Porphyria: the facts behind the so-called vampire disease

Vampires have existed in myth and folklore for hundreds of years and have a well‑established place in popular culture. Just look at the Halloween costumes on sale at this time of year and you will find vampire capes and plastic fangs among the witches, skeletons and ghosts.

It is possible that a rare inherited blood disorder, called porphyria, gave rise to the myth of vampires and in turn, porphyria has the nickname the vampire disease. Porphyria is actually a group of disorders some of which cause skin blisters and other cutaneous symptoms when skin is exposed to sunlight; it is this fact that is often used to connect porphyria and vampires.

What is porphyria?

As mentioned, porphyria is the name given to a group of related disorders. In all cases, substances called porphyrins build up in the body causing a variety of symptoms. Porphyrins are molecules that undergo a series of reactions catalyzed by enzymes to create heme, a key component of hemoglobin. Hemoglobin is found in red blood cells and its main function is to carry oxygen around the body. Disturbances in the heme production pathway mean that heme cannot be produced despite the presence of porphyrin; this causes porphyrins and precursors to build up in tissues and organs and leads to a heme deficiency [1]. Disease occurs when the porphyrins affect the nervous system or are activated by light.

It is estimated that 1 in 200,000 people have porphyria with geographical differences seen [2].

Types of porphyria

The porphyrias can be divided into two broad categories: acute porphyria and cutaneous porphyria [3].

Acute porphyria

The acute porphyrias have a sudden onset and mainly affect the nervous system, although there may be some skin involvement. In all cases, porphyrins build up in the liver. The acute porphyrias are:

• Acute intermittent porphyria
• ALAD (delta-aminolevulinic acid dehydratase deficiency) porphyria
• Hereditary coproporphyria
• Variegate porphyria

Cutaneous porphyria

The cutaneous porphyrias mainly involve the skin, and porphyrins typically build up in the liver or bone marrow. The cutaneous porphyrias are:

• Porphyria cutanea tarda
• Congenital erythropoietic porphyria
• Hepatoerythropoietic porphyria
• Protoporphyria: erythropoietic protoporphyria and X-linked protoporphyria

Porphyria cutanea tarda is the most common porphyria overall, being responsible for around 20% of cases, and acute intermittent porphyria is the most common type of acute porphyria [4, 5].

Symptoms of porphyria

The common symptom among the porphyrias is red, brown or purple urine. Other symptoms differ between the two types of porphyria [6].

Symptoms of acute porphyria

The symptoms of acute porphyria appear quickly and can be severe. They can last days to weeks and vary in severity and duration [3, 7]. The main symptoms include

• red or brown urine
• abdominal pain, pain in chest, back or extremities
• nausea, vomiting
• constipation, diarrhea
• anxiety, confusion, hallucinations, paranoia, disorientation
• urinary retention or incontinence
• muscle weakness, paralysis
• seizures
• breathing problems
• palpitations
• high blood pressure

Symptoms of cutaneous porphyria

The symptoms of cutaneous porphyria are chronic, meaning they last a long time. They also vary in severity and duration [3, 7]. The main symptoms occur when there is exposure to sunlight and include

• red or brown urine
• sensitivity to sunlight: pain, burning and stinging, redness, swelling and itching
• blisters on exposed skin (not seen in erythropoietic protoporphyria and x-linked protoporphyria)
• fragile skin
• infected blisters
• scarring
• changes in skin color
• excessive hair growth in affected areas

Porphyria and vampire myths

Several symptoms of porphyria have been used to explain some features attributed to modern vampires [8, 9]. At first glance, it is easy to see how the two could have been come intertwined. Some people with porphyria develop blisters and other skin symptoms on exposure to sunlight that may mean they only go out once the sun has gone down. The similarities with vampires, who are famously active at night and cannot tolerate the sun, are clear. Less obviously, the characteristic red color of urine may have been incorrectly assumed to be evidence of drinking blood. Some vampire characteristics, such as fangs or an aversion to garlic, are harder to explain and counter arguments have been published [10].

Causes of porphyria

Most porphyrias are genetic disorders. Pathogenic variants (mutations) in the genes coding for the enzymes involved in making heme result in changes that disrupt the heme production pathway. There are at least 8 enzymes involved in this process, and disruption at any point in the pathway causes porphyrins or porphyrin precursors to build up, potentially leading to porphyria. Each type of porphyria is related to a different enzyme in the process [2, 4].

Genetics

Genetic disorders are hereditary diseases. This means that pathogenic variants, in this case that lead to porphyria, can be passed on from parent to child. Inheritance is autosomal dominant (gene from one parent), autosomal recessive (genes from both parents) or x-linked. See our infographic for an explanation of the modes of inheritance.

The table below summarizes the type of inheritance and the gene involved for each type of porphyria. The genes are in order of the heme production pathway sequence [2, 4, 11].

Type of porphyria	Category	Inheritance	Gene
X-linked protoporphyria	Cutaneous	X-linked	ALAS2
ALAD porphyria	Acute	Autosomal recessive	ALAD
Acute intermittent porphyria	Acute	Autosomal dominant	PBGD (also called HMBS)
Congenital erythropoietic porphyria	Cutaneous	Autosomal recessive*	UROS
Porphyria cutanea tarda	Cutaneous	Autosomal dominant	UROD**
Hepatoerythropoietic porphyria	Cutaneous	Autosomal recessive	UROD
Hereditary coproporphyria	Acute	Autosomal dominant	CPOX
Variegate porphyria	Acute	Autosomal dominant	PPOX
Erythropoietic protoporphyria	Cutaneous	Autosomal recessive	FECH

*Rarely, a GATA1 variant can cause an X-linked form of congenital erythropoietic porphyria [4, 11].

**About 20% of cases have a genetic cause; the remainder are classed as sporadic. Variants in the HFE gene are also associated with porphyria cutanea tarda [12].

Other factors

Inheriting a gene variant for porphyria does not automatically lead to the disease. Other factors may be required before symptoms develop; these include taking certain medication, environmental factors (sunlight, chemicals) or lifestyle changes (diet, alcohol or drug use, stress) [13] and some carriers of a gene variant will never develop porphyria [2].

Modifying genes also play a role in the development and severity of erythropoietic and hepatic porphyrias. In particular, a variant in the CLPX or CLPP genes increases the severity of erythropoietic porphyria [11].

Acquired porphyrias

Porphyria cutanea tarda is often acquired rather than inherited and occurs when the enzyme production is affected by specific triggers. These include excess iron in the body, liver disease, smoking or excessive alcohol consumption [13], medication containing estrogen (hormone replacement or contraceptive pill) or infection [3].

Outlook for people with porphyria

Porphyria cannot be cured, but it can be treated and managed. Healthcare professionals can treat attacks of porphyria and offer lifestyle advice to help prevent attacks or complications, such as limiting sun exposure.

Genetic testing and genetic counseling

Genetic testing enables relatives of someone with porphyria to find out whether they have also inherited the gene variant. Genetic counseling helps people decide if genetic testing is right for them and what the outcome of the test means. The knowledge can help people make choices that limit exposure to potential triggers and therefore avoid the onset of symptoms.

Famous cases of porphyria

The most famous case of porphyria is that of King George III of Great Britain and Ireland who reigned from 1760-1820 [14]. His diagnosis was based on the retrospective analysis of medical records by Macalpine and Hunter in 1966, centuries after his death [15]. The authors also published a follow-up study [16] tracing the inheritance of porphyria through the royal houses, back to Mary Queen of Scots (reign 1542-1567 [17]) and her son, James VI of Scotland and I of England (reign 1567-1625 [18]). The fact that King James had wine colored urine is reportedly well-documented [16].

While this diagnosis effectively removed the suspicion of madness or insanity in the royal bloodline, it was not without its opponents, and other causes such as arsenic poisoning [19] have been suggested. However, evidence has confirmed the presence of porphyria in a descendant of King George III, Princess Charlotte of Prussia (1860-1919). Furthermore, a grandson of King George V, a member of the modern day house of Windsor, Prince William of Gloucester (1941-1972), is also known to have been diagnosed with porphyria [20].

Conclusions

Porphyrias are a group of inherited blood disorders with a variety of symptoms that vary in duration and severity, and which despite the nickname vampire disease, do not account for all reported characteristics of vampires.

In reality, vampires are a myth while the porphyrias are real, albeit rare, conditions. Our increased understanding of rare diseases means that we understand the importance of not stigmatizing or sensationalizing people who have them, and we should not lose sight of what is important, which is to support these people.

References

[1] Porphyria News. What Are Porphyrins and How Are They Connected to Porphyria? Retrieved 21 September 2021 from https://porphyrianews.com/health-insights/what-are-porphyrins-how-do-they-connect-with-porphyria/

[2] NORD Rare disease database. Porphyrias. Retrieved 26 September 2021from https://rarediseases.org/rare-diseases/porphyria/

[3] National Institute of Diabetes and Digestive and Kidney Diseases. Porphyria. Retrieved 21 September 2021 from https://www.niddk.nih.gov/health-information/liver-disease/porphyria

[4] Porphyria News. Causes of porphyria. Retrieved 21 September 2021 from https://porphyrianews.com/causes-of-porphyrias/

[5] Porphyria News. Types of porphyria. Retrieved 26 September 2021 from https://porphyrianews.com/types-of-porphyria/

[6] Porphyria News. What is Porphyria? Retrieved 26 September 2021 from https://porphyrianews.com/what-is-porphyria

[7] Porphyria News. Symptoms of Porphyria. Retrieved 21 September 2021 from https://porphyrianews.com/symptoms-porphyria/

[8] Hefferon M. 29 June 2020. Vampire myths originated with a real blood disorder. Queen’s University. Retrieved 21 September 2021 from https://www.queensu.ca/gazette/stories/vampire-myths-originated-real-blood-disorder

[9] Snider L. 28 October 2020. 3 Real Diseases That Influenced Vampire Folklore. Visible Body Blog. Retrieved 21 September 2021 from https://www.visiblebody.com/blog/3-real-diseases-that-influenced-vampire-folklore

[10] Cox AM. Porphyria and vampirism: another myth in the making. Postgrad Med J 1995 71:643-4. doi: 10.1136/pgmj.71.841.643-a. PMID: 7494765; PMCID: PMC2398345. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2398345/pdf/postmedj00035-0005b.pdf

[11] Yasuda M et al. Recent advances on porphyria genetics: Inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes. Mol Genet Metab 2019 128(3):320-331. doi: 10.1016/j.ymgme.2018.11.012. Epub 2018 Nov 30. PMID: 30594473; PMCID: PMC6542720. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542720/

[12] NIH National Library of Medicine, Medline Plus. Porphyria. Retrieved 26 September 2021 from https://medlineplus.gov/genetics/condition/porphyria/

[13] Mayo Clinic. Porphyria. Retrieved 26 September 2021 from https://www.mayoclinic.org/diseases-conditions/porphyria/symptoms-causes/syc-20356066

[14] George III (r. 1760-1820) Retrieved 22 September 2021 from https://www.royal.uk/george-iii

[15] Macalpine I, Hunter R. The “insanity” of King George 3d: a classic case of porphyria. Br Med J 1966 1:65-71. doi: 10.1136/bmj.1.5479.65. PMID: 5323262; PMCID: PMC1843211. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1843211/pdf/brmedj02532-0029.pdf

[16] Macalpine I et al. Porphyria in the royal houses of Stuart, Hanover, and Prussia. A follow-up study of George 3d’s illness. Br Med J 1968 1:7-18. doi: 10.1136/bmj.1.5583.7. PMID: 4866084; PMCID: PMC1984936. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1984936/pdf/brmedj02065-0057.pdf

[17] Mary, Queen of Scots (r.1542-1567) Retrieved 22 September 2021 from https://www.royal.uk/mary-queen-scots-r1542-1567

[18] James VI and I (r. 1567-1625) Retrieved 22 September 2021 from https://www.royal.uk/james-vi-and-i-r-1567-1625

[19] Cox TM et al. King George III and porphyria: an elemental hypothesis and investigation. The Lancet 2005 366:332-335 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)66991-7/fulltext

[20] Bulletin the University of Sussex newsletter. 25 June 1999. The Royal Family’s Toxic Time-Bomb. Retrieved 22 September 2021 from https://archive.sussex.ac.uk/news/bulletin/bulletin/www.sussex.ac.uk/internal/bulletin/archive/25jun99/article1.html