Porphyrias are a series of genetically-inherited diseases caused by malfunctions in the body’s production of heme, the molecule used to carry oxygen in the blood. Porphyria comes from the Greek word porphyra, meaning purple pigment, which refers to the purplish glow the urine of porphyria patients emits when exposed to light (Signal, 1993). Porphyrias are generally divided into two classes: erythropoietic and hepatic. Erythropoietic porphyrias are characterized by increased sensitivity to sunlight that causes chronic blistering (Figure 1) (Signal, 1993). Hepatic porphyrias, on the other hand, involve attacks of intense abdominal pain and neurological dysfunction, such as seizures (Signal, 1993). Variegate porphyria (VP) is classified as a hepatic porphyria, however it is unusual in that patients can also exhibit erythropoietic symptoms.
While VP is quite rare, it is most common in South Africa where 1,200/1 million people are diagnosed as opposed to only 7/1 million in Europe (Hift, 2012). The prevalence of VP in South Africa is somewhat coincidental in that it was first brought to the country in 1688 by Dutch settlers of Cape Town. Today, >95% of VP cases in South Africa can be traced back to this original couple (Hift, 2012).
The specific cause of VP is a mutation in the enzyme protoporphyrinogen oxidase (PPOX), which makes protoporphyrinogen IX in the second-to-last step in heme synthesis (Figure 2). This causes heme precursors to accumulate in the body – typically in fat, the liver, and even the brain.
Since VP is so uncommon, diagnosis can be difficult, and genetic testing is often required (Signal, 1993). While the disease can be managed and some treatments are available, no cure has been developed to date. Since VP involves both erythropoietic and hepatic symptoms, care must be taken to handle both aspects of the disease. Blistering that occurs upon exposure to sunlight can be limited by wearing protective clothing and reducing exposure to UV rays (Signal, 1993). Hepatic attacks are often induced by substances such as barbiturates, alcohol, and certain antibiotics; therefore, avoiding these materials is important as well (Signal, 1993). In the event of an attack, patients are often administered glucose and/or hemin intravenously, which work to stop heme synthesis and prevent the accumulation of unused metabolites (Signal, 1993).
Recent advances in VP treatment demonstrate that antioxidants such as vitamins E and C can help reduce the occurrence and severity of hepatic attacks (Ferrer et al. 2013). While this work is a step in the right direction, treatments available for VP remained limited due to its rarity. Therefore, a deeper understanding of the disease is necessary in order to provide better ways for handling it in the clinic.
Check out the links below for more information:
History and Metabolic Context of Variegate Porphyria
The Molecular Bases of Variegate Porphyria
Treatment and Management of Variegate Porphyria
This was a great introduction to you paper! What are the toxic metabolites that accumulate? Is there any information on the mechanism by which the metabolite induces neurological symptoms like seizures? Also, I noticed that Ferrer’s paper discusses the utility of vitamins E and C specifically as antioxidants– is reactive oxygen species accumulation a significant part of the pathology of this disease?
Thanks Becca! The metabolites that accumulate tend to be protoporphyrinogen IX, the substrate of PPOX, and the porphyrin precursors aminolevulinate and porphobilinogen.
The neurological effects of the disease are not well understood, but it is believed that they result from the ability of aminolevulinate to inhibit the release of GABA.
In regards to reactive oxygen species (ROS), since porphyrins have extensive conjugation, they are able to absorb UV light and form ROS. Since porphyrins are large and hydrophobic, they can accumulate in fat at high levels, as is the case in VP patients. Since UV light penetrates best near the skin, and fat is a major component of the integumentary system, this process of ROS formation results in the cutaneous symptoms of VP I described above such as chronic blistering.
Hey, super thorough and yet succinct. I loved it. I was curious about the metabolites. Not necessarily what they are, since that might be a bit much to go into in the title page, especially for a lay audience, but where do they accumulate? The stomach? Abdominal muscle?
Otherwise, really well written and easy to follow.
Thanks Ed, it depends on the metabolite. For the most part, they accumulate in fat and/or the liver due to their size and lipophilicity. However, some of the smaller precursors (aminolevulinate and porphobilinogen) can actually cross the blood brain barrier and accumulate in the brain.
I think that this is a great cover page! The content is all here (the history, mechanism of disease, as well as treatments) in a manner that is very easy to follow and I think that terms are adequately linked to the biochem primer. I was really interested in looking at the Signal and Anderson 2013 paper to see what specific mutation in PPOX is the cause for it’s malfunction. I feel that this is a much more relevant topic to the mechanism page of the website but I was curious to what specific mutation (it seems to be a clear single mutation) is the cause and why it stops the function of the enzyme. I was wondering if there was crystal structure data showing the binding of PPOX with it’s substrate and a comparative one to show the exact reason it doesn’t work. Again, this is info for the mechanism section of the website but I am just curious. Overall I think that this is a really effective cover page and that it makes me want to learn more about this disease.
Hi Mark, thanks for the comment!
There are actually >130 mutations that can cause VP, but the most common one is called the founder mutation as it originated from the Dutch settlers of South Africa I mentioned above. This is a R59W mutation that does not affect PPOX’s ability to bind its substrate, but instead reduces the enzyme’s affinity for FAD. Though the mechanism of PPOX is not completely understood, it is known to require both FAD and O2. Studies suggest that the FAD is required to transfer electrons from protoporphyrinogen IX (the substrate) to O2, forming both the product and H2O2. Since the R59W mutation replaces a residue with a positively charged side chain for one with a large hydrophobic indole ring, the hydrophilic pocket in which FAD normally resides is distorted, lowering its ability to bind. I will have more specific information about this in the molecular bases part of my page, but that’s the general idea of what’s happening.
This disease is very interesting. Also, this was a very well written title page. I enjoyed how the biochemistry resulted in the accumulation of toxic metabolites. I was wondering how do these metabolites lead to the actual phenotypes that you described? What is the connection between the skin blistering and accumulation of the heme metabolites? Also, why does it make the urine turn purple? All of these questions I am sure you will answer in the following sections, but it would be interesting to hear a little bit about the connection earlier. Overall the title page was very well written. I look forward to hearing more about this disease.
Hi Ian, thanks for your comment.
Both of your questions have to do with the ability of porphyrins to absorb UV light due to their extensive conjugation. In regards to the skin blistering, excess porphyrins are able to accumulate in fat near the skin where they are readily exposed to UV light. When they absorb UV radiation, they are able to form reactive oxygen species that then induce blistering and so forth by oxidative damage of skin cells.
As you may know, conjugation also can allow molecules to fluoresce. In the case of the porphyrins used to make heme, their conjugation enables them to give off a purple fluorescence when exposed to light based off the specific electronic transitions that occur within these molecules.
Well written title page, it was easy to follow. This disease is really interesting. I am curious about a couple of things. So VP results in both cutaneous and acute porphyrias, but the root cause is a mutation in PPOX. How does the mutation in just this one protein result in both symptoms that are often a result of two different genetic mutations? I would also like to hear a little more about the metabolites. What exactly is meant by “previous” metabolites and how do some of these metabolites lead to some of the symptoms you talked about? I’m assuming they are the metabolites involved in the heme formation pathway. For a lay audience, I think this could be a little confusing as to what is meant by previous metabolites. Also, can you expand just a little bit more about how vitamins E and C may help to the occurrence and severity of acute attacks?
Thanks for your comment Dom, good point about the “previous” metabolites, I can understand how that might be confusing!
While the exact mechanisms of VP are not completely understood, it is known that both porphyrin and porphyrin precursors involved in the heme biosynthetic pathway can accumulate in the body of patients with VP. Essentially, the porphyrins are able to accumulate in fat and/or the liver, resulting in cutaneous symptoms and the abdominal pain of acute attacks. On the other hand, porphyrin precursors like aminolevulinate can cross the blood brain barrier and induce neurological effects like seizures.
The neuological effects of aminolevulinate is not really understood, but most of the symptoms associated with VP have to do with the ability of porphyrins to produce reactive oxygen species by the absorption of UV light (which is facilitated by their conjugation). These ROS then induce oxidative damage in cells that result in both acute and cutaneous symptoms. Since both vitamins E and C act as cellular reductants, they are able to treat VP by reacting with and destroying the ROS formed.
This was a very well written and concise page, well done! As others have said the page covers the various aspects of the disease very well, and does so in a manner that is accessible. I do have a question concerning this disease, though. You mention that there are neurological affects of this disease, and that in the variegate form both the skin related and neurological effects are present. I am curious as to what is the common molecule between these two symptoms, and if it is simply a matter of where the molecule accumulates, or if there are multiple factors.
Thanks Evan. Well all symptoms of porphyrias, including VP, are due to an accumultion of heme precursors accumulating in the body. The neurological symptoms are less understood than the skin-related ones, but they believe it has to do with aminolevulinate inhibiting GABA release in the brain. The cutaneous symptoms, however, are a result of ROS formation by porphyrins. Since these are highly conjugated molecules, they are able to absorb UV light and make superoxide, which can cause oxidative damage, which results in the chronic blistering and other skin conditions of the disease. So, the answer to your question is that there is a single molecule causing both sets of symptoms, but instead different precursors to heme that accumulate in different areas of the body due to decreased PPOX activity.
I noticed that you found that South Africa has the largest occurrence of variegated Porphyria, I would be interested to know what the rate of occurrence would be along the same latitude across the globe. Is there a correlation to proximity to the equator and the increased sensitivity to light?
Thanks for your question, Rick. The reason variegate porphyria is most common in South Africa doesn’t have much to do with its proximity to the equator. Instead, it has to do with the fact that it was brought to South Africa by some Dutch settlers who resided in Cape Town. Most of their descendants who inherited the gene that causes variegate porphyria remained in South Africa and continued passing it on. This eventually resulted in thousands of descendants who have the same genetic mutation.
While there are certainly cases of variegate porphyria outside of South Africa, this passing of the variegate porphyria gene within the family tree caused it to be quite concentrated in this area of the world.