080/17512433.2022.2075848. PMID: 35531651
Gilles A, Vermeersch S, Vermeersch P, Wolff F, Cotton F, Tilleux S, Cassiman D
Acta Clin Belg 2022 Aug;77(4):735-741. Epub 2021 Aug 7 doi: 10.1080/17843286.2021.1961056. PMID: 34369323

Curated

Orphanet, Acute hepatic porphyria neuro-visceral crisis, 2007

Recent clinical studies

Etiology

Dickey AK, Leaf RK, Balwani M
Annu Rev Med 2024 Jan 29;75:321-335. Epub 2023 Aug 4 doi: 10.1146/annurev-med-042921-123602. PMID: 37540847
Balwani M, Sardh E, Ventura P, Peiró PA, Rees DC, Stölzel U, Bissell DM, Bonkovsky HL, Windyga J, Anderson KE, Parker C, Silver SM, Keel SB, Wang JD, Stein PE, Harper P, Vassiliou D, Wang B, Phillips J, Ivanova A, Langendonk JG, Kauppinen R, Minder E, Horie Y, Penz C, Chen J, Liu S, Ko JJ, Sweetser MT, Garg P, Vaishnaw A, Kim JB, Simon AR, Gouya L; ENVISION Investigators
N Engl J Med 2020 Jun 11;382(24):2289-2301. doi: 10.1056/NEJMoa1913147. PMID: 32521132
Bustos J, Vargas L, Quintero R
Biomedica 2020 Mar 1;40(1):14-19. doi: 10.7705/biomedica.4767. PMID: 32220159Free PMC Article
Phillips JD
Mol Genet Metab 2019 Nov;128(3):164-177. Epub 2019 Apr 22 doi: 10.1016/j.ymgme.2019.04.008. PMID: 31326287Free PMC Article
Ramanujam VS, Anderson KE
Curr Protoc Hum Genet 2015 Jul 1;86:17.20.1-17.20.26. doi: 10.1002/0471142905.hg1720s86. PMID: 26132003Free PMC Article

Diagnosis

Wang B, Bonkovsky HL, Lim JK, Balwani M
Gastroenterology 2023 Mar;164(3):484-491. Epub 2023 Jan 13 doi: 10.1053/j.gastro.2022.11.034. PMID: 36642627Free PMC Article
Gerischer LM, Scheibe F, Nümann A, Köhnlein M, Stölzel U, Meisel A
Brain Behav 2021 Nov;11(11):e2389. Epub 2021 Oct 17 doi: 10.1002/brb3.2389. PMID: 34661997Free PMC Article
Bustos J, Vargas L, Quintero R
Biomedica 2020 Mar 1;40(1):14-19. doi: 10.7705/biomedica.4767. PMID: 32220159Free PMC Article
Bissell DM, Anderson KE, Bonkovsky HL
N Engl J Med 2017 Aug 31;377(9):862-872. doi: 10.1056/NEJMra1608634. PMID: 28854095
Ramanujam VS, Anderson KE
Curr Protoc Hum Genet 2015 Jul 1;86:17.20.1-17.20.26. doi: 10.1002/0471142905.hg1720s86. PMID: 26132003Free PMC Article

Therapy

Balwani M, Sardh E, Ventura P, Peiró PA, Rees DC, Stölzel U, Bissell DM, Bonkovsky HL, Windyga J, Anderson KE, Parker C, Silver SM, Keel SB, Wang JD, Stein PE, Harper P, Vassiliou D, Wang B, Phillips J, Ivanova A, Langendonk JG, Kauppinen R, Minder E, Horie Y, Penz C, Chen J, Liu S, Ko JJ, Sweetser MT, Garg P, Vaishnaw A, Kim JB, Simon AR, Gouya L; ENVISION Investigators
N Engl J Med 2020 Jun 11;382(24):2289-2301. doi: 10.1056/NEJMoa1913147. PMID: 32521132
Bustos J, Vargas L, Quintero R
Biomedica 2020 Mar 1;40(1):14-19. doi: 10.7705/biomedica.4767. PMID: 32220159Free PMC Article
Vidaurre J, Gedela S, Yarosz S
Pediatr Neurol 2017 Dec;77:23-36. Epub 2017 Sep 22 doi: 10.1016/j.pediatrneurol.2017.09.013. PMID: 29097018
Bissell DM, Anderson KE, Bonkovsky HL
N Engl J Med 2017 Aug 31;377(9):862-872. doi: 10.1056/NEJMra1608634. PMID: 28854095
Besur S, Schmeltzer P, Bonkovsky HL
J Emerg Med 2015 Sep;49(3):305-12. Epub 2015 Jul 7 doi: 10.1016/j.jemermed.2015.04.034. PMID: 26159905

Prognosis

Vidaurre J, Gedela S, Yarosz S
Pediatr Neurol 2017 Dec;77:23-36. Epub 2017 Sep 22 doi: 10.1016/j.pediatrneurol.2017.09.013. PMID: 29097018
Bissell DM, Anderson KE, Bonkovsky HL
N Engl J Med 2017 Aug 31;377(9):862-872. doi: 10.1056/NEJMra1608634. PMID: 28854095
Besur S, Schmeltzer P, Bonkovsky HL
J Emerg Med 2015 Sep;49(3):305-12. Epub 2015 Jul 7 doi: 10.1016/j.jemermed.2015.04.034. PMID: 26159905
Kauppinen R
Lancet 2005 Jan 15-21;365(9455):241-52. doi: 10.1016/S0140-6736(05)17744-7. PMID: 15652607
Grandchamp B
Semin Liver Dis 1998;18(1):17-24. doi: 10.1055/s-2007-1007136. PMID: 9516674

Clinical prediction guides

Lin CN, Shiao MS, Cheng ML, Chen CM, Kuo HC
Cells 2021 Sep 28;10(10) doi: 10.3390/cells10102579. PMID: 34685558Free PMC Article
Balwani M, Sardh E, Ventura P, Peiró PA, Rees DC, Stölzel U, Bissell DM, Bonkovsky HL, Windyga J, Anderson KE, Parker C, Silver SM, Keel SB, Wang JD, Stein PE, Harper P, Vassiliou D, Wang B, Phillips J, Ivanova A, Langendonk JG, Kauppinen R, Minder E, Horie Y, Penz C, Chen J, Liu S, Ko JJ, Sweetser MT, Garg P, Vaishnaw A, Kim JB, Simon AR, Gouya L; ENVISION Investigators
N Engl J Med 2020 Jun 11;382(24):2289-2301. doi: 10.1056/NEJMoa1913147. PMID: 32521132
Esteve-Valverde E, Tapiz-Reula A, Ruiz D, Alijotas-Reig J
Rheumatol Int 2020 May;40(5):777-783. Epub 2019 Dec 21 doi: 10.1007/s00296-019-04500-8. PMID: 31865445
Phillips JD
Mol Genet Metab 2019 Nov;128(3):164-177. Epub 2019 Apr 22 doi: 10.1016/j.ymgme.2019.04.008. PMID: 31326287Free PMC Article
Thunell S, Floderus Y, Henrichson A, Harper P
Physiol Res 2006;55 Suppl 2:S109-118. doi: 10.33549/physiolres.930000.55.S2.109. PMID: 17298215

Recent systematic reviews

Li S, Lei JJ, Dong BX, Ren Y, Yang J
Medicine (Baltimore) 2023 Sep 29;102(39):e35144. doi: 10.1097/MD.0000000000035144. PMID: 37773850Free PMC Article
Barletta EA, Belsuzarri TAB, Urena ARB, Iunes EA
Cardiovasc Hematol Agents Med Chem 2021;19(1):3-7. doi: 10.2174/1871525718666200910162000. PMID: 32914723
Jaramillo-Calle DA, Solano JM, Rabinstein AA, Bonkovsky HL
Mol Genet Metab 2019 Nov;128(3):242-253. Epub 2019 Nov 1 doi: 10.1016/j.ymgme.2019.10.011. PMID: 31706631

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    Curated

    • Orphanet, 2007
      Orphanet, Acute hepatic porphyria neuro-visceral crisis, 2007

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