Porphyrias are a group of genetic disorders that are caused by disruptions in heme production.
Heme is a molecule that is needed for oxygen transport in living cells. It is made up of iron and protoporphyrin IX, which is built step-wise out of other porphyrins and precursor molecules.
When the metabolic pathway leading to heme production is disrupted, porphyrins and their precursors build up to toxic levels throughout the body — often in the kidneys and skin, although not limited to those organs — while limiting the amount of oxygen carried in the blood.
Each type of porphyria stems from the loss of a specific enzyme necessary for heme production.
Porphyrias result from the combination of genetic and environmental triggers. The genetic mutations associated with porphyrias — often considered more as predisposing factors than outright causes — can be inherited in one of three manners: autosomal recessive, autosomal dominant, or X-linked.
Each person generally inherits two copies of a given gene — one from their mother and one from their father.
Autosomal recessive disorders occur when both copies of a gene carry a disease-causing mutation, while autosomal dominant disorders need only a single faulty gene copy to arise.
X-linked disorders stem from mutations carried on the X chromosome, of which females receive two, while males inherit only the one from their mother.
Males who inherit the mutation-bearing X chromosome generally develop the associated disease, while females may or may not, depending on which specific X chromosome is active in their cells. (Although females inherit two X chromosomes, only one is active at a time.)
Although inherited genetic mutations underlie all porphyrias, not everyone carrying these mutations will experience symptoms. Mutations are more often seen as predisposing factors that make some people more sensitive to certain environmental disease triggers. Common triggers for porphyrias include excessive alcohol consumption, sunlight exposure, use of certain medications, stress, and fasting.
Genes involved in porphyrias
The extremely rare X-linked protoporphyria (XLP) arises from mutations in the ALAS2 gene. Located on the X chromosome, ALAS2 provides instructions for making an enzyme called delta-aminolevulinic acid (ALA) synthase, which is needed for one of the first steps in the heme production pathway.
Once the ALAS2 enzyme makes ALA, the ALA dehydratase (ALAD) enzyme takes over, converting ALA into porphobilinogen. Mutations in the ALAD gene that prevent this step from happening underlie the autosomal recessive ALAD porphyria.
Porphobilinogen then is converted into hydroxymethylbilane by the porphobilinogen deaminase enzyme (PBGD), also known as hydroxymethylbilane synthase (HMBS). Acute intermittent porphyria (AIP) — an autosomal dominant form of porphyria — occurs when mutations in the associated HMBS gene interfere with this enzyme’s function.
Mutations in UROS and GATA1 genes underlie congenital erythropoietic porphyria (CEP), one of the rarest forms of porphyria. Also known as Günther disease, CEP is characterized by the lack of uroporphyrinogen III synthase, the enzyme that coverts hydroxymethylbilane into uroporphyrinogen. The disease may be inherited in an autosomal recessive manner when caused by UROS mutations, and in an X-linked manner in the case of GATA1 mutations.
Mutations in the UROD gene cause familial porphyria cutanea tarda (PCT), a rarer subtype of PCT, which is the most common form of porphyria. These mutations result in the lack of uroporphyrinogen decarboxylase, the next enzyme in the heme pathway. This autosomal dominant condition accounts for approximately 20% of all PCT cases. More often, PCT arises from a combination of environmental factors and mutations in the HFE gene.
UROD mutations also may cause the autosomal recessive hepatoerythropoietic porphyria (HEP). These genetic changes usually lower UROD activity levels to less than 10% of its normal level, causing porphyrins to accumulate throughout the body, but especially within the bone marrow, red blood cells, liver and skin.
The UROD enzyme helps make coproporphyrinogen, which is converted to protoporphyrinogen by the coproporphyrinogen oxidase (CPOX) enzyme. Mutations in the CPOX gene, which encodes this enzyme, predispose people to hereditary coproporphyria (HCP), in which porphyrins and their precursors tend to accumulate in the liver.
Disease-causing mutations in PPOX, the gene that provides instructions to make the protoporphyrinogen oxidase enzyme, which is needed in the next-to-last step of the heme production process, can result in variegate porphyria (VP).
Finally, mutations in the FECH gene cause a deficiency in ferrochelatase, the enzyme needed in the last step of heme production, resulting in erythropoietic protoporphyria (EPP).
Last updated: April 1, 2021
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