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Variegate porphyria
This rare genetic condition occurs due to a deficiency in an enzyme involved in haem production. It can lead to sudden, severe symptoms affecting the nervous system and digestive tract, as well as chronic skin problems, typically in adulthood.
Overview
Variegate porphyria (VP) is one of the acute hepatic porphyrias, a group of conditions caused by problems in the body's haem production pathway [PMID:33675073]. Haem is a vital component of haemoglobin, which carries oxygen in the blood, and is also found in other important proteins. In VP, there is a deficiency in the enzyme protoporphyrinogen oxidase (PPOX). This enzyme is crucial for one of the steps in converting precursor molecules into haem. When PPOX is deficient, certain precursor molecules, called porphyrin precursors and porphyrins, can build up in the body, leading to the condition's varied symptoms [PMID:28135890].
VP is primarily characterised by two main types of symptoms: acute neurovisceral attacks and chronic skin involvement. Acute attacks can be triggered by various factors, including certain medications, alcohol, fasting, infections, and hormonal changes. During these attacks, individuals can experience severe abdominal pain, neurological dysfunction, and psychiatric symptoms. The skin symptoms, often presenting as fragility and blistering, are triggered by exposure to sunlight or certain types of artificial light.
Symptoms & clinical features
The symptoms of variegate porphyria can be quite diverse and may vary significantly from person to person. Many individuals with the genetic change never develop symptoms, a phenomenon known as reduced penetrance. When symptoms do occur, they typically manifest in adulthood, though onset can occasionally be earlier.
Acute attacks are a hallmark of VP and can be life-threatening if not managed appropriately. These attacks often involve severe, unlocalised abdominal pain, which can be accompanied by nausea, vomiting, and constipation. Neurological symptoms may include muscle weakness, ranging from mild limb weakness to paralysis, and can affect breathing. Psychiatric symptoms are also common during acute attacks, such as anxiety, depression, hallucinations, and confusion [PMID:28135890]. High blood pressure and a fast heart rate are also frequently observed. These acute episodes are often precipitated by factors like certain drugs, alcohol, stress, fasting, or infections.
Chronic skin symptoms are another prominent feature, typically affecting areas exposed to the sun. These include skin fragility, blistering, increased hair growth (hirsutism), and changes in skin pigmentation. These skin manifestations are not typically present during acute attacks but can occur independently. Some individuals may experience only skin symptoms, others only acute attacks, and some may have both.
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Affected organs
Variegate porphyria primarily affects the nervous system, digestive system, and skin. During acute attacks, the accumulation of porphyrin precursors can be toxic to the nervous system, leading to neurological symptoms such as peripheral neuropathy (damage to nerves outside the brain and spinal cord) and central nervous system effects, including psychiatric disturbances. The severe abdominal pain experienced during attacks is thought to be due to effects on the autonomic nervous system, which controls involuntary bodily functions.
The digestive system is significantly impacted during acute attacks, with symptoms like severe abdominal pain, nausea, vomiting, and constipation. The liver is the primary site where haem synthesis occurs and where the deficient PPOX enzyme leads to the build-up of porphyrin precursors. The skin is affected due to the photosensitive properties of the accumulating porphyrins, which react with light to cause damage, leading to fragility and blistering in sun-exposed areas.
Risks & severity
The severity of variegate porphyria symptoms can vary widely, even within the same family. Many individuals who inherit the genetic change for VP never develop symptoms in their lifetime. For those who do, symptoms typically begin in adulthood, often between the ages of 18 and 40, though onset can occur at any age after puberty. Acute attacks can be severe and require urgent medical attention; if untreated, they can lead to significant neurological damage, including paralysis, and can be fatal. Long-term complications, such as chronic kidney disease and liver cancer (hepatocellular carcinoma), have been reported in some individuals with VP, particularly those who experience recurrent acute attacks [PMID:28135890].
The prevalence of variegate porphyria varies globally. In South Africa, it is estimated to affect approximately 1 in 3,000 individuals, making it one of the more common porphyrias in that population. The exact prevalence in the UK and other populations is not as well established but is thought to be much lower. Identification of the genetic change allows for careful monitoring and avoidance of triggers, which can significantly reduce the risk and severity of symptoms.
Genetic causes
Variegate porphyria is caused by pathogenic variants in the *PPOX* gene. This gene provides instructions for making an enzyme called protoporphyrinogen oxidase, which plays a critical role in the haem biosynthesis pathway. This pathway is a series of eight steps that convert small molecules into haem, a molecule essential for red blood cells and other proteins throughout the body [PMID:33675073].
Specifically, the PPOX enzyme is responsible for the seventh step in this pathway, converting protoporphyrinogen IX into protoporphyrin IX. When a pathogenic variant in *PPOX* reduces the enzyme's activity, protoporphyrinogen IX and other porphyrin precursors accumulate in the liver. These accumulated precursors, especially when oxidised to porphyrins, are believed to be responsible for the symptoms of VP. The specific mechanism by which these molecules cause neurological damage during acute attacks is complex and continues to be an area of research.
- PPOX protoporphyrinogen oxidase
Inheritance pattern
Variegate porphyria is inherited in an autosomal dominant pattern. This means that a person needs to inherit only one copy of a changed *PPOX* gene to have an increased risk of developing the condition. The changed gene can be inherited from an affected parent or, rarely, can arise spontaneously as a new (de novo) genetic change in the affected individual [PMID:33675073].
If one parent has a pathogenic variant in *PPOX*, there is a 50% chance with each pregnancy that their child will inherit the changed gene. It is important to remember that inheriting the gene change does not guarantee that a person will develop symptoms; many individuals with the gene change remain asymptomatic throughout their lives. Genetic counselling is available to discuss the implications of autosomal dominant inheritance for individuals and their families.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosing variegate porphyria typically involves a combination of clinical evaluation, biochemical tests, and genetic testing. During an acute attack, diagnostic suspicion often arises from the characteristic constellation of severe abdominal pain, neurological symptoms, and psychiatric disturbances. Biochemical tests, such as measuring porphyrin precursors (e.g., porphobilinogen and delta-aminolevulinic acid) and porphyrins in urine, faeces, and plasma, are crucial for confirming an acute porphyria and differentiating between the types [PMID:28135890]. Elevated levels of specific porphyrins are indicative of VP.
Confirmation of variegate porphyria is achieved through genetic testing, which identifies pathogenic variants in the *PPOX* gene. This can be arranged through the NHS Genomic Medicine Service (GMS) following referral by a specialist, often a clinical geneticist or metabolic specialist. The relevant NHS Genomic Medicine Service 'R' code for genetic testing for acute porphyrias, including VP, would typically be R356 Acute Porphyrias. Genetic testing can also be offered to asymptomatic relatives of an affected individual to identify those who carry the gene change and may be at risk, enabling them to take preventive measures.
Management & lifestyle
The management of variegate porphyria focuses on preventing acute attacks, treating symptoms during an attack, and managing chronic manifestations like skin sensitivity. Prevention involves identifying and avoiding known triggers, such as certain medications (a comprehensive list of safe and unsafe drugs is available from porphyria specialist centres), alcohol, recreational drugs, fasting, and excessive stress. Individuals are typically advised to maintain a balanced diet and avoid crash dieting.
During an acute attack, treatment often involves hospitalisation and administration of intravenous haem arginate, which helps to suppress the production of the toxic porphyrin precursors. Pain relief, anti-sickness medication, and management of neurological symptoms are also crucial during an attack. For skin manifestations, protective measures against sunlight, such as sun-protective clothing and high-SPF sunscreens, are recommended. Regular follow-up with a specialist team, often including a metabolic specialist, dermatologist, and clinical geneticist, is important for ongoing monitoring and support. Genetic counsellors can provide valuable information and support to individuals and families affected by VP, helping them understand the condition and its inheritance.
UK care pathway
In the UK, the care pathway for individuals with suspected or confirmed variegate porphyria typically begins with referral to a specialist centre. This often involves a clinical geneticist, metabolic specialist, or an endocrinologist with expertise in rare metabolic conditions. Genetic testing is provided through the NHS Genomic Medicine Service (GMS) and is generally requested by these specialists. The relevant 'R' code for genetic testing for acute porphyrias in the GMS is R356. Following a diagnosis, ongoing care is often managed by a multidisciplinary team, potentially including neurologists and dermatologists, to address the diverse symptoms. Genetic counsellors play a key role in explaining the condition, its inheritance patterns, and the implications for family members, as well as providing psychological support.
Frequently asked questions
What triggers an acute attack in variegate porphyria?
Acute attacks can be triggered by various factors, including certain medications, alcohol consumption, fasting or restrictive diets, infections, surgical procedures, and hormonal changes, such as those occurring during menstruation. Avoiding known triggers is a key part of managing the condition.
Can variegate porphyria be cured?
Currently, there is no cure for variegate porphyria. Management focuses on preventing acute attacks, treating symptoms when they occur, and managing chronic issues like skin sensitivity. Research into new therapies is ongoing.
If I have the gene change, will I definitely get symptoms?
No, not everyone who inherits a pathogenic variant in the *PPOX* gene will develop symptoms. This is known as reduced penetrance. Many individuals with the genetic change remain asymptomatic throughout their lives, although they can still pass the gene change to their children.
How does variegate porphyria affect daily life?
For individuals with symptoms, variegate porphyria can significantly impact daily life. Managing the condition often involves careful avoidance of triggers, regular medical monitoring, and being prepared for potential acute attacks. Skin sensitivity requires precautions like sun protection. Support from specialist teams and genetic counsellors can help individuals navigate these challenges.
Is genetic testing available for family members?
Yes, once a pathogenic variant in the *PPOX* gene has been identified in an affected individual, predictive genetic testing can be offered to asymptomatic family members. This allows at-risk relatives to know their genetic status and take appropriate preventive measures if they carry the gene change.
References
- Adam MP, Bick S, Mirzaa GM. Variegate Porphyria. 1993. PMID: 23409300
- Stölzel U, Doss MO, Schuppan D. Clinical Guide and Update on Porphyrias. Gastroenterology. 2019. PMID: 31085196
- Muschalek W, Hermasch MA, Poblete-Gutiérrez P. The Porphyrias. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 2022. PMID: 35304965
- Besur S, Schmeltzer P, Bonkovsky HL. Acute Porphyrias. The Journal of emergency medicine. 2015. PMID: 26159905
- Wang B, Bonkovsky HL, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review. Gastroenterology. 2023. PMID: 36642627
- Schulenburg-Brand D, Katugampola R, Anstey AV. The cutaneous porphyrias. Dermatologic clinics. 2014. PMID: 24891059
- Marques I, Marcos P. Acute hepatic porphyrias. Porto biomedical journal. 2025. PMID: 41287633
- Kothadia JP, LaFreniere K, Shah JM. Acute Hepatic Porphyria. 2023. PMID: 30725863