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Variegate Porphyria (VP)

Variegate Porphyria is a rare genetic metabolic disorder characterized by deficient function of the enzyme protoporphyrinogen oxidase (PPO or PPOX). This deficiency is caused by heterozygous mutations in the PPOX gene and leads to the accumulation of certain chemicals called porphyrins and toxic porphyrin precursors in the body, which, in turn, can potentially result in a variety of symptoms. Specific symptoms can vary greatly from one person to another. Some affected individuals present with skin symptoms, some with neurological symptoms and some with both. Blistering and fragility of sun-exposed skin are the most common skin (cutaneous) symptoms. Common neurological symptoms include abdominal pain, nausea, vomiting, constipation, extremity pain and weakness, anxiety, restlessness and convulsions. Many different PPOX mutations have been identified in different families with Variegate Porphyria. The genetic mutation in a family is inherited as an autosomal dominant trait, but many individuals who inherit a PPOX mutation do not develop any symptoms (asymptomatic).

Acute attacks almost always start with severe pain in the abdomen but sometimes in the chest, back, or thighs, and are often accompanied by nausea, vomiting, and constipation. Heart rate and blood pressure are commonly increased. These symptoms and signs are all due to the effects of the disease on the nervous system. Confusion, convulsions, and muscular weakness, due to impairment of the nerves controlling the muscles, may lead to paralysis. An acute attack usually lasts for days or weeks. Recovery from severe paralysis is generally slow.

VP is especially common in South Africa in individuals of Dutch ancestry, where it has been estimated that 3 in 1,000 of the white population are affected. It is much less prevalent in other countries. Like AIP and HCP, it is an autosomal dominant disorder, meaning that a mutation is present in only one of the pair of PPOX genes.

Some reports suggest that Variegate Porphyria affects more women than men. The incidence is estimated to occur in 1 in 100,000 individuals in the general population in European populations. The disorder occurs with the greatest frequency in South Africa in individuals of Dutch ancestry due to a founder effect. A founder effect is when a small isolated population of settlers (founders) expands over several generations leading to a high prevalence of a genetic trait. Most individuals with Variegate Porphyria in South Africa carry the same PPOX mutation and are descendents of a Dutch settler from the late 1600s. The incidence of Variegate Porphyria in South Africa among Caucasians is estimated to be 1 to 3 in 1,000 individuals.

Although, in most cases, the symptoms of Variegate Porphyria occur after puberty or later, very rare cases have been described where symptoms developed during infancy or childhood. Most such cases are homozygous cases who have inherited a PPOX mutation from each parent. Homozygous cases may have impaired mental development and photosensitivity, but acute attacks are not prominent.

Synonyms of Variegate Porphyria
  • porphyria variegate
  • VP

CAUSE

VP is caused by a mutation in the enzyme protoporphyrinogen oxidase (PPOX), which is part of the heme biosynthesis pathway that produces porphyrins and heme. Acute attacks are similar to those in AIP and HCP but are unusual. A more common sign of the disease is blistering skin lesions, which are chronic in many people with VP.

As in HCP, acute attacks of VP are unusual except in the presence of environmental activating factors, such as drugs, hormones, and dietary changes. See HCP for discussion of these issues.

Variegate Porphyria is caused by mutations of the PPOX gene. A PPOX genetic mutation is inherited as an autosomal dominant trait within a family, meaning that a single mutation is inherited from one parent and, in the presence of other triggering factors, is sufficient to cause the disease. The abnormal gene can be inherited from either parent, or on rare occasions can be the result of a new de novo mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

The PPOX gene contains instructions for creating PPOX, one of the eight enzymes necessary for the production of heme. Heme is an iron-containing porphyrin (iron protoporphyrin) and is a part of many heme-containing proteins (hemoproteins) in the body. Hemoproteins interact with oxygen and some are involved in electron transport and energy metabolism. The best-known hemoprotein is hemoglobin, which is made in the bone marrow, makes red blood cells red, and transports oxygen from the lungs to other tissues. However, the bone marrow and hemoglobin are not affected in Variegate Porphyria. In this condition the heme pathway in the liver, which makes heme for other important hemoproteins, is affected.

Mutations of the PPOX gene result in deficient levels of PPOX, which, in turn, disrupts the biochemical process to create heme in the liver. This disruption causes porphyrins and porphyrin precursors to accumulate in the liver and these are then transported to other parts of the body to affect the nervous system and skin causing the varied symptoms of an acute Porphyria attack.

A variety of different triggers are known to lead to attacks in individuals with Variegate Porphyria. Many of these triggers act by increasing heme synthesis in the liver, which makes the PPOX deficiency more significant and increases the accumulation of porphyrins and porphyrin precursors such as porphobilinogen (PBG) and neurotoxic aminolevulenic acid (ALA). As noted above, triggers include a variety of drugs, hormones, (especially progesterone), reduced intake of calories and carbohydrate, alcohol, and stress induced by infection or other illness.

SIGNS AND SYMPTOMS

The symptoms and severity of Variegate Porphyria can vary greatly from one person to another. Symptoms are rarely apparent before puberty. Affected individuals often develop skin (cutaneous) or neurological abnormalities or both. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician about their specific case, associated symptoms and overall prognosis.

Many individuals with Variegate Porphyria may not develop any notable symptoms (asymptomatic) for all or most of their lives. Other individuals can develop a variety of symptoms. Cutaneous symptoms are chronic and commonly last for months or years. Neurological symptoms usually occur as acute attacks lasting days or weeks and occasionally become chronic. Acute attacks can be severe and may occur in the absence of skin abnormalities.

Symptoms during an attack may include intense abdominal discomfort or pain, which is usually steady but may be cramping, nausea, vomiting, constipation (occasionally diarrhea) and trouble urinating. These symptoms are due to effects on the nerves of the bowel and bladder. The central nervous system is often affected with insomnia, restlessness, agitation, confusion, hallucinations and convulsions. The level of sodium in the blood may decrease and cause convulsions. The peripheral nerves are affected, leading to severe pain in the extremities, back or chest and, especially with more prolonged attacks, paralysis of muscles. This may progress to involve all extremities and the muscles that control breathing. The urine may be reddish due to increased porphyrins, and dark due to porphobilin, which is a brownish degradation product of PBG.

Increases in heart rate and blood pressure are very common on examination during attacks. Fever is usually absent or slight, because the neuropathy is not inflammatory. Reflexes may be increased initially and decreased or absent if motor neuropathy advances.

A variety of triggers are known to set off an acute attack. These include a variety of drugs, steroid hormones alcohol, decreased intake of calories or carbohydrates, and metabolic or possibly psychological stress. Women may have attacks during the second half of the menstrual cycle when progesterone levels are highest. In some cases, no trigger can be identified.

Chronic skin abnormalities result from photosensitivity, a condition in which the skin is abnormally sensitive to sunlight, causing blistering skin lesions. Symptoms include abnormally fragile skin, blisters (bullae), milia, which are tiny, white bumps or cysts, and excessive hair growth (hypertrichosis). Blisters are slow to heal and can scar leaving patches of skin that are abnormally dark (hyperpigmentation) or light (hypopigmentation). Skin symptoms may be less common in individuals who live in nontropical climates. Some individuals with Variegate Porphyria only develop skin abnormalities, others only develop neurological symptoms, and some have both.

Individuals with Variegate Porphyria are at an increased risk for developing a form of liver cancer known as hepatocellular carcinoma. There is also risk of developing chronic kidney disease.

DIAGNOSIS

Urine ALA and PBG are increased during attacks, but as in HCP, these may increase less and decrease more rapidly than in AIP. Plasma porphyrins are frequently increased in VP, in contrast to AIP and HCP, and the plasma of VP patients displays a distinctive fluorescence peak, which is diagnostic. Fecal porphyrins are also elevated and are predominantly coproporphyrin III and protoporphyrin.

The prognosis is usually good if the disease is recognized and treated promptly, before nerve damage develops. Although symptoms usually resolve after an attack, recovery of neuromuscular function (in a severe case) may require several months. Mental symptoms may occur during attacks but are not chronic. Premenstrual attacks often resolve quickly with the onset of menses.

A diagnosis of Variegate Porphyria is suspected based upon symptoms and examination of the skin. None of the symptoms are specific, so the diagnosis must be confirmed by biochemical testing. In the evaluation of neurological symptoms, the other acute porphyrias need to be considered. For initial screening, a spot urine sample should be obtained for measurement of PBG, ALA and total porphyrins. If none of these is elevated, acute porphyrias can be excluded as a cause of recent or concurrent symptoms. PBG measurement is most important and specific for acute porphyrias. However, PBG and ALA may be less elevated and return to normal more quickly after an attack of Variegate Porphyria (or Hereditary Coproporphyria) than in Acute Intermittent Porphyria. Therefore, measurement of total urine porphyrins is important, keeping in mind that an elevation of urine porphyrins can occur in many other medical conditions.

When blistering skin manifestations are present, Porphyria Cutanea Tarda, Hereditary Coproporphyria and even Congenital Erythropoietic Porphyria are possibilities to differentiate. Measurement of plasma and fecal porphyrins and determining the wavelength of the fluorescence peak of plasma porphyrins is useful in differentiating these conditions.

Molecular genetic testing to identify a PPOX mutation is recommended for all biochemically confirmed cases of Variegate Porphyria. Molecular testing is sometimes useful when symptoms have been absent for months or years and biochemical abnormalities are no longer present. Knowing the PPOX mutation is a family enables other family members to be tested reliably for the same mutation.

TREATMENT

The treatment of acute attacks of Variegate Porphyria is the same as for Acute Intermittent Porphyria and Hereditary Coproporphyria. Hospitalization is usually indicated for pain control and treatment of other severe symptoms such as nausea and vomiting, electrolyte imbalances and convulsions. Monitoring for these manifestations as well and muscle weakness and respiratory embarrassment is also indicated in severe attacks. A narcotic analgesic is generally required for pain, and a phenothiazine or ondansetron for nausea and vomiting. Triggering factors such as unsafe medications should be identified and discontinued when possible. See Safe/Unsafe Drug List  Specific therapies are glucose loading and hemin for injection, which is available in the U.S. as lyophilized hematin (Panhematin®). Hemin works by slowing down or ‘repressing’ the heme biosynthesis pathway in the liver, thereby lowering toxic levels of ALA, PBG and porphyrins leading to a rapid recovery from an attack. Glucose given intravenously has a similar effect, but because it is less potent is used only for mild attacks.

Can attacks be prevented? Yes, particularly with regard to drugs and diet. Genetic VP carriers should become informed on medications to avoid (see information on AIP and HCP) and should be prepared to point their healthcare providers to on-line drug lists that are regularly updated. See Safe/Unsafe Drug List  A Medic Alert bracelet is useful for a situation in which the patient is incapacitated. Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue (Lupron, Zoladex, others) administered with expert guidance. In selected cases, frequent noncyclic attacks can be prevented by once- or twice-weekly infusions of hemin.

Individuals who are prone to attacks should consume a normal balanced diet. Despite on-line discussion, there is no evidence that pushing carbohydrate prevents attacks, and it has the side effect of weight gain, which is undesirable for most people. Fasting, fad diets (for example, high protein) and gastric reduction surgery should be avoided. If weight loss is desired, it is advisable to consult a physician and a dietitian about an individualized diet with modest caloric restriction (ca. 10%), which will produce gradual weight loss without increasing the risk of an attack of porphyria. Exercise is safe in porphyria and recommended.

Management and prevention are the same as in AIP and HCP. Blistering skin lesions are much more common than in HCP and are not readily treated. The only effective preventive measure is use of protective clothing.

Cimetidine has also been recommended based on little evidence and should not be used as a substitute for hemin or even glucose. Acute attacks are potentially life-threatening especially if not treated promptly, but most patients recover completely. Future attacks can be prevented by avoiding triggering factors. Frequent attacks that are cyclic can be prevented by administration of a GnRH analogue. Frequent noncyclic attacks are rare and can sometimes be prevented by prophylactic administration of hemin – perhaps a single dose weekly.

Chronic skin manifestations may improve if triggering factors are avoided. Hemin and glucose have not been found to be useful for this and other chronic symptoms. Treatments that are effective in Porphyria Cutanea Tarda, namely phlebotomies and low-dose hydroxychloroquine or chloroquine, are not useful in Variegate Porphyria because, even though the skin abnormalities are the same, the underlying abnormalities in the liver are very different. Avoidance of exposure to sunlight is important and may lead to gradual improvement. The use of appropriate clothing (e.g., hats, long sleeved shirts) and opaque sunscreen products can be beneficial (regular sunscreen products are generally ineffective).

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

Wearing a Medic Alert bracelet or the use of a wallet card is advisable in individuals who have VP.

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