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Markedly elevated plasma and urinary concentrations of the porphyrin precursors, ALA and/or PBG, which originate from the liver, are especially evident during attacks of neurologic manifestations of the four acute porphyrias—ADP, AIP, HCP, and VP. In PCT, excess porphyrins also accumulate initially in the liver and cause chronic blistering of sun-exposed areas of the skin.
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ALA DEHYDRATASE-DEFICIENT PORPHYRIA (ADP)
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ADP is a rare autosomal recessive acute hepatic porphyria caused by a severe deficiency of ALA dehydratase activity. To date, there are only a few documented cases, some in children or young adults, in which specific gene mutations have been identified. These affected homozygotes had <10% of normal ALA dehydratase activity in erythrocytes, but their clinically asymptomatic parents and heterozygous relatives had about half-normal levels of activity and did not excrete increased levels of ALA. The frequency of ADP is unknown, but the frequency of heterozygous individuals with <50% normal ALA dehydratase activity was ~2% in a screening study in Sweden. Because there are multiple causes for deficient ALA dehydratase activity, it is important to confirm the diagnosis of ADP by mutation analysis.
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The clinical presentation depends on the amount of residual ALA dehydratase activity. Four of the documented patients were male adolescents with symptoms resembling those of AIP, including abdominal pain and neuropathy. One patient was an infant with more severe disease, including failure to thrive beginning at birth. The earlier age of onset and more severe manifestations in this patient reflect a more significant deficiency of ALA dehydratase activity. Another patient developed an acute motor polyneuropathy at age 63 that was associated with a myeloproliferative disorder. He was heterozygous for an ALAD mutation that presumably was present in erythroblasts that underwent clonal expansion due to the bone marrow malignancy.
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All patients had significantly elevated levels of plasma and urinary ALA and urinary coproporphyrin (COPRO) III; ALAD activities in erythrocytes were <10% of normal. Hereditary tyrosinemia type 1 (fumarylacetoacetase deficiency) and lead intoxication should be considered in the differential diagnosis because either succinylacetone (which accumulates in hereditary tyrosinemia and is structurally similar to ALA) or lead can inhibit ALA dehydratase, increase urinary excretion of ALA and COPRO III, and cause manifestations that resemble those of the acute porphyrias. Heterozygotes are clinically asymptomatic and do not excrete increased levels of ALA but can be detected by demonstration of intermediate levels of erythrocyte ALA dehydratase activity or a specific mutation in the ALAD gene. To date, molecular studies of ADP patients have identified nine point mutations, two splice-site mutations, and a two-base deletion in the ALAD gene (Human Gene Mutation Database; www.hgmd.org). The parents in each case were not consanguineous, and the index cases had inherited a different ALAD mutation from each parent. Prenatal diagnosis of this disorder is possible by determination of ALA dehydratase activity and/or gene mutations in cultured chorionic villi or amniocytes.
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TREATMENT ALA-Dehydratase Deficient Porphyria
The treatment of ADP acute attacks is similar to that of AIP (see below). The severely affected infant referred to above was supported by hyperalimentation and periodic blood transfusions but did not respond to intravenous hemin and died after liver transplantation.
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ACUTE INTERMITTENT PORPHYRIA (AIP)
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This hepatic porphyria is an autosomal dominant condition resulting from the half-normal level of HMB synthase activity. The disease is widespread but is especially common in Scandinavia and Great Britain. Clinical expression is highly variable, and activation of the disease is often related to environmental or hormonal factors, such as drugs, diet, and steroid hormones. Attacks can be prevented by avoiding known precipitating factors. Rare homozygous dominant AIP also has been described in children (see below).
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Induction of the rate-limiting hepatic enzyme ALA synthase in heterozygotes who have half-normal HMB synthase activity is thought to underlie the acute attacks in AIP. The disorder remains latent (or asymptomatic) in the great majority of those who are heterozygous for HMBS mutations, and this is almost always the case prior to puberty. In patients with no history of acute symptoms, porphyrin precursor excretion is usually normal, suggesting that half-normal hepatic HMB synthase activity is sufficient and that hepatic ALA synthase activity is not increased. However, under conditions where heme synthesis is increased in the liver, half-normal HMB synthase activity may become limiting, and ALA, PBG, and other heme pathway intermediates may accumulate and be excreted in the urine. Common precipitating factors include endogenous and exogenous steroids, porphyrinogenic drugs, alcohol ingestion, and low-calorie diets, usually instituted for weight loss.
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The fact that AIP is almost always latent before puberty suggests that adult levels of steroid hormones are important for clinical expression. Symptoms are more common in women, suggesting a role for estrogens or progestins. Premenstrual attacks are probably due to endogenous progesterone. Acute porphyrias are sometimes exacerbated by exogenous steroids, including oral contraceptive preparations containing progestins. Surprisingly, pregnancy is usually well tolerated, suggesting that beneficial metabolic changes may ameliorate the effects of high levels of progesterone. Table 430-4 provides a partial list of the major drugs that are harmful in AIP (and also in HCP and VP). Extensive lists of unsafe and safe drugs are available on websites sponsored by the American Porphyria Foundation (www.porphyriafoundation.com) and the European Porphyria Initiative (www.porphyria-europe.org), and at the Drug Database for Acute Porphyrias website (www.drugs-porphyria.com). Reduced intake of calories and carbohydrate, as may occur with illness or attempts to lose weight, can also increase porphyrin precursor excretion and induce attacks of porphyria. Increased carbohydrate intake may ameliorate attacks. Studies in a knockout AIP mouse model indicate that the hepatic ALAS1 gene is regulated by the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Hepatic PGC-1α is induced by fasting, which in turn activates ALAS1 transcription, resulting in increased heme biosynthesis. This finding suggests an important link between nutritional status and the attacks in acute porphyrias. Attacks also can be provoked by infections, surgery, and ethanol.
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Because the neurovisceral symptoms rarely occur before puberty and are often nonspecific, a high index of suspicion is required to make the diagnosis. The disease can be disabling but is rarely fatal. Abdominal pain, the most common symptom, is usually steady and poorly localized but may be cramping. Ileus, abdominal distention, and decreased bowel sounds are common. However, increased bowel sounds and diarrhea may occur. Abdominal tenderness, fever, and leukocytosis are usually absent or mild because the symptoms are neurologic rather than inflammatory. Nausea; vomiting; constipation; tachycardia; hypertension; mental symptoms; pain in the limbs, head, neck, or chest; muscle weakness; sensory loss; dysuria; and urinary retention are characteristic. Tachycardia, hypertension, restlessness, tremors, and excess sweating are due to sympathetic overactivity.
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The peripheral neuropathy is due to axonal degeneration (rather than demyelinization) and primarily affects motor neurons. Significant neuropathy does not occur with all acute attacks; abdominal symptoms are usually more prominent. Motor neuropathy affects the proximal muscles initially, more often in the shoulders and arms. The course and degree of involvement are variable and sometimes may be focal and involve cranial nerves. Deep tendon reflexes initially may be normal or hyperactive but become decreased or absent as the neuropathy advances. Sensory changes such as paresthesia and loss of sensation are less prominent. Progression to respiratory and bulbar paralysis and death occurs especially when the diagnosis and treatment are delayed. Sudden death may result from sympathetic overactivity and cardiac arrhythmia.
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Mental symptoms such as anxiety, insomnia, depression, disorientation, hallucinations, and paranoia can occur in acute attacks. Seizures can be due to neurologic effects or to hyponatremia. Treatment of seizures is difficult because most antiseizure drugs can exacerbate AIP (clonazepam may be safer than phenytoin or barbiturates). Hyponatremia results from hypothalamic involvement and inappropriate vasopressin secretion or from electrolyte depletion due to vomiting, diarrhea, poor intake, or excess renal sodium loss. Persistent hypertension and impaired renal function may occur. When an attack resolves, abdominal pain may disappear within hours, and paresis begins to improve within days and may continue to improve over several years.
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Homozygous dominant AIP is a rare form of AIP in which patients inherit HMBS mutations from each of their heterozygous parents and, therefore, have very low (<2%) enzyme activity. The disease has been described in a Dutch girl, two young British siblings, and a Spanish boy. In these homozygous affected patients, the disease presented in infancy with failure to thrive, developmental delay, bilateral cataracts, and/or hepatosplenomegaly. Urinary ALA and PBG concentrations were markedly elevated. All of these patients’ HMBS mutations (R167W, R167Q, and R172Q) were in exon 10 within five bases of each other. Studies of the brain magnetic resonance images (MRIs) of children with homozygous AIP have suggested damage primarily in white matter that was myelinated postnatally, while tracks that myelinated prenatally were normal. Most children with homozygous AIP die at an early age.
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ALA and PBG levels are substantially increased in plasma and urine, especially during acute attacks, and become normal only after prolonged latency. For example, urinary PBG excretion during an attack is usually 50–200 mg/24 h (220–880 μmol/24 h) (normal, 0–4 mg/24 h, [0–18 μmol/24 h]), and urinary ALA excretion is 20–100 mg/24 h (150–760 μmol/24 h) (normal, 1–7 mg/24 h [8–53 μmol/24 h]).Because levels often remain high after symptoms resolve, the diagnosis of an acute attack in a patient with biochemically proven AIP is based primarily on clinical features. Excretion of ALA and PBG decreases over a few days after intravenous hemin administration. A normal urinary PBG level before hemin effectively excludes AIP as a cause for current symptoms. Fecal porphyrins are usually normal or minimally increased in AIP, in contrast to HCP and VP. Most AIP heterozygotes with no history of symptoms have normal urinary excretion of ALA and PBG. Therefore, the detection of the family’s HMBS mutation will diagnose asymptomatic family members.
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Patients with HMBS mutations in the initiation of translation codon in exon 1 and in the intron 15′-splice donor site have normal enzyme levels in erythrocytes and deficient activity only in nonerythroid tissues. This occurs because the erythroid and housekeeping forms of HMB synthase are encoded by a single gene, which has two promoters. Thus, the enzyme assay may not be diagnostic, and genetic testing should be used to confirm the diagnosis.
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More than 390 HMBS mutations have been identified in AIP, including missense, nonsense, and splicing mutations and insertions and deletions, with most mutations found in only one or a few families (Human Gene Mutation Database, www.hgmd.org). The prenatal diagnosis of a fetus at risk can be made with cultured amniotic cells or chorionic villi. However, this is seldom done, because the prognosis of individuals with HMBS mutations is generally favorable.
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TREATMENT Acute Intermittent Porphyria
During acute attacks, narcotic analgesics may be required for abdominal pain, and phenothiazines are useful for nausea, vomiting, anxiety, and restlessness. Chloral hydrate can be given for insomnia, and benzodiazepines are probably safe in low doses if a minor tranquilizer is required. Carbohydrate loading, usually with intravenous glucose (at least 300 g daily), may be effective in milder acute attacks of porphyria (without paresis, hyponatremia, etc.) if hemin is not available. Intravenous hemin is more effective and should be used as first-line therapy for all acute attacks. The standard regimen is 3–4 mg/kg of heme, in the form of lyophilized hematin (Recordati Pharmaceuticals), heme albumin (hematin reconstituted with human albumin), or heme arginate (Orphan Europe), infused daily for 4 days. Heme arginate and heme albumin are chemically stable and are less likely than hematin to produce phlebitis or an anticoagulant effect. Recovery depends on the degree of neuronal damage and usually is rapid if therapy is started early. Recovery from severe motor neuropathy may require months or years. Identification and avoidance of inciting factors can hasten recovery from an attack and prevent future attacks. Inciting factors are usually multiple, and removal of one or more hastens recovery and helps prevent future attacks. Frequent attacks that occur during the luteal phase of the menstrual cycle may be prevented with a gonadotropin-releasing hormone analogue, which prevents ovulation and progesterone production, or by prophylactic hematin administration.
The long-term risk of hypertension and chronic renal disease is increased in AIP; a number of patients have undergone successful renal transplantation. Chronic, low-grade abnormalities in liver function tests are common, and the risk of hepatocellular carcinoma is increased. Hepatic imaging is recommended at least yearly for early detection of these tumors.
An allogeneic liver transplant was performed on a 19-year-old female AIP heterozygote who had 37 acute attacks in the 29 months prior to transplantation. After transplantation, her elevated urinary ALA and BPG levels returned to normal in 24 h, and she did not experience acute neurologic attacks for more than 3 years after transplant. Two AIP patients had combined liver and kidney transplants secondary to uncontrolled acute porphyria attacks, chronic peripheral neuropathy, and renal failure requiring dialysis. Both patients had a marked improvement with no attacks and normal urinary PBG levels after transplantation, as well as improvement of their neuropathic manifestations. More recently, a group from the United Kingdom reported their experience with liver transplantation in 10 AIP patients with recurrent attacks that were refractory to medical management and impaired quality of life. Patients had a complete biochemical and symptomatic resolution after transplant. The investigators reported a high rate of hepatic artery thrombosis in their series. Clearly, liver transplantation is a high-risk procedure and should be considered as a last resort in patients with severe recurrent attacks. Recently, liver-directed gene therapy has proven successful in the prevention of drug-induced biochemical attacks in a murine model of human AIP, and clinical trials of AAV-HMBS gene transfer have been initiated. In addition, preclinical studies of a hepatic-targeted RNA interference (RNAi) therapy directed to inhibit the markedly elevated hepatic ALAS1 mRNA in the AIP mouse model prevented induced biochemical attacks and rapidly reduced the ALAS1 mRNA during an ongoing attack.
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PORPHYRIA CUTANEA TARDA (PCT)
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PCT, the most common of the porphyrias, can be either sporadic (type 1) or familial (type 2) and can also develop after exposure to halogenated aromatic hydrocarbons. Hepatic URO decarboxylase is deficient in all types of PCT, and for clinical symptoms to manifest, this enzyme deficiency must be substantial (~20% of normal activity or less); it is currently attributed to generation of an URO decarboxylase inhibitor in the liver, which forms uroporphomethene in the presence of iron and under conditions of oxidative stress. The majority of PCT patients (~80%) have no UROD mutations and are said to have sporadic (type 1) disease. PCT patients heterozygous for UROD mutations have familial (type 2) PCT. In these patients, inheritance of a UROD mutation from one parent results in half-normal enzyme activity in liver and all other tissues, which is a significant predisposing factor, but is insufficient by itself to cause symptomatic PCT. As discussed below, other genetic and environmental factors contribute to susceptibility for both types of PCT. Because penetrance of the genetic trait is low, many patients with familial (type 2) PCT have no family history of the disease. HEP is an autosomal recessive form of porphyria that results from the marked systemic deficiency of URO decarboxylase activity with clinical symptoms in childhood.
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Blistering skin lesions that appear most commonly on the backs of the hands are the major clinical feature (Fig. 430-3). These rupture and crust over, leaving areas of atrophy and scarring. Lesions may also occur on the forearms, face, legs, and feet. Skin friability and small white papules termed milia are common, especially on the backs of the hands and fingers. Hypertrichosis and hyperpigmentation, especially of the face, are especially troublesome in women. Occasionally, the skin over sun-exposed areas becomes severely thickened, with scarring and calcification that resembles systemic sclerosis. Neurologic features are absent.
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A number of susceptibility factors, in addition to inherited UROD mutations in type 2 PCT, can be recognized clinically and can affect management. These include hepatitis C, HIV, excess alcohol, elevated iron levels, and estrogens. The importance of excess hepatic iron as a precipitating factor is underscored by the finding that the incidence of the common hemochromatosis-causing mutations, hemochromatosis gene (HFE) mutations C282Y and H63D, are increased in patients with types 1 and 2 PCT (Chap. 428). Excess alcohol is a long-recognized contributor, as is estrogen use in women. HIV is probably an independent but less common risk factor that, like hepatitis C, does not cause PCT in isolation. Multiple susceptibility factors that appear to act synergistically can be identified in the individual PCT patient. Patients with PCT characteristically have chronic liver disease and sometimes cirrhosis and are at risk for hepatocellular carcinoma. Various chemicals can also induce PCT; an epidemic of PCT occurred in eastern Turkey in the 1950s as a consequence of wheat contaminated with the fungicide hexachlorobenzene. PCT also occurs after exposure to other chemicals, including di- and trichlorophenols and 2,3,7,8-tetrachlorodibenzo-(p)-dioxin (TCDD, dioxin).
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Porphyrins are increased in the liver, plasma, urine, and stool. The urinary ALA level may be slightly increased, but the PBG level is normal. Urinary porphyrins consist mostly of uroporphyins and heptacarboxylate porphyrin, with lesser amounts of coproporphyrin and hexa- and pentacarboxylate porphyrins. Plasma porphyrins are also increased, and fluorometric scanning of diluted plasma at neutral pH can rapidly distinguish VP and PCT (Table 430-3). Isocoproporphyrins, which are increased in feces and sometimes in plasma and urine, are diagnostic for hepatic URO decarboxylase deficiency.
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Type 2 PCT and HEP can be distinguished from type 1 by finding decreased URO decarboxylase in erythrocytes. URO decarboxylase activity in liver, erythrocytes, and cultured skin fibroblasts in type 2 PCT is approximately 50% of normal in affected individuals and in family members with latent disease. In HEP, the URO decarboxylase activity is markedly deficient, with typical levels of 3–10% of normal. Over 121 mutations have been identified in the UROD gene (Human Gene Mutation Database; www.hgmd.org). Of the mutations listed in the database, ~65% are missense or nonsense and ~10% are splice-site mutations. Most UROD mutations have been identified in only one or two families.
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TREATMENT Porphyria Cutanea Tarda
Alcohol, estrogens, iron supplements, and, if possible, any drugs that may exacerbate the disease should be discontinued, but this step does not always lead to improvement. A complete response can almost always be achieved by the standard therapy, repeated phlebotomy, to reduce hepatic iron. A unit (450 mL) of blood can be removed every 1–2 weeks. The aim is to gradually reduce excess hepatic iron until the serum ferritin level reaches the lower limits of normal. Because iron overload is not marked in most cases, remission may occur after only five or six phlebotomies; however, PCT patients with hemochromatosis may require more treatments to bring their iron levels down to the normal range. To document improvement in PCT, it is most convenient to follow the total plasma porphyrin concentration, which becomes normal some time after the target ferritin level is reached. Hemoglobin levels or hematocrits and serum ferritin should be followed closely to prevent development of iron deficiency and anemia. After remission, continued phlebotomy may not be needed. Plasma porphyrin levels are followed at 6- to 12-month intervals for early detection of recurrences, which are treated by additional phlebotomy.
An alternative when phlebotomy is contraindicated or poorly tolerated is a low-dose regimen of chloroquine or hydroxychloroquine, both of which complex with the excess porphyrins and promote their excretion. Small doses (e.g., 125 mg chloroquine phosphate twice weekly) should be given, because standard doses can induce transient, sometimes marked increases in photosensitivity and hepatocellular damage. Recent studies indicate that low-dose hydroxychloroquine is as safe and effective as phlebotomy in PCT. Hepatic imaging can diagnose or exclude complicating hepatocellular carcinoma. Treatment of PCT in patients with end-stage renal disease is facilitated by administration of erythropoietin.
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HEREDITARY COPROPORPHYRIA (HCP)
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HCP is an autosomal dominant hepatic porphyria that results from the half-normal activity of COPRO oxidase. The disease presents with acute attacks, as in AIP. Cutaneous photosensitivity also may occur, but much less commonly than in VP. HCP patients may have acute attacks and cutaneous photosensitivity together or separately. HCP is less common than AIP and VP. Homozygous dominant HCP and harderoporphyria, a biochemically distinguishable variant of HCP, present with clinical symptoms in children (see below).
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HCP is influenced by the same factors that cause attacks in AIP. The disease is latent before puberty, and symptoms, which are virtually identical to those of AIP, are more common in women. HCP is generally less severe than AIP. Blistering skin lesions are identical to PCT and VP and begin in childhood in rare homozygous cases.
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COPRO III is markedly increased in the urine and feces in symptomatic patients, and often persists, especially in feces, when there are no symptoms. Urinary ALA and PBG levels are increased (but less than in AIP) during acute attacks, but may revert to normal more quickly than in AIP when symptoms resolve. Plasma porphyrins are usually normal or only slightly increased, but they may be higher in cases with skin lesions. The diagnosis of HCP is readily confirmed by increased fecal porphyrins consisting almost entirely of COPRO III, which distinguishes it from other porphyrias.
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Although the diagnosis can be confirmed by measuring COPRO oxidase activity, the assays for this mitochondrial enzyme are not widely available and require cells other than erythrocytes. To date, over 64 mutations have been identified in the CPOX gene, 67% of which are missense or nonsense (Human Gene Mutation Database; www.hgmd.org). Detection of a CPOX mutation in a symptomatic individual permits the identification of asymptomatic family members.
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TREATMENT Hereditary Coproporphyria
Neurologic symptoms are treated as in AIP (see above). Phlebotomy and chloroquine are not effective for the cutaneous lesions.
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VARIEGATE PORPHYRIA (VP)
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VP is an autosomal dominant hepatic porphyria that results from the deficient activity of PROTO oxidase, the seventh enzyme in the heme biosynthetic pathway, and can present with neurologic symptoms, photosensitivity, or both. VP is particularly common in South Africa, where 3 of every 1000 whites have the disorder. Most are descendants of a couple who emigrated from Holland to South Africa in 1688. In other countries, VP is less common than AIP. Rare cases of homozygous dominant VP, presenting in childhood with cutaneous symptoms, also have been reported.
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VP can present with skin photosensitivity, acute neurovisceral crises, or both. In two large studies of VP patients, 59% had only skin lesions, 20% had only acute attacks, and 22% had both. Acute attacks are identical to those in AIP and are precipitated by the same factors as AIP (see above). Blistering skin manifestations are similar to those in PCT, but are more difficult to treat and usually are of longer duration. Homozygous VP is associated with photosensitivity, neurologic symptoms, and developmental disturbances, including growth retardation, in infancy or childhood; all cases had increased erythrocyte levels of zinc protoporphyrin, a characteristic finding in all homozygous porphyrias so far described.
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Urinary ALA and PBG levels are increased during acute attacks, but may return to normal more quickly than in AIP. Increases in fecal protoporphyrin and COPRO III and in urinary COPRO III are more persistent. Plasma porphyrin levels also are increased, particularly when there are cutaneous lesions. VP can be distinguished rapidly from all other porphyrias by examining the fluorescence emission spectrum of porphyrins in plasma since VP has a unique fluorescence peak at neutral pH.
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Assays of PROTO oxidase activity in cultured fibroblasts or lymphocytes are not widely available. Over 174 mutations have been identified in the PPOX gene from unrelated VP patients (Human Gene Mutation Database; www.hgmd.org). The missense mutation R59W is the common mutation in most South Africans with VP of Dutch descent. Five missense mutations were common in English and French VP patients; however, most mutations have been found in only one or two families.
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TREATMENT Variegate Porphyria
Acute attacks are treated as in AIP, and hemin should be started early in most cases. Other than avoiding sun exposure, there are few effective measures for treating the skin lesions. β-Carotene, phlebotomy, and chloroquine are not helpful.