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Porphyria Consortium 101

Overview of the Porphyrias

Disorder Definitions
The porphyrias are inherited genetic conditions, which means that people with a porphyria have changes to certain genes that affect their body’s ability to regulate itself.  When genes are copied, either to make new cells or to make a child, sometimes the body makes an imperfect copy.  There can be little changes in the genes, called mutations, which can occur randomly.  Sometimes these changes do not make any difference in how well the gene works, but other times they can keep the gene from working properly (referred to as mutations) and are disease causing.
In the porphyrias, these mutations are in the genes involved in a certain chemical pathway, called the heme biosynthetic pathway. Heme is a compound that the body needs to make hemoglobin and there are several steps to make this compound in the body. Each type of porphyria is caused by a defect in a specific enzyme in the heme biosynthetic pathway. Without these enzymes working properly, the body is not able to finish making heme and it causes a buildup of other compounds, called porphyrins. It is the buildup of different types of porphyrins that causes the different types of porphyria.
Most commonly the porphyrias are divided into the “acute“ and “cutaneous” porphyrias, depending on the primary symptoms. The acute porphyrias [acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA-dehydratase deficiency porphyria (ALD)] present with sudden attacks of severe stomach pain that last for several days; VP and HCP may also have skin symptoms of blistering after sun exposure. The cutaneous porphyrias present with blistering and scarring of the skin, pain, and/or redness and swelling in sun-exposed areas. The porphyrias may also be classified as “hepatic” or “erythropoietic”, depending on the organ where the porphyrins accumulate, the liver for the hepatic porphyrias [AIP, HCP, VP, porphyria cutanea tarda (PCT), and hepatoerythropoietic porphyria (HEP)] or the bone marrow for the erythropoietic porphyrias [congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLP)].

The Acute Porphyrias

There are four types of acute porphyrias; acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and δ-aminolevulinic acid dehydratase porphyria (ADP), and they have similar symptoms. These are genetic disorders that are very rare and may be difficult to diagnose for this reason. It is estimated that about 1 in 10,000 Europeans or people of European ancestry have a mutation in one of the genes that cause AIP, VP or HCP. These mutations have been found in all races and many other ethnicities in addition to Europeans.
Approximately 80-90% of individuals who carry a gene mutation for acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria, remain asymptomatic, and others may have only one or a few acute attacks throughout life. The most frequent symptom is severe abdominal pain and is often accompanied by nausea, vomiting, and constipation. Other symptoms may include heart palpitations, seizures, and hallucinations. People with VP and HCP may also have skin symptoms of blistering after sun exposure.

The Cutaneous Porphyrias

All but one of the cutaneous porphyrias cause skin blistering and fragility on sun-exposed areas of the body, most commonly the backs of the hands, forearms, face, ears and neck. The cutaneous porphyrias are porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLP).
CEP and HEP occur in childhood with severe blistering skin lesions. PCT occurs in adulthood generally and less severe blistering skin lesions after sun exposure. Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) have the same symptoms of painful, but nonblistering, reactions to sunlight. There can also be swelling and redness of the sun exposed areas of the skin with EPP and XLP. 
Each type of porphyria is caused by a mutation, or change, in the gene coding for a specific enzyme in the heme pathway. PCT is unique as it is the only porphyria where most patients do not have mutations in a gene, but instead have acquired, or sporadic, PCT.    

Types of porphyria, their patterns of inheritance, and the enzyme that is deficient in each.

TypeInheritanceDeficient EnzymeGene
ALA-Dehydratase Porphyria (ADP)
Autosomal recessiveALA-DehydrataseALAD
Acute Intermittent Porphyria (AIP)
Autosomal dominantHydroxymethylbilane synthase (Porphobilinogen deaminase)
Congenital Erythropoietic Porphyria (CEP)
Autosomal recessiveUroporphyrinogen III synthaseUROS
Porphyria Cutanea Tarda (PCT), familial form
Autosomal dominantUroporphyrinogen decarboxylaseUROD
Hepatoerythropoietic Porphyria (HEP)
Autosomal recessiveUroporphyrinogen decarboxylaseUROD
Hereditary Coproporphyria (HCP)
Autosomal dominantCoproporphyrinogen oxidaseCPOX
Variegate Porphyria (VP)
Autosomal dominantProtoporphyrinogen oxidasePPOX
Erythropoietic Protoporphyria (EPP)
X-linked Protoporphyria (XLP)
Autosomal recessive
δ-Aminolevulinate synthase 2
The inherited porphyrias are either autosomal dominant (inherited from one parent), autosomal recessive (inherited from both parents), or X-linked (the gene is located on the X-chromosome). "Autosomal" genes always occur in pairs, with one coming from each parent. Individuals with an autosomal dominant form of porphyria have one mutated gene paired with a normal gene, and there is a 50% chance with each pregnancy that the mutated gene will be passed to a child. 
Individuals with an autosomal recessive type of porphyria have mutations on both copies of a specific gene, one passed to them from each of their parents. Each of their children will inherit one mutated gene for that porphyria, and the child will be a “carrier” but will not have symptoms.
In X-linked disorders, the gene is located on one of the sex chromosomes, called the X-chromosome. Females have two X-chromosomes, and males have one X-chromosome and one Y-chromosome. Both males and females will likely have symptoms from a mutated gene on the X-chromosome, but females, with a normal gene on the other X-chromosome, usually are less severely affected than males. The risk for children depends on the gender of the affected parent. A female with an X-linked gene mutation will have a 50% risk of passing that mutation to any of her children with each pregnancy. However, a male will pass the mutation to all of his daughters but none of his sons.
There are many laboratory tests available for the porphyrias, and the right tests to order depend on the type of porphyria the doctor suspects. When abdominal and neurological symptoms suggest an acute porphyria, the best screening tests are urinary aminolevulinic acid (ALA) and porphobilinogen (PBG). When there are cutaneous symptoms that suggest porphyria, the best screening test is a plasma porphyrin assay. If one of these screening tests is abnormal, more extensive testing, including urinary, fecal, and red blood cell porphyrins, are often indicated.
DNA testing to identify the specific mutation in an individual’s porphyria-causing gene is also recommended. Before requesting DNA testing, it is helpful that patients have biochemical testing. However, many patients have not had an acute attack or are not symptomatic at present, so biochemical testing may be inconclusive.
In contrast, DNA testing is the most accurate and reliable method for determining if a person has a specific porphyria and is considered the "gold standard" for the diagnosis of genetic disorders. If a mutation (or change) in the DNA sequence is found in a specific Porphyria-causing gene, the diagnosis of that Porphyria is confirmed. DNA analysis will detect more than 97% of disease-causing mutations. DNA testing can be performed whether the patient is symptomatic or not. Once a mutation has been identified, DNA analysis can then be performed on other family members to determine if they have inherited that Porphyria, thus allowing identification of individuals who can be counseled about appropriate management in order to avoid or minimize disease complications.

Porphyrias Defined


Genetics 101

Have a Tour of Basic Geneticsfrom the Genetic Science Learning Center at the University of Utah

    Acute Porphyrias

    Cutaneous Porphyrias

What is Acute Intermittent Porphyria?

Acute Intermittent Porphyria (AIP) is an inherited genetic condition. The genetic mutations that cause AIP are in the HMBS gene. They result in the genes to produce too little of the enzyme hydroxymethylbilane synthase (also called porphobilinogen deaminase). Without enough of this enzyme, the body is not able to finish converting porphobilinogen into heme chains, causing them to build up to much higher levels than usual. This buildup can cause the pain attacks of AIP, but about 80-90% of patients with AIP mutations will not develop symptoms.
When patients do suffer an attack, they will usually experience severe abdominal pain. This is often extremely painful and patients may need to go to the hospital for help. Because these attacks will often not involve any visible symptoms, the ER staff may not know to treat patients for porphyria if they are unaware of the diagnosis. It is very important for patients to speak with their local hospital and health care provider to make sure a plan is in place before an attack so they are able to receive care as quickly as possible.
Patients can also experience numbness, weakness, nausea, constipation, confusion, restlessness, hallucination, seizures, and difficulty with urination during acute attacks. These symptoms can be very severe and hard to treat if a doctor does not know to suspect AIP. It is important for family members of AIP patients to get tested even if they have never had an attack before. If they do have a mutation in one of their copies of the HMBS gene, knowing this will allow their doctor to give them the appropriate care if any symptoms arise.
Patients with AIP also have a slightly increased risk than the general population of developing liver cancer, called hepatocellular carcinoma.

How is Acute Intermittent Porphyria diagnosed?

There are two types of testing; biochemical, meaning looking for “biomarkers” in the blood or urine, and genetic, meaning looking at the gene we know causes the disease directly from a blood sample.
Biochemical: To diagnose AIP the most important test is to measure the level of porphobilinogen (PBG) in the urine. This test is often combined with measuring the total amount of porphyrins in the urine and another biomarker called aminolevulinic acid (ALA). The level of PBG in the body can vary so the best time to take samples is during an acute attack (e.g. when someone is having abdominal pain, etc). In people with AIP the level of PBG is very high.
Genetic: A blood sample is used to look at a person’s genes and by doing this it is possible to see if their genes have mutations that can cause disease. The gene that causes AIP is called HMBS. Genetic testing is recommended for patients even if they have very high PBG levels.
If a patient has a mutation, their immediate family members should be tested for that same mutation as well. This includes their parents, their siblings, and any children they may have. This will allow all family members to receive appropriate care and counseling even though 80-90% of people with a mutation will not develop symptoms of AIP.
Also see FAQ: What diagnostic tests are available?

What are treatments for Acute Intermittent Porphyria?

AIP attacks can be triggered by a number of factors. One known trigger is progesterone, a hormone which naturally increases in women during their menstrual cycle. Female AIP patients are more likely to have attacks in the second half of their menstrual cycle, when their uterine lining is thickening but before it begins to shed (when they begin bleeding). Dieting can also be a trigger, so patients should avoid fasting and dieting. Patients with AIP should eat a balanced diet. Drugs can be another trigger, especially barbiturates, sulfonamide antibiotics, anti-seizure drugs, and oral contraceptives (progesterone in particular). There is an online drug database to check which medications may be unsafe for people with AIP. The American Porphyria Foundation offers a mobile phone app that pulls up this information online (
During an attack, patients may often need to be hospitalized. This will allow them to receive medications to handle their pain and IV fluids if they are unable to stop vomiting or are too nauseous to eat. If the attack was triggered by using drugs for a long time, the muscles which control breathing may be weak and the patient may need respiratory support.
Patients can receive heme therapy through an IV. Panhematin is an FDA approved medication which can help decrease the severity and length of the attack, and is more effective the earlier they receive it.
Attacks can be prevented in many cases by avoiding harmful drugs and fasting or dieting. Wearing a Medic Alert bracelet is recommended for patients who have had attacks. Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance. In some cases, frequent attacks can be prevented by regularly scheduled infusions of hemin.
Individuals with AIP who are prone to attacks should eat a normal balanced diet and should not fast or diet, even for short periods of time. If weight loss is desired, it is advisable to consult a physician and a dietitian to have them an individualized diet plan created.

How is AIP Inherited?

AIP is an autosomal dominant condition. Autosomal means that the defect is not on the chromosomes that determine sex, and dominant means that you only need to inherit one mutated gene to manifest the disease. The gene that causes AIP is called HMBS.
Genes are inherited randomly, so a parent has an equal chance of passing on either of their two copies of each gene. Since most AIP patients have one mutated copy and one normal copy, this means that each of their children will have a 50% chance of inheriting the mutated copy and 50% chance of inheriting the working copy.


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