History and Metabolic Context of Variegate Porphyria

Porphyrias – Heme Biosynthesis Gone Wrong

The cofactor heme plays a number of roles in the body including carrying oxygen, performing enzymatic activity, and providing oxidizing power to cytochromes. Heme is made in the liver and erythropoietic tissues by an eight-step enzymatic pathway, half of which occurs in the mitochondria – steps 1, 6, 7, and 8 – while the remaining reactions take place in the cytosol (Scheme 1) (Bhagavan 2011). The first step of this process, catalyzed by aminolevulinate synthase (ALAS), is the rate-limiting step and can be allosterically inhibited by the molecule hematin, an oxidized form of heme (Bhagavan 2011). There are two isoforms of ALAS, ALAS-1 and ALAS-2, the former regulates heme synthesis in the liver while the latter is used in erythropoietic tissues (Bhagavan 2011).

Scheme 1. Heme biosynthesis
Scheme 1. Heme biosynthesis.

Mutations in the genes coding any of the eight enzymes involved result in a class of disease known as porphyrias. These diseases are characterized by the accumulation and excretion of excess porphyrins and their precursors (Bhagavan 2011). As these molecules play no biological role aside from the production of heme, their accumulation in the body tends to produce negative effects due to their reactivity. The name porphyria comes from the Greek porphyra, meaning purple, which refers to the purple fluorescence given off by the urine of porphyria patients when exposed to light due to the fluorescent nature of porphyrins (Figure 1) (Singal, 1993).

Figure 1. Comparison between fluorescent urine of a VP patient (left) and that of a healthy individual (right).
Figure 1. Comparison between fluorescent urine of a VP patient (left) and that of a healthy individual (right). Source: http://img.medscape.com/pi/emed/ckb/dermatology/1048885-1094517-1113.jpg

Variegate Porphyria – A Class of its Own

Porphyrias are divided into two classes based upon the location in which the excess heme precursors accumulate, which is dictated by differences in their solubility and size (Bhagavan 2011). In erythropoietic porphyrias, the porphyrin precursors to heme accumulate near the skin due to their lipophilicity. Due to their ability to absorb UV light, based on their conjugation, they can induce oxidative damage by the formation of free radicals (Sassa, 2006). This causes patients to experience increased sensitivity to light, often resulting in chronic blistering upon UV exposure. Hepatic porphyrias, on the other hand often involve excessive amounts of the porphyrin precursors aminolevulinate (ALA) and/or porphobilinogen (PBG). The mechanism by which these molecules induce symptoms such as intense abdominal pain and neuropathy is not well understood, but is proposed to involve the ability of ALA to hit GABA receptors and induce oxidative stress in neuronal cells (Meyer 1998).

Variegate porphyria (VP), results from a decrease in activity of protoporphyrinogen oxidase (PPOX), which catalyzes the second-to-last step of heme synthesis. Though VP is categorized as a hepatic porphyria, patients exhibit an accumulation of ALA, PBG, and protoporphyrinogen, resulting in the presence of both erythropoietic and hepatic symptoms (Sassa, 2006). Specifically, symptoms of VP include: skin fragility, bullae, hyperpigmentation, hypertrichosis, and attacks of abdominal pain, neuropathy, hypertension, and tachycardia (Siegesmund 2010) (Figures 2a-b). These symptoms can be exacerbated by exposure to sunlight, fasting, sulfonamide antibiotics, barbiturates, and alcohol which either induce the formation of reactive oxygen species or increase the rate of heme biosynthesis (Singal, 1993).

Figure 2. Bullae on the ankle of a patient with VP.
Figure 2a. Bullae on the ankle of a patient with VP. Source: Chen (2009).
Figure 3. Hyperpigmentation on the arm of a patient with VP.
Figure 2b. Hyperpigmentation on the arm of a patient with VP. Source: Chen (2009).

Diagnosis of Variegate Porphyria – Difficulties with Rarity

Variegate porphyria is quite rare, making its diagnosis and treatment difficult, especially for inexperienced physicians. However, VP is most common in South Africa where roughly 1,200/1 million people are diagnosed as opposed to only 7/1 million in Europe (Hift, 2012). The prominence of VP in South Africa is somewhat coincidental, and can be traced back to Dutch settlers of Cape Town who landed in 1688 (Hift, 2012). Today, over 95% of the cases in South Africa can be attributed to the specific mutation first brought over by this couple in the late 17th century; because of this, it has become known as the “founder mutation” (Hift, 2012).

Typically, people are not diagnosed with VP until all other possibilities are ruled out, however when patients present symptoms that suggest this disease, the presence of a porphyria can be tested by assessing levels of heme precursors in both urine and feces (Singal, 1993). A more helpful test involves fluorescence scanning of blood plasma as a characteristic peak from 626-628 nm is typically observed in patients with VP (Sigesmund, 2010). In order to definitively diagnose the patient with VP, biochemical tests, such as sequence analysis, must be done to prove the individual has a mutation in the PPOX gene (Singal, 1993).