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.

Type Inheritance Deficient Enzyme Gene

ALA-Dehydratase Porphyria (ADP)

Autosomal recessive ALA-Dehydratase ALAD

Acute Intermittent Porphyria (AIP)

Autosomal dominant Hydroxymethylbilane synthase (Porphobilinogen deaminase)

HMBS

Congenital Erythropoietic Porphyria (CEP)

Autosomal recessive Uroporphyrinogen III synthase UROS

Porphyria Cutanea Tarda (PCT), familial form

Autosomal dominant Uroporphyrinogen decarboxylase UROD

Hepatoerythropoietic Porphyria (HEP)

Autosomal recessive Uroporphyrinogen decarboxylase UROD

Hereditary Coproporphyria (HCP)

Autosomal dominant Coproporphyrinogen oxidase CPOX

Variegate Porphyria (VP)

Autosomal dominant Protoporphyrinogen oxidase PPOX

Erythropoietic Protoporphyria (EPP)
X-linked Protoporphyria (XLP)

Autosomal recessive

X-linked

Ferrochelatase

δ-Aminolevulinate synthase 2

FECH

ALAS2

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.

FAQ: Are the diagnostic tests the same of all the porphyrias?

Porphyrias Defined

Definitions of the different types of porphyrias

 

Genetics 101

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

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 (porphyriadrugs.com).

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.

What is Hereditary Coproporphyria (HCP)?

HCP is an inherited genetic condition but it is rarer than AIP. In HCP, the gene responsible is CPOX which produces the enzyme coproporphyinogen oxidase, and without this enzyme working properly, porphyrins build up and can cause symptoms similar to those seen in AIP. However, the acute attacks can be milder in people with HCP when compared to AIP. Patients with HCP have the same slight increased risk of liver cancer that AIP patients have. Unlike AIP, people with HCP can also have blistering skin lesions on sun exposed areas, so the blistering is commonly on the back of the hands and face. As in AIP, about 80-90% of patients with HCP mutations will not develop symptoms.

How is Hereditary Coproporphyria 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 HCP, the testing involves measuring the levels of porphobilinogen (PBG), aminolevulinic acid (ALA), and total porphyrins in the urine. Also porphyrins in the blood and stool should be measured. 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). Slight elevations in porphyrins are not diagnostic of HCP, the levels need to be 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 changes that can cause disease, called mutations. The gene that causes HCP is called CPOX. Genetic testing is recommended for patients even if they have a biochemical diagnosis of HCP.

If a patient has a mutation, their immediate family members should be tested for that same mutation.  This includes their parents, siblings, and children. This will allow all family members to receive appropriate care and counseling even though 80-90% of people with a mutation will not have symptoms of HCP.

What are treatments for Hereditary Coproporphyria?

The treatments  and preventive measures are the same as in AIP. In addition, patients with blistering from sun exposure will need to protect themselves from sunlight.

How is HCP Inherited?

HCP 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 HCP is called CPOX.

Genes are inherited randomly, so a parent has an equal chance of passing on either one of the two copies of each gene.  Since most HCP 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.

What is Variegate Porphyria (VP)?

VP is an inherited genetic condition with similar clinical signs and symptoms as AIP, but  is more rare than AIP. VP is especially common in South African individuals of Dutch ancestry, where it has been estimated that 3 in 1,000 of the Caucasian population is affected. In VP, the gene responsible is PPOX which produces the enzyme coproporphyinogen oxidase, and without this enzyme working properly porphyrins build up and can cause symptoms similar to those seen in AIP. However the acute attacks can be milder in people with VP when compared to AIP. Patients with VP have the same slightly increased risk of liver cancer that AIP patients have. Unlike AIP, people with VP can also have blistering on their skin in response to sun exposure and the primary affected areas are on the back of the hands and face. The occurrence of blistering skin lesions are much more common in VP than in HCP and are not easily treated. The only effective preventive measure is use of protective clothing and avoidance of prolonged sun exposure. As in AIP, about 80-90% of patients with VP mutations will not develop symptoms.

How is Variegate 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 VP, measurement of porphobilinogen (PBG), aminolevulinic acid (ALA), and total porphyrins in the urine should be done. Also porphyrins in the blood should be measured. 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.). Slight elevations in porphyrins are not diagnostic of VP; the levels need to be 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 changes that can cause disease, called mutations. VP is caused by mutations in the PPOX gene. Genetic testing is recommended for patients even if they have a biochemical diagnosis of VP.

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 have symptoms of VP.

What are treatments for Variegate Porphyria?

The treatments and preventive measures are the same as in AIP. In addition patients with blistering from sun exposure will need to protect themselves from sunlight by using sun protective clothing and avoiding prolonged sun exposure.

How is Variegate Porphyria Inherited?

VP 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 HCP is called PPOX.

Genes are inherited randomly, so a parent has an equal chance of passing on either copies of each gene. Since most VP 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.

What is δ-Aminolevulinic Acid Dehydratase Porphyria (ADP)?

ADP is more severe than the other acute porphyrias and can present in childhood. It is an inherited genetic condition, but is extremely rare. Only ~10 cases have been reported worldwide and all of the reported cases have been males, in contrast to the other acute porphyrias where more women have symptoms. In ADP, the gene responsible is ALAD which produces the enzyme δ-aminolevulinic acid dehydratase. When this enzyme is working properly, porphyrins build up and can cause symptoms similar to those seen in AIP.

How is δ-Aminolevulinic Acid Dehydratase Porphyria diagnosed?

Biochemical testing means looking for “biomarkers” in the blood or urine. To diagnose ADP, measurements of porphobilinogen (PBG), aminolevulinic acid (ALA), and total porphyrins in the urine should be done. Also porphyrins in the blood should be measured. 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). Slight elevations in porphyrins are not diagnostic of ADP; the levels need to be very high.

What are treatments for δ-Aminolevulinic Acid Dehydratase Porphyria?

The treatments and preventive measures are the same as in AIP.

How is δ-Aminolevulinic Acid Dehydratase Porphyria Inherited?

ADP is an autosomal recessive condition. Autosomal means that the defect is not on the chromosomes that determine sex, and recessive means that both copies of the gene are mutated. The gene that causes ADP is called ALAD.

What is Porphyria Cutanea Tarda (PCT)

Porphyria cutanea tarda (PCT) is the most common type of porphyria, with a prevalence of approximately 1 case for every 10,000 people. PCT is caused by low levels of  the enzyme uroporphyrinogen decarboxylase (UROD). There are two types of PCT, one is inherited and called Familial PCT, and the other is not inherited and called Sporadic PCT. The sporadic type is more common. For both types, to develop PCT symptoms, other factors must be present to make the level of this enzyme drop to less than 20% of normal in the liver. Some of these other factors include excessive alcohol use, smoking, use of estrogens (birth control pills, hormone replacement therapy, etc.), hepatitis C infection, HIV (human immunodeficiency virus) infection, and a disease called hemochromatosis which causes iron overload.  

Patients with PCT can develop blistering skin lesions on sun-exposed areas, such as the back of the hands and face and generally start in adulthood. The skin  may also become fragile and/or peel after minor trauma. People with PCT can also have increased hair growth, as well as darkening and thickening of the skin.  Acute attacks that are seen in patients with AIP do NOT occur in patients with PCT.

Abnormal liver function tests can be seen in patients with PCT, but they are usually mild. PCT is often associated with hepatitis C infection, which also can cause these liver complications. However, liver tests are generally abnormal even in PCT patients without hepatitis C infection. Progression to cirrhosis and even liver cancer has been reported in some patients.

How is Porphyria Cutanea Tarda 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 PCT, measurements of total porphyrins in the urine or blood should be done. These levels are generally very high in people with PCT.

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 changes that can cause disease, called mutations.  The gene that causes the familial form of PCT is called UROD. Genetic testing is recommended for all patients with PCT in addition to biochemical testing to help establish the type of PCT, sporadic versus familial form.

If a patient has a mutation, their immediate family members should be tested for that same mutationincluding their parents, siblings, and children. This will allow all family members to receive appropriate counseling even though many people with a mutation in the UROD gene will not have symptoms of PCT.

What are treatments for Porphyria Cutanea Tarda?

Treatment and management are the same for both types of PCT. They can be treated either with regularly scheduled phlebotomies (removal of a certain amount of blood), or with a low dose hydroxychloroquine, a medication normally given for malaria. In addition, patients should be tested to see if they have any of the infections listed above and treated accordingly. Other susceptible factors including alcohol use, smoking, estrogen exposure should be avoided. PCT is the most treatable of the porphyrias; however, some patients can have relapse of symptoms after completing treatment. Treatment is the same for recurrences.

How is Porphyria Cutanea Tarda Inherited?

As mentioned above, only the familial form of PCT can be inherited, and even in this form patients with PCT may not have any family members with symptoms. Familial PCT 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 responsible for familial PCT is called UROD.

Genes are inherited randomly, so a parent has an equal chance of passing on either copy of each gene.  Since most Familial PCT 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.

What is Hepatoerythropoietic Porphyria (HEP)?

HEP is caused by low levels of the same enzyme that causes PCT, called uroporphyrinogen decarboxylase (UROD). In Familial PCT, there is only one mutated copy of the UROD gene, the other copy is normal. In HEP both copies of the UROD gene have mutations. The symptoms of HEP resemble Congenital Erythropoietic Porphyria (CEP), with symptoms of skin blistering that usually begin in infancy or early childhood. HEP is more severe than PCT.

Skin photosensitivity (sun sensitivity) in HEP results in severe blistering and scarring. Increased hair growth (hypertrichosis) on sun-exposed skin, and reddish-colored urine are common.

HEP is caused by a deficiency of the enzyme uroporphyrinogen decarboxylase, due to the inheritance of mutations in both copies of a person’s URO-decarboxylase genes.

Who gets Hepatoerythropoietic Porphyria diagnosed?

HEP is a very rare type of autosomal recessive porphyria. For a child to be affected, he/she must have received a mutated gene from each parent. This means each parent of an affected individual has Familiar PCT.

How is Hepatoerythropoietic 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 HEP the tests that need to be done are to measure the levels of total porphyrins in the urine or blood. These levels are generally very high in people with HEP.

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 changes that can cause disease, called mutations. The gene that causes HEP is called UROD. Genetic testing is recommended for all patients even if they have a biochemical diagnosis.

Once the UROD mutations have been found, the patient’s immediate family members should be tested for the same mutations. This includes their parents, their siblings, and any children they may have. This will allow all family members to receive appropriate counseling even though many people with one mutation in the UROD gene will not have symptoms of Familial PCT.

What are treatments for Hepatoerythropoietic Porphyria?

The treatments for PCT: regularly scheduled phlebotomies (removal of certain amounts of blood), or low doses of hydroxychloroquine, are generally less effective in HEP but can still be attempted. The main way to manage symptoms is avoidance and/or protection from sunlight.

How is Hepatoerythropoietic Porphyria inherited?

HEP is an autosomal recessive condition. Autosomal means that the defect is not on the chromosomes that determine sex, and recessive means that patients who have HEP have inherited two mutated copies of the UROD gene, one from each of their parents. When someone with HEP has children, all their children will have Familial PCT since they will inherit one copy of the mutated UROD gene. The children will not necessarily develop symptoms of PCT but should be counseled accordingly.

What is Congenital Erythropoietic Porphyria (CEP)?

CEP is a very rare, severe disorder. There are only a few hundred cases reported worldwide. CEP is caused by a lack of the enzyme uroporphyrinogen III synthase (UROS). CEP is one of the most severe porphyrias; symptoms usually begin soon after birth or in early childhood. Some severe cases have been diagnosed before birth as a cause of anemia and fluid accumulation in the fetus, called fetal hydrops. Less severe cases may occur in adults in association with another bone marrow conditions.

Skin photosensitivity results in severe blistering and scarring, often so severe it leads to mutilation and loss of facial features (tip of the nose, lips, etc) and fingers. Bacteria may infect the damaged skin and contribute to mutilation and scarring. Increased hair growth (hypertrichosis) on sun-exposed skin, brownish-colored teeth (erythrodontia), and reddish-colored urine are also common. There may be bone fragility due to expansion of the bone marrow and vitamin deficiencies, especially vitamin D. Red blood cells have a shortened life-span, and mild or severe hemolytic anemia often results. The spleen can also be enlarged in patients with CEP.

How is Congenital Erythropoietic 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 CEP the tests that need to be done are to measure the levels of total porphyrins in the urine and blood. These levels are generally very high in people with CEP.

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 changes that can cause disease, called mutations. The gene that causes CEP is called UROS. Genetic testing is recommended for all patients even if they have a biochemical diagnosis, as the types of mutations can give information about how severe the disease may be.

Once the UROS mutations have been found, future siblings of the patient can be tested as well.

What are treatments for Congenital Erythropoietic Porphyria?

Avoiding exposure to sunlight is the most important way to manage symptoms for someone with CEP. Patients need to take care to wear protective clothing, and have appropriate window tints on their cars and houses. Blood transfusions to correct anemia are required in severe cases, and this may reduce porphyrin production by the marrow. Identifying the mutations in a family enables diagnosis before birth in future pregnancies.

How is Congenital Erythropoietic Porphyria inherited?

CEP is an autosomal recessive condition. Autosomal means that the defect is not on the chromosomes that determine sex, and recessive means that patients who have CEP have inherited two mutated copies of the UROS gene, one from each of their parents. When someone with CEP has children, all their children will have one mutated copy of the UROS gene, but they will not have symptoms of CEP.

What is Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP)?

EPP and XLP are both porphyrias with similar symptoms and similar biochemical findings, but each is caused by changes, called mutations, in two different genes.

EPP and XLP, combined, are the third most common porphyria, with an incidence of possibly 2 to 5 per 1,000,000. They are the most common porphyria in children. EPP is caused by a lack of the enzyme, ferrochelatase due to mutations in the FECH gene. 

XLP is caused by the enzyme amino-levulinic acid synthase being too active, due to a mutation in the ALAS2 gene. 

Both result in excess production of protoporphyrin in the bone marrow, transportation to the skin, and collection in the liver. Symptoms usually first occur in early childhood, and include sun sensitivity of severe burning pain, and possibly swelling and redness of sun-exposed areas of the skin (face, backs of the hands, etc). Typically EPP and XLP do not have blistering after sun exposure. Both EPP and XLP have significant elevations of a specific compound, called protoporphyrin, and this elevation primarily comes from the liver. Sometimes this may results in severe liver complications that are difficult to treat and could require liver transplantation.

How is Erythropoietic Protoporphyria or X-Linked Protoporphyria 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 EPP/XLP the tests that need to be done are to measure the levels of protoporphyrin and total porphyrins in the blood. These levels are generally very high in people with EPP/XLP.

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 changes that can cause disease, called mutations.  The gene that causes EPP is called FECH, and the gene that causes XLP is called ALAS2. Genetic testing is recommended for all patients even if they have a biochemical diagnosis.

What are treatments for Erythropoietic Protoporphyria and X-Linked Protoporphyria?

Treatment with pharmaceutical grade β-carotene (Lumitene, Tishcon) or cysteine may improve sunlight tolerance but they do not lower protoporphyrin levels and have mixed reports about their effectiveness. Most patients must learn to avoid sunlight as much as possible. Anti-itch treatments like cortisone or antihistamines do not help the symptoms of EPP/XLP. Iron and Vitamin D levels can be low in patients with EPP and XLP so these should be checked for and supplemented accordingly. To protect the liver from further injury, Hepatitis A and B vaccinations are recommended, as is the avoidance of large amounts of alcohol and medications which may be harmful to the liver (called hepatotoxic).

Liver failure can appear suddenly and progress quickly in some patients. It is generally treated with a combination of plasmapheresis (liquid from the blood, called plasma, is separated from the other components of the blood), blood transfusions, infusions of Panhematin (the treatment usually given for the acute porphryias), the medications like cholestyramine, vitamin E, and ursodeoxycholic acid. The level of protoporphyrin in the blood should be followed closely during treatment. Liver transplantation is sometimes necessary.  It is not yet possible to predict which patients will develop liver failure. 

How is Erythropoietic Protoporphyria inherited?

EPP is an autosomal recessive condition. Autosomal means that the defect is not on the chromosomes that determine sex, and recessive which means that patients who have EPP have inherited two mutated copies of the FECH gene, one from each parent.  All children of an EPP patient will inherit one of the mutated copies of the FECH gene.

How is X-Linked Protoporphyria inherited?

XLP is an X-linked inherited genetic disorder. This means that the defect is on the X chromosome. Females have two copies of the X chromosome, while males have only one copy. The gene that causes XLP is called ALAS2. Because females have two copies of the X chromosome, they have one mutated copy of ALAS2 and one working copy. A random process in the body causes one X chromosome to be turned off. For this reason, females can present with a varying degree of symptoms ranging from no symptoms to severe XLP symptoms. There is no way to predict this ahead of time. Therefore it is important for family members of XLP patients to be tested for this mutation so that they can receive appropriate counseling.

Genes are inherited randomly, so each parent has an equal chance of passing on either one of their sex chromosomes. If the father has XLP, each of his children has a 50% chance of inheriting his X chromosome (which has the mutated gene) and a 50% chance of inheriting his Y chromosome (which does not have the gene).  If they have inherited the X chromosome, they will be female and have one mutated copy of ALAS2. If they have inherited the Y chromosome, they will be male and not have XLP.

If a father has XLP, all of his daughters will have XLP but none of his sons will be affected.