Porphyria refers to a group of related disorders caused by a disruption in one of the steps involved in creating a protein called heme. Heme is an integral part of hemoglobin, the molecule that carries oxygen inside red blood cells.
There are eight main types of porphyria. The two main categories are acute or cutaneous (skin) depending on the symptoms. Some researchers also may categorize them based on where they originate in the body: hepatic (the liver) or erythropoietic (the bone marrow).
Acute porphyrias lead to symptoms that typically are more neurological. These manifest as “attacks” with severe stomach pain being very common. The underlying cause of acute porphyrias are genetic mutations. However, in many cases, symptoms don’t occur unless triggered by external factors such as medications, stress, or hormonal changes. These additional factors often lead to the body increasing the production of heme, leading to an additional buildup of the heme precursors called porphyrins.
Following are the four types of acute porphyria:
Acute intermittent porphyria
Acute intermittent porphyria (AIP) is the most common form of acute porphyria in most countries. It is caused by a mutation in the HMBS gene that contains the instructions necessary for cells to make the enzyme hydroxymethylbilane synthase, also known as porphobilinogen deaminase, which plays a role in the third of the eight steps of the heme-production pathway. A child inherits AIP in an autosomal dominant pattern, which means that only one faulty copy of the gene is needed from parents for the child to have the disease.
Symptoms of AIP may include stomach pain, nausea, vomiting, constipation, back and limb pain, muscle weakness, fast or pounding heartbeat, insomnia, hallucinations, confusion, and seizures. Patients do not experience skin issues with this type of porphyria.
Hereditary coproporphyria (HCP) is due to a mutation in the CPOX gene leading to the loss of functional coproporphyrinogen oxidase enzyme. This enzyme is necessary for the sixth step of heme production. HCP also is inherited in an autosomal dominant pattern.
HCP usually leads to pain in the abdomen that increases over a few days and may begin to radiate to other parts of the body, including the back, buttocks, arms, and legs. Other symptoms may include constipation, vomiting, fast heart rate (tachycardia), high blood pressure, irregular heartbeats, a drop in blood pressure when standing, seizures, burning or tingling sensations in the limbs (peripheral neuropathy), weakness, paralysis, hallucinations, dementia, paranoia, confusion, and other psychological disorders. Some patients may develop skin symptoms related to sunlight exposure, including burning and itching sensations, blisters, discolored scars, and excessive hair growth.
The PPOX gene is mutated in variegate porphyria (VP). Children inherit the disease in an autosomal dominant pattern. The PPOX gene carries the information necessary for cells to make the protoporphyrinogen oxidase enzyme. The seventh step of heme production requires the protoporphyrinogen oxidase enzyme.
Symptoms of VP can vary considerably from patient to patient. Some may have neurological symptoms while others have skin symptoms. Some patients may have both.
Neurological symptoms include pain and cramping in the abdomen, nausea, vomiting, trouble with the bladder and bowels, tingling and burning in the limbs, insomnia, agitation, convulsions, hallucinations, weakness, paralysis, increased heart rate, increased blood pressure, and hyperactive reflexes that later decline.
Skin symptoms can include sensitivity to light that leads to pain and blisters, fragile skin, cysts, and excessive hair growth.
Patients with VP also may be at a higher risk for hepatocellular carcinoma (a type of cancer) and chronic kidney disease.
Delta-aminolevulinic acid dehydratase (ALAD) porphyria is a very rare form of porphyria resulting from mutations in the ALAD gene. The delta-aminolevulinate dehydratase enzyme produced by the ALAD gene is necessary for the second step in the production of heme. ADP is an autosomal recessive disorder, meaning that children must inherit a defective copy of the ALAD gene from each parent in order to develop it.
Unlike the other types of acute porphyria in which symptoms usually don’t occur until after puberty or until the patient reaches their 20s and 30s, the symptoms of ALAD can occur in childhood. Symptoms are neurological in nature with abdominal cramping and pain, vomiting and nausea. In young children, these gastrointestinal symptoms may lead to a lack of sufficient nutrition, slowing growth and weight gain. Other symptoms can include numbness and tingling in the hands and feet, sensitivity to touch, burning pain, lack of coordination, weakness or paralysis of muscles, rapid heart rate, high blood pressure, seizures, psychosis, and breathing problems.
The cutaneous porphyrias primarily affect the skin. The most common symptom of all types of cutaneous porphyria is sensitivity to light.
Porphyria cutanea tarda
The most common type of porphyria is porphyria cutanea tarda (PCT). PCT is generally an acquired disease but genetic mutations in the UROD gene may make people more prone to it. The UROD gene provides instructions for making the enzyme uroporphyrinogen decarboxylase, which plays a role in the fifth step of heme production. Besides mutations in the UROD gene, several other environmental factors can contribute to a lack of the uroporphyrinogen decarboxylase enzyme, such as hepatitis C and HIV infections, iron, alcohol, and some estrogens.
Patients with PCT usually have skin that is very sensitive to sunlight and can peel or blister from small impacts. Damage from the sun can lead to blistering, scarring, and discoloration of the skin (darker or lighter than usual). The skin also can form small white bumps on the back of the hands and lead to excessive hair growth, especially on the face.
Erythropoietic protoporphyria (EPP) can be caused by mutations in the FECH gene or the ALAS2 gene. When it is due to mutations in the ALAS2 gene, EPP is usually referred to as X-linked protoporphyria (XLP) since this gene resides on the X chromosome. EPP is the third-most common type of porphyria and the most common form of the disease in children.
The FECH gene carries instructions for making ferrochelatase, an enzyme that plays a role in the final step of heme production ,while the ALAS2 gene enables production of the enzyme 5’-aminolevulinate synthase 2, or erythroid ALA-synthase, which is important in the first step of heme production. EPP due to either mutation is inherited in a dominant manner, although women with XLP may have less severe symptoms than men.
Sun exposure in EPP leads to redness, itching, burning, and swelling. Blistering and scarring are not very common. The areas affected by sunlight may become abnormally thick. Patients also may experience deformed nails, issues with their gallbladder, and liver problems. Skin sensitivity to light can occur as early as infancy. In some patients, it may not be present until they reach adolescence or adulthood.
Congenital erythropoietic porphyria
Uroporphyrinogen III synthase is the defective enzyme in this very rare form of porphyria called congenital erythropoietic porphyria (CEP). The UROS gene on chromosome 10 provides instructions for making this enzyme. Children inherit CEP in an autosomal recessive pattern.
Symptoms of CEP usually occur in infancy or early childhood with the first symptom being reddish urine. Patients with CEP often have extreme sensitivity to sunlight. This usually results in blistering and scarring as well as possible swelling and redness around the damaged skin. The blisters can become infected leading to erosion of the tissue and causing disfigurement, especially on areas frequently exposed to sunlight, such as the hands and face. Patients also may have deformities in the fingers and nails, brownish teeth, anemia, and enlarged spleen.
Hepatoerythropoietic porphyria (HEP) has similar symptoms to CEP with sun sensitivity usually starting in infancy. HEP is an autosomal recessive form of familial PCT caused by mutations in the UROD gene.
Fragile skin that easily peels or blisters is a common symptom of HEP, as is extreme sensitivity to light. As with CEP, sun damage can cause frequent blistering, scarring, and erosion of the skin leading to disfigurement. Damaged areas of the skin also may develop abnormal hair growth and changes in skin color. Patients may have small bumps with whiteheads on their skin, and some patients may have reddish-brown teeth. Early destruction of red blood cells in HEP can lead to mild-to-moderate levels of anemia in patients. Some patients may have an enlarged liver or spleen.
How to tell which porphyria you may have
Doctors will review your symptoms to narrow the list of possible porphyrias. Some types may not be distinguishable from another based solely on symptoms and physical examination; that requires biochemical testing of blood, urine, and/or stool to check for levels of different porphyrins or porphyrin precursors. The testing helps to determine whether the symptoms are due to porphyria or another disease with similar symptoms. Genetic testing can more reliably determine the type of porphyria you may have.
Last updated: Dec. 2, 2020
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