X-Linked Protoporphyria

X-Linked Protoporphyria (XLP) also called X-linked dominant protoporphyria or X-linked dominant erythropoietic protoporphyria is an extremely rare genetic disorder of the heme-biosynthetic pathway known as the porphyrias that usually present in early life with nonblistering painful and abnormal sensitivity to the sun (photosensitivity) that can cause severe pain, burning, and itching of sun-exposed skin ¹, ², ³, ⁴, ⁵, ⁶. X-linked protoporphyria (XLP) symptoms may occur immediately or shortly after exposure to the sun, including direct exposure or indirect exposure such as sunlight that passes through window glass or that is reflected off water or sand. Redness and swelling of affected areas can also occur. Blistering and severe scarring occur infrequently. Chronic episodes of photosensitivity may lead to changes in the skin of sun-exposed areas. Some individuals with X-linked protoporphyria (XLP) eventually develop potentially severe liver disease.

X-linked protoporphyria (XLP) is caused by gain-of-function mutations to the 5-aminolevulinate synthase 2 (ALAS2) gene located on the X chromosome and is inherited as an X-linked dominant trait ². Males often develop a severe form of the disorder while females may not develop any symptoms (asymptomatic) or can develop a form as severe as that seen in males. The ALAS2 gene is located on the short arm (p) of the X chromosome (Xp11.21)*. The ALAS2 gene provides instructions for making an enzyme called 5′-aminolevulinate synthase 2 or erythroid ALA-synthase ⁶. The 5′-aminolevulinate synthase 2 or erythroid ALA-synthase (ALAS2) enzyme is found only in developing red blood cells found in bone marrow that develop into red blood cells (erythrocytes) called erythroblasts. 5′-aminolevulinate synthase 2 or erythroid ALA-synthase (ALAS2) enzyme also plays an important role in the production of heme. Heme is a component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). Heme is vital for all of the body’s organs, although it is most abundant in the blood, bone marrow, and liver. The production of heme is a multi-step process that requires 8 different enzymes. ALA-synthase (ALAS2) enzyme is responsible for the first step in this process, the formation of a compound called delta-aminolevulinic acid (δ-ALA or ALA) (see Figures 4 and 5 below). Mutations of the ALAS2 gene lead to the overproduction of ALA-synthase or 5′-aminolevulinate synthase 2 enzyme, which, in turn, results in the rate of delta-aminolevulinic acid (δ-ALA or ALA) formation being increased, and the insertion of iron into protoporphyrin IX (PPIX) by ferrochelatase (FECH) the last step in heme synthesis becomes the rate-limiting for heme synthesis in erythroid tissues (the tissues where red blood cells or erythrocytes are produced and develop, in adults, the primary erythroid tissue is the bone marrow) resulting in accumulation of protoporphyrin IX (PPIX) in the the bone marrow ⁷, ⁸. If protoporphyrin IX (PPIX) compounds build up in erythroblasts (a precursor to red blood cells in the bone marrow), they can leak out and be transported through the bloodstream to your skin and other tissues such as your liver ⁷, ⁸. High levels of protoporphyrin IX (PPIX) in the skin cause the oversensitivity to sunlight that is characteristic of X-linked protoporphyria (XLP) ⁹, ¹⁰. For example, when protoporphyrins absorb energy from sunlight, they enter an excited state (photoactivation) and this abnormal activation results in the characteristic damage to the skin. Accumulation of protoporphyrins in the liver causes toxic damage to the liver and may contribute to the formation of gallstones. Protoporphyrin is formed within red blood cells in the bone marrow and then enters the blood plasma, which carries it to the skin where it can be photoactivated by sunlight and cause damage. The liver removes protoporphyrin from the blood plasma and secretes it into the bile.

Protoporphyrin IX (PPIX) is released from the bone marrow into the circulating red blood cells and plasma where it is taken up by the liver and vascular endothelium including the superficial skin vasculature. The protoporphyrin IX (PPIX) molecules are photodynamic (light sensitive chemical that is activated by light) and absorb light radiation in visible blue-violet light in the Soret band and to a lesser degree in the long-wave UV region ¹¹, ¹². When protoporphyrin IX (PPIX) molecules absorb light they enter an excited energy state. This energy is presumably released as fluorescence and by formation of singlet oxygen and other oxygen radicals that can produce tissue and vessel damage secondary to activation of the complement system ². The release of histamines, kinins, and chemotactic factors may bring about skin damage ¹³. Accumulated liver (hepatic) protoporphyrin IX (PPIX) can precipitate in liver cells (hepatocytes) and small bile ducts (bile canaliculi) that collect bile secreted by these liver cells (hepatocytes), causing liver toxicity, decreased bile formation and flow, and cholestatic liver failure in some patients ¹⁴, ¹⁵. Large amounts of porphyrins in the gallbladder can also cause gallstones. Less commonly, a buildup of porphyrins in the liver can result in liver damage that leads to cirrhosis and liver failure.

X-linked protoporphyria (XLP) accounts for 2 to 10% of protoporphyria cases with about 2% of cases in Europe and approximately 10% of cases in the United States ¹⁶, ¹⁷, ¹⁸.

The diagnosis of X-linked protoporphyria (XLP) is established in a male index case (the affected individual through whom a family with a genetic disorder is ascertained) with markedly increased free red blood cell (erythrocyte) protoporphyrin IX (PPIX) and zinc-chelated erythrocyte protoporphyrin IX (PPIX) by identification of a hemizygous pathogenic gain-of-function variant in ALAS2 on molecular genetic testing.

The diagnosis of X-linked protoporphyria (XLP) is established in a female index case with increased free erythrocyte protoporphyrin IX (PPIX) and zinc-chelated erythrocyte protoporphyrin IX (PPIX) by identification of a heterozygous pathogenic gain-of-function variant in ALAS2 on molecular genetic testing.

The treatment of X-linked protoporphyria is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may benefit affected individuals and their families.

There is no specific, FDA-approved therapy for individuals with X-linked protoporphyria (XLP). Because the disorder is so rare, most treatment information is based on erythropoietic protoporphyria (EPP), which is clinically similar to X-linked protoporphyria (XLP).

Avoidance of sunlight will benefit affected individuals and can include the use of clothing styles with long sleeves and pant legs, made with double layers of fabric or of light-exclusive fabrics, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective, unless they contain light-reflective ingredients (e.g., zinc oxide). Some tanning products with ingredients that increase pigmentation may be helpful. Affected individuals may also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars.

Avoidance of sunlight can potentially cause vitamin D deficiency and some individuals may require supplemental vitamin D.

A high potency form of oral beta-carotene (Lumitene) may be given to improve an affected individual’s tolerance of sunlight. This drug causes skin discoloration and may improve tolerance to sunlight. Oral Lumitene (beta-carotene) (120–180 mg/dL) has been used to improve tolerance to sunlight if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600–800 μg/dL), causing mild skin discoloration due to carotenemia. The beneficial effects of beta-carotene (Lumitene) may involve quenching of singlet oxygen or free radicals. However, a systematic review of about 25 studies showed that the available data are unable to prove efficacy of treatments including beta-carotene, N-acetyl cysteine, and vitamin C ¹⁹. For more information on oral beta-carotene (Lumitene) treatment, contact the American Porphyria Foundation and the Prophyria Consortium of the Rare Diseases Clinical Research Network.

Another drug sometimes used to improve tolerance to sunlight is cysteine.

In 2019, the Food and Drug Administration (FDA) approved Afamelanotide (Scenesse®) for the treatment of adult patients with erythropoietic protoporphyria (EPP). Afamelanotide (Scenesse) is a controlled-release, long-acting injectable implant, alpha-melanocyte-stimulating hormone (α-MSH) analogue, that increases eumelanin by binding to the melanocortin-1 receptor and provides sun protection and improves sun tolerance by increasing skin pigmentation and antioxidant properties ²⁰, ²¹. Afamelanotide (Scenesse) was available in Europe for a period of time before its approval in the United States. Afamelanotide (Scenesse) was approved for patients with the erythropoietic protoporphyria (EPP) by the European Medicines Agency in 2014, and by the FDA in October 2019. Afamelanotide showed positive results in Phase III clinical trials in the US and Europe ²². Long-term studies in Europe show good compliance, clinical effectiveness, and improved quality of life ²³.

Other treatment is symptomatic and supportive. Individuals with high levels of protoporphyrin in the plasma and red blood cells should be observed closely by a physician for possible liver malfunction that could eventually lead to liver failure.

When iron deficiency is present, iron supplements may be given. A drug called Prevalite (cholestyramine) or activated charcoal maybe prescribed to interrupt the circulation of protoporphyrin through the liver and intestines in patients with liver disease.

Liver transplantation has been performed as a life-saving measure in patients with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) related liver failure. Bone marrow transplant can also be performed after liver transplant to prevent further damage to the liver.

X-linked protoporphyria (XLP) patients should also receive vaccination against hepatitis A and B to prevent other causes of liver damage.

X-linked protoporphyria (XLP) patients should be seen at least yearly to monitor protoporphyrin levels, anemia, liver enzymes, iron and vitamin D levels.

Figure 1. Porphyrin molecular structure

Footnote: Molecular structure of porphyrin (M represent metal ions, such as Mg, Cu, Fe, Zn, etc.).

[Source ²⁴ ]

Figure 2. Hemoglobin molecular structure

[Source ²⁵ ]

Figure 3. Heme (haem) molecular structure

Footnote: Heme A and heme B molecular structures

[Source ²⁶ ]

Figure 4. Heme biosynthesis pathway

Figure 5. Heme synthesis pathway and porphyrias

Footnotes: The heme biosynthetic pathway requires 8 enzymatic steps. Heme synthesis pathway showing the enzymes involved in the heme synthesis pathway and the associated porphyrias with the disruption of each specific enzyme. Gain-of-function variants in ALAS2 result in X-linked protoporphyria (XLP), and loss-of-functions variants in FECH result in erythropoietic protoporphyria (EPP). In both X-linked protoporphyria (XLP) and erythropoietic protoporphyria (EPP), metal-free protoporphyrin IX (PPIX) accumulates in erythroblasts, erythrocytes, the plasma, and the biliary system. Metal-free protoporphyrin IX (PPIX) is photosensitive, particularly to visible light in the blue range, and the light-mediated activation of metal-free protoporphyrin IX (PPIX) produces free radicals that damage the surrounding tissues.

Enzymes, encoded by genes, catalyze each of the steps. Gene mutations cause deficient enzyme production. Disruptions are indicated by red lines connecting enzymes with the resultant porphyrias. ALAS (ALAS2) = aminolevulinate synthase (aminolevulinate synthase 2); ALAD = delta-aminolevulinic acid dehydratase; PBGD = porphobilinogen dehydratase; HMBS = hydroxymethylbilane synthase; UROS = uroporphyrinogen-III synthase; UROD = uroporphyrinogen III decarboxylase; CPOX = coproporphyrinogen-III oxidase; PPOX = protoporphyrinogen oxidase; FECH = ferrochelatase.

Porphyrias resulting from disruption of enzyme production. XLP (X-linked protoporphyria); ADP (aminolevulinic acid dehydratase porphyria); AIP (acute intermittent porphyria); CEP (congenital erythropoietic porphyria); PCT (porphyria cutanea tarda); HCP (hereditary coproporphyria); VP (variegate porphyria); EPP (erythropoietic protoporphyria).

Abbreviations: ALA = aminolevulinic acid; PBG = porphobilinogen; HMB = hydroxymethylbilane; URO III = uroporphyrinogen III; COPRO III = coproporphyrinogen III; PROTO’gen IX protoporphyrinogen IX; PPIX = protoporphyrin IX; Fe2+ = iron.

[Source ²⁷ ]

X-Linked Protoporphyria cause

X-linked protoporphyria (XLP) is caused by gain-of-function mutations to the 5-aminolevulinate synthase 2 (ALAS2) gene located on the X chromosome and is inherited as an X-linked dominant trait ². Males often develop a severe form of the disorder while females may not develop any symptoms (asymptomatic) or can develop a form as severe as that seen in males. The ALAS2 gene is located on the short arm (p) of the X chromosome (Xp11.21)*. The ALAS2 gene provides instructions for making an enzyme called 5′-aminolevulinate synthase 2 or erythroid ALA-synthase ⁶. The 5′-aminolevulinate synthase 2 or erythroid ALA-synthase (ALAS2) enzyme is found only in developing red blood cells found in bone marrow that develop into red blood cells (erythrocytes) called erythroblasts. 5′-aminolevulinate synthase 2 or erythroid ALA-synthase (ALAS2) enzyme also plays an important role in the production of heme. Heme is a component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). Heme is vital for all of the body’s organs, although it is most abundant in the blood, bone marrow, and liver. The production of heme is a multi-step process that requires 8 different enzymes. ALA-synthase (ALAS2) enzyme is responsible for the first step in this process, the formation of a compound called delta-aminolevulinic acid (δ-ALA or ALA) (see Figures 4 and 5 below). Mutations of the ALAS2 gene lead to the overproduction of ALA-synthase or 5′-aminolevulinate synthase 2 enzyme, which, in turn, results in the rate of delta-aminolevulinic acid (δ-ALA or ALA) formation being increased, and the insertion of iron into protoporphyrin IX (PPIX) by ferrochelatase (FECH) the last step in heme synthesis becomes the rate-limiting for heme synthesis in erythroid tissues (the tissues where red blood cells or erythrocytes are produced and develop, in adults, the primary erythroid tissue is the bone marrow) resulting in accumulation of protoporphyrin IX (PPIX) in the the bone marrow ⁷, ⁸. If protoporphyrin IX (PPIX) compounds build up in erythroblasts (a precursor to red blood cells in the bone marrow), they can leak out and be transported through the bloodstream to your skin and other tissues such as your liver ⁷, ⁸. High levels of protoporphyrin IX (PPIX) in the skin cause the oversensitivity to sunlight that is characteristic of X-linked protoporphyria (XLP) ⁹, ¹⁰. For example, when protoporphyrins absorb energy from sunlight, they enter an excited state (photoactivation) and this abnormal activation results in the characteristic damage to the skin. Accumulation of protoporphyrins in the liver causes toxic damage to the liver and may contribute to the formation of gallstones. Protoporphyrin is formed within red blood cells in the bone marrow and then enters the blood plasma, which carries it to the skin where it can be photoactivated by sunlight and cause damage. The liver removes protoporphyrin from the blood plasma and secretes it into the bile.

Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. For example, “chromosome Xp22.2-22.1” refers to bands 22.2 through 22.1 on the short arm of chromosome X.

X-linked protoporphyria (XLP) results from gain-of-function mutations in erythroid-specific ALAS2 ²⁸. Mutations associated with X-linked protoporphyria (XLP) have only been observed in exon 11, which encodes the C-terminus, and result in a gain-of-function of ALAS2. These mutations result in stop or frameshift lesions that prematurely truncate or abnormally elongate the wild-type enzyme, leading to increased ALAS2 activity ²⁸, ¹⁸. In X-linked protoporphyria (XLP), all males are affected ¹. In heterozygous females (females with one normal copy and one mutated copy of ALAS2 gene on their X chromosomes) with X-linked protoporphyria (XLP), the random X-inactivation pattern directly influences the penetrance and the severity of the phenotype. X-linked protoporphyria (XLP) females can be asymptomatic clinically with normal protoporphyrins, be asymptomatic clinically with slightly elevated protoporphyrin levels or have significant symptoms based on the pattern of X-inactivation ²⁹, ¹.

X-linked protoporphyria inheritance pattern

X-linked protoporphyria (XLP) is passed down through families in an X-linked manner ³⁰. Males have one X chromosome and one Y chromosome, while females have two X chromosomes.This means that males have only one copy of the ALAS2 gene and females have two copies of the ALAS2 gene. When a male has a mutation is his single copy of ALAS2 gene, he is expected to have symptoms of X-linked protoporphyria (XLP). In a woman with a mutation in one of her ALAS2 genes, the second functioning copy of the ALAS2 gene can help compensate and may lead to less severe symptoms or no symptoms at all. It is not possible to predict or control the severity of X-linked protoporphyria (XLP) in females. Men with XLP pass on their X chromosome to their daughters and their Y chromosome to their sons. Therefore, a man with X-linked protoporphyria (XLP) with pass on his genetic change to all his daughters, and none of his sons. For a female with XLP, she will pass on the X chromosome with the genetic change 50% of the time. Thus, in each pregnancy, there is a 50% chance of having a child with a mutation in ALAS2 gene.

Genetic counseling is recommended for affected individuals and their families.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://abgc.learningbuilder.com/Search/Public/MemberRole/Verification) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (https://clinics.acmg.net/) has a searchable database of medical genetics clinic services in the United States.

Figure 6. X-linked protoporphyria (XLP) inheritance pattern

X-Linked Protoporphyria Pathophysiology

Bone marrow reticulocytes are thought to be the primary source of the accumulated protoporphyrin IX (PPIX) that is excreted in bile and feces ¹. Most of the excess protoporphyrin IX (PPIX) in circulating erythrocytes is found in a small percentage of cells, and the rate of protoporphyrin IX (PPIX) leakage from these cells is proportional to their protoporphyrin content.

The skin of persons with X-linked protoporphyria (XLP) is maximally sensitive to visible blue-violet light near 400 nm, which corresponds to the so-called “Soret band” (the narrow peak absorption maximum that is characteristic for protoporphyrin and other porphyrins) ¹. When porphyrins absorb light they enter an excited energy state. This energy is presumably released as fluorescence and by formation of singlet oxygen and other oxygen radicals that can produce tissue and vessel damage. This may involve lipid peroxidation, oxidation of amino acids, and cross-linking of proteins in cell membranes ¹.

Photoactivation of the complement system and release of histamine, kinins, and chemotactic factors may mediate skin damage ¹. Histologic changes occur predominantly in the upper dermis and include deposition of amorphous material containing immunoglobulin, complement components, glycoproteins, glycosaminoglycans, and lipids around blood vessels. Damage to capillary endothelial cells in the upper dermis has been demonstrated immediately after light exposure in this disease ³¹.

Long-term observations of individuals with protoporphyria generally show little change in protoporphyrin levels in erythrocytes, plasma, and feces ³². In contrast, severe liver complications, when they occur, often follow increasing accumulation of protoporphyrin in erythrocytes, plasma, and liver. Iron deficiency and factors that impair liver function sometimes contribute. Enterohepatic circulation of protoporphyrin may favor its return and retention in the liver, especially when liver function is impaired. Liver damage probably results at least in part from protoporphyrin accumulation itself ¹. As this porphyrin is insoluble, it tends to form crystalline structures in liver cells, can impair mitochondrial functions in liver cells, and can decrease hepatic bile formation and flow ³³.

X-Linked Protoporphyria signs and symptoms

Hypersensitivity of the skin to sunlight beginning in infancy or childhood is the characteristic finding of X-linked protoporphyria (XLP) ⁹, ¹. Most patients develop symptoms within 30 minutes of sun exposure. Affected individuals develop tingling, burning, pain, and itching of the skin after exposure to sunlight. Sometimes these symptoms are accompanied by swelling and redness (erythema) of the affected areas ⁹, ¹. Large blisters and severe scarring, which are common to other forms of cutaneous porphyria, usually do not occur in individuals with X-linked protoporphyria ¹. The back of the hands and face are most commonly affected but any sun exposed area can be affected. Symptoms may be noticed as quickly as a few minutes after exposure to the sun ³⁴. Although most symptoms usually subside within 24-48 hours (may take up to 4–7 days), pain and a red or purple discoloration of the skin may persist for several days after the initial incident ³⁴, ³⁵. Pain is disproportionately severe in relation to the visible skin lesions. Pain associated with X-linked protoporphyria can be excruciating and is often resistant to pain medications, even narcotics.

Photosensitivity is lifelong. Repeated episodes of photosensitivity may eventually causes changes in the skin of affected individuals. Such changes include thickening and hardening of the sun-exposed skin (lichenification), development of a rough or leathery texture, small facial pock-like pits, and grooving around the lips and loss of lunulae of the nails ¹³, ¹.

Some individuals with X-linked protoporphyria develop liver disease, which can range from mild liver abnormalities to liver failure ¹. Information on liver disease is limited, but the risk of liver disease is believed to be higher in X-linked protoporphyria than in erythropoietic protoporphyria (EPP). Affected individuals may experience back pain and severe abdominal pain especially in the upper right area of the abdomen. In some affected individuals, the flow of bile through the gallbladder and bile ducts may be interrupted (cholestasis) leading to gallstones. These stones can cause obstruction and inflammation of the gallbladder (cholecystitis). Scarring of the liver (cirrhosis) may also develop and some individuals may eventually develop end stage liver failure.

Additional symptoms have been reported in individuals with X-linked protoporphyria including mild anemia (low levels of circulating red blood cells) and iron deficiency.

The signs and symptoms in heterozygous females (females with one normal copy and one mutated copy of ALAS2 gene on their X chromosomes) ranges from asymptomatic to as severe as in affected males ¹.

Figure 7. X-linked protoporphyria

Footnote: Skin redness (erythema) and swelling (edema) on the back of hands and forearm seen after acute phototoxic episode.

[Source ² ]

Liver disease

The excess protoporphyrin in erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) is excreted by the liver into the bile where it enters the enterohepatic circulation ³⁶. Progressive accumulation of protoporphyrin IX (PPIX) may occur in the liver when the biliary excretion does not keep pace with the load being presented to the liver. When hepatocellular damage reaches a critical stage, protoporphyrin IX (PPIX) accumulation will rapidly accelerate due to marked impairment of biliary excretion ¹⁵, ³⁷, ¹. Concomitant conditions such as viral hepatitis, excessive alcohol consumption, and use of drugs which induce cholestasis may contribute to worsening liver disease. End-stage liver disease is typically preceded by an elevation in plasma and erythrocyte protoporphyrin IX (PPIX) levels. Patients may also develop a motor neuropathy in the setting of liver failure ³⁸, ³⁹.

The excess amounts of free protoporphyrin IX (PPIX) may become insoluble and aggregate in the hepatocytes and small biliary canaliculi leading to obstruction to bile flow and cholestasis. About 20–30% of patients with erythropoietic protoporphyria (EPP) will have elevations in serum aminotransferases20. Protoporphyrin in bile may also crystallize forming gallstones. In one series, cholelithiasis were seen in 23.5% of patients ³⁵.

Anemia

Mild anemia, typically microcytic anemia can be seen in erythropoietic protoporphyria (EPP) patients ⁴⁰. Patients with erythropoietic protoporphyria (EPP) appear to have an abnormal iron metabolism but the mechanism of iron deficiency is unclear ⁴¹, ⁴². The cause of microcytic anemia and low iron and ferritin levels in erythropoietic protoporphyria (EPP) patients is unknown ⁴³, ⁴⁴. Previous studies suggest that erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) patients have normal iron absorption and an appropriate hepcidin response ⁴⁵. The iron deficiency in erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) patients does not appear to be related to chronic inflammation or iron loss. The cause and mechanism of iron deficiency in these patients remains to be resolved.

Vitamin D deficiency

X-linked protoporphyria (XLP) and erythropoietic protoporphyria (EPP) patients can develop vitamin D deficiency secondary to sun avoidance ⁴⁶, ⁴⁷. A recent report showed that the prevalence of osteopenia (low bone mineral density) and osteoporosis is increased in patients in erythropoietic protoporphyria (EPP) ⁴⁸.

X-Linked Protoporphyria diagnosis

A diagnosis of X-linked protoporphyria is based upon identification of characteristic symptoms (e.g., non-blistering photosensitivity), a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests ⁹, ⁴⁹, ⁵⁰, ¹.

X-linked protoporphyria (XLP) should be suspected in individuals with the following clinical findings and initial laboratory findings ¹:

• Clinical findings
  • Skin photosensitivity, usually beginning in childhood
  • Burning, tingling, pain, and itching of the skin (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling
  • Painful symptoms; may occur without obvious skin damage
  • Absent or sparse blisters and bullae
  • Note: The absence of skin damage (e.g., scarring), vesicles, and bullae often make it difficult to suspect the diagnosis.
  • Liver complications, particularly cholestatic liver disease, may develop in fewer than 5% of affected individuals.

A diagnosis of X-linked protoporphyria may be made through blood tests that can detect markedly increased levels of metal-free and zinc-bound protoporphyrins within red blood cells (erythrocytes). A higher ratio of zinc-bound protoporphyrin to metal-free protoporphyrin can differentiate X-linked protoporphyria from erythropoietic protoporphyria.

Note: It is essential to use an assay for erythrocyte protoporphyrin that distinguishes between free protoporphyrin and zinc-chelated protoporphyrin to differentiate X-linked protoporphyria (XLP) from erythropoietic protoporphyria (EPP) and several other conditions that may lead to elevation of erythrocyte protoporphyrins.

• Initial laboratory findings. Detection of markedly increased free erythrocyte protoporphyrin IX (PPIX) and zinc-chelated erythrocyte protoporphyrin IX (PPIX) is the most sensitive biochemical diagnostic test for X-linked protoporphyria (XLP).
  • Erythroid-specific 5-aminolevulinate synthase 2 (ALAS2) enzyme activity >100% of normal
  • Free protoporphyrin/zinc-chelated protoporphyrin ratio 90:10 to 50:50
  • Urine Protoporphyrins not detectable
  • Stool Protoporphyrin normal or increased
  • Plasma porphyrins increased

Molecular genetic testing can confirm a diagnosis of X-linked protoporphyria (XLP) by detecting mutations in the ALAS2 gene (the only gene known to cause this disorder).

Additional tests may be performed such as blood tests to evaluate anemia and iron stores in the body and vitamin D levels, or an abdominal sonogram to detect and evaluate liver disease potentially associated with X-linked protoporphyria.

Newer imaging modalities such as Fibroscan® may be useful in evaluating liver fibrosis; however, this has not been validated in erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP) ¹.

X-linked protoporphyria differential diagnosis

X-linked protoporphyria differential diagnosis include ⁵¹:

• Phototoxic drug reaction: Phototoxic drug reaction is a non-immunologic skin reaction that appears acutely within minutes to hours on sun-exposed skin after taking photosensitising medications. There must be a history of the introduction of any new drug. Phototoxic skin damage begins when the drug or its metabolite within the skin absorbs ultraviolet radiation (UVR) or visible light. Patients experience painful reddish skin immediately after sun exposure ⁵², ⁵³.
• Hydroa vacciniforme: Hydroa vacciniforme is one of the rarest forms of photosensitivity dermatoses. Hydroa vacciniforme affects sun-exposed skin and is characterized by recurrent fluid-filled blisters (‘hydroa’) over sun-exposed sites that heal with pox-like (‘vacciniform’) scars ⁵⁴.
• Solar urticaria: Solar urticaria is a condition in which exposure to sunlight or an artificial light source emitting ultraviolet radiation causes urticaria ⁵⁵. Like EPP, symptoms often develop within minutes. Symptoms of solar urticaria are often itchy rather than painful. The reaction may subside within a few minutes or it may persist for up to an hour or more where it can become very disabling. The cause of solar urticaria is not clearly defined but may be due to an antigen-antibody reaction ⁵⁵. It seems that a chemical created in the body (a photoallergen) reacts with UV radiation to cause an allergic reaction that manifests as urticaria.
• Polymorphic light eruption (PMLE): Polymorphic light eruption also called a sun allergy or sun poisoning. Polymorphic light eruption is a common seasonal, acquired, idiopathic photodermatosis occurring in spring and early summer that typically occurs during the first three decades of life ⁵⁶. Symptoms occur in sun-exposed areas. Patients present with discrete lesions such as pruritic papules, vesicles, or plaques on sun-exposed areas.
• Discoid lupus erythematosus: It presents as scaly erythematous plaques on sun-exposed areas.
• Sunburn: It is a transient inflammatory skin response to ultraviolet radiation from sunlight or artificial sources. Sunburn can occur in individuals without an underlying dermatologic condition, with sensitivity depending on the degree of skin pigmentation and hair and eye color ⁵⁷.

X-Linked Protoporphyria treatment

The treatment of X-linked protoporphyria is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may benefit affected individuals and their families.

There is no specific, FDA-approved therapy for individuals with X-linked protoporphyria (XLP). Because the disorder is so rare, most treatment information is based on erythropoietic protoporphyria (EPP), which is clinically similar to X-linked protoporphyria (XLP).

Avoidance of sunlight will benefit affected individuals and can include the use of clothing styles with long sleeves and pant legs, made with double layers of fabric or of light-exclusive fabrics, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective, unless they contain light-reflective ingredients (e.g., zinc oxide). Some tanning products with ingredients that increase pigmentation may be helpful. Affected individuals may also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars.

Avoidance of sunlight can potentially cause vitamin D deficiency and some individuals may require supplemental vitamin D.

A high potency form of oral beta-carotene (Lumitene) may be given to improve an affected individual’s tolerance of sunlight. This drug causes skin discoloration and may improve tolerance to sunlight. Oral Lumitene (beta-carotene) (120–180 mg/dL) has been used to improve tolerance to sunlight if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600–800 μg/dL), causing mild skin discoloration due to carotenemia. The beneficial effects of beta-carotene (Lumitene) may involve quenching of singlet oxygen or free radicals. However, a systematic review of about 25 studies showed that the available data are unable to prove efficacy of treatments including beta-carotene, N-acetyl cysteine, and vitamin C ¹⁹. For more information on oral beta-carotene (Lumitene) treatment, contact the American Porphyria Foundation and the Prophyria Consortium of the Rare Diseases Clinical Research Network.

Another drug sometimes used to improve tolerance to sunlight is cysteine.

In 2019, the Food and Drug Administration (FDA) approved Afamelanotide (Scenesse®) for the treatment of adult patients with erythropoietic protoporphyria (EPP). Afamelanotide (Scenesse) is a controlled-release, long-acting injectable implant, alpha-melanocyte-stimulating hormone (α-MSH) analogue, that increases eumelanin by binding to the melanocortin-1 receptor and provides sun protection and improves sun tolerance by increasing skin pigmentation and antioxidant properties ²⁰, ²¹. Afamelanotide (Scenesse) was available in Europe for a period of time before its approval in the United States. Afamelanotide (Scenesse) was approved for patients with the erythropoietic protoporphyria (EPP) by the European Medicines Agency in 2014, and by the FDA in October 2019. Afamelanotide showed positive results in Phase III clinical trials in the US and Europe ²². Long-term studies in Europe show good compliance, clinical effectiveness, and improved quality of life ²³.

Other treatment is symptomatic and supportive.

X-linked protoporphyria (XLP) patients should be seen at least yearly to monitor protoporphyrin levels, anemia, liver enzymes, iron and vitamin D levels.

Liver disease treatment

Treatment of liver disease and complications, which may be accompanied by motor neuropathy, is difficult.

• Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement ⁵⁸.
  • Cholestyramine absorbs porphyrin. Cholestyramine may interrupt the recirculation of protoporphyrin secreted into the bile back into the liver and promote its excretion through the feces. Other drugs that absorb porphyrins such as activated charcoal have also been used to treat affected individuals.
  • Cholestyramine and other porphyrin absorbents, such as activated charcoal may lead to improvement of liver disease.
• Plasmapheresis and intravenous hemin have been used to treat people with erythropoietic protoporphyria (EPP) ⁵⁹.
• Liver transplantation has been performed as a lifesaving measure in individuals with severe protoporphyric liver disease ³⁸, ⁶⁰. However, many liver transplant recipients experience a recurrence of the protoporphyric liver disease in the transplanted liver. Combined bone marrow and liver transplantation is indicated in patients with liver failure to prevent future damage to the allografts ⁶¹, and sequential liver and bone marrow transplantation has been successful in curing protoporphyric liver disease ⁶².
• Bone marrow transplantation has also been attempted without liver transplantation in some instances. A child age two years with X-linked protoporphyria (XLP) and stage 4 liver fibrosis was treated with a hematopoietic progenitor cell transplantation that stabilized his liver disease, thus avoiding liver transplantation ⁶³.

Individuals with any form of protoporphyria should avoid substances associated with cholestasis including alcohol and certain drugs such as estrogens. 

In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery ⁶⁴.

Additional treatment

• Vitamin D supplementation is advised as patients are predisposed to vitamin D deficiency resulting from sun avoidance.
• Immunizations for hepatitis A and B are recommended as well.
• Iron supplementation may be attempted in persons with X-linked protoporphyria (XLP) who have anemia and low ferritin levels. Iron supplementation therapy requires strict monitoring by physicians. Whatley et al ⁷ reported some evidence of diminished iron stores in males with X-linked protoporphyria (XLP); in one patient with iron deficiency, iron repletion decreased protoporphyrin accumulation and corrected the anemia. Subsequent reports indicate that iron supplementation can improve protoporphyrin levels, liver damage, and anemia in X-linked protoporphyria (XLP) ⁶⁵. A pilot study using oral iron supplementation in persons with X-linked protoporphyria (XLP) showed a reduction in protoporphyrin levels, but also carries a risk of increased photosensitivity ⁶⁶.

Pregnancy Management

There is no information on pregnancy management in X-linked protoporphyria (XLP). Based on experience with erythropoietic protoporphyria (EPP), pregnancy is unlikely to be complicated by X-linked protoporphyria (XLP) ⁶⁷.

Investigational Therapies

A Phase 2 clinical trial with MT-7117, an oral small molecule that works as a melanocortin 1 receptor agonist and increases skin pigmentation in subjects with erythropoietic protoporphyria (EPP) has been completed ⁶⁸. A Phase 3 clinical trial for adults and children is planned for MT-7117.

X-Linked Protoporphyria prognosis

The natural history of X-linked protoporphyria (XLP) is not as well characterized as that of the autosomal recessive type of erythropoietic protoporphyria (EPP) ¹. A natural history study from the US described 22 individuals with X-linked protoporphyria (XLP) from seven unrelated families ³⁵.

X-linked protoporphyria (XLP) in Males

While the skin signs and symptoms in males with X-linked protoporphyria (XLP) are similar to those of erythropoietic erythropoietic protoporphyria (EPP), Balwani et al ³⁵ suggest that males with X-linked protoporphyria (XLP) have significantly higher protoporphyrin levels and increased risk of liver dysfunction.

Photosensitivity

Onset of photosensitivity is typically in infancy or childhood with the first exposure to sun; in most individuals with X-linked protoporphyria (XLP) the photosensitivity is lifelong.

Most males with X-linked protoporphyria (XLP) develop acute cutaneous photosensitivity within five to 30 minutes following exposure to sun or ultraviolet light. Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band, to a lesser degree in the long-wave UV region.

The initial symptoms reported are tingling, burning, and/or itching that may be accompanied by swelling and redness. Symptoms vary based on the intensity and duration of sun exposure; pain may be severe and refractory to narcotic analgesics, persisting for hours or days after the initial phototoxic reaction. Symptoms may seem out of proportion to the visible skin lesions. Blistering lesions are uncommon.

Affected males are also sensitive to sunlight that passes through window glass, which does not block long-wave UVA or visible light.

Skin signs and symptoms

Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. The back of the hands is most notably affected.

Severe scarring is rare, as are hyper- or hypopigmentation, skin friability, and hirsutism.

Unlike in other cutaneous porphyrias, blistering and scarring rarely occur.

Liver problems

Protoporphyrin is not excreted in the urine by the kidneys, but is taken up by the liver and excreted in the bile. Accumulated protoporphyrin in the bile can form stones, reduce bile flow, and damage the liver. Protoporphyric liver disease may cause back pain and severe abdominal pain (especially in the right upper quadrant).

The information on X-linked protoporphyria (XLP) and liver disease is limited ¹. The risk for liver dysfunction in X-linked protoporphyria (XLP) (observed in 5/31 affected individuals) is higher than the risk in erythropoietic protoporphyria (EPP) ⁷. A natural history study in the US showed that 40% of males with X-linked protoporphyria (XLP) had a history of abnormal liver enzymes compared to 33% of persons with erythropoietic protoporphyria (EPP). Gallstones were seen in 40% of males with X-linked protoporphyria (XLP) and 33.3% of females with X-linked protoporphyria (XLP) compared to 22.1% of individuals with erythropoietic protoporphyria (EPP).

Note that the information on liver involvement presented below is based on experience with liver disease in autosomal recessive erythropoietic protoporphyria (EPP). Gallstones composed in part of protoporphyrin may be symptomatic in individuals with X-linked protoporphyria (XLP) and need to be excluded as a cause of biliary obstruction in persons with hepatic decompensation.

Life-threatening liver complications are preceded by increased levels of plasma and erythrocyte protoporphyrins, worsening liver function tests, increased photosensitivity, and increased deposition of protoporphyrins in liver cells and bile canaliculi. End-stage liver disease may be accompanied by motor neuropathy, similar to that seen in acute porphyrias. Comorbid conditions, such as viral hepatitis, alcohol abuse, and use of oral contraceptives, which may impair hepatic function or protoporphyrin metabolism, may contribute to hepatic disease in some ³⁸.

Blood problems

Anemia and abnormal iron metabolism can occur in X-linked protoporphyria (XLP). Mild anemia with microcytosis and hypochromia or occasionally reticulocytosis can be seen ¹. However, hemolysis is absent or mild ¹. In a recent series, 30% of males with X-linked protoporphyria (XLP) and 75% of females with X-linked protoporphyria (XLP) were anemic ³⁵.

Vitamin D deficiency

Individuals with X-linked protoporphyria (XLP) who avoid sun/light are at risk for vitamin D deficiency ⁴⁶, ⁴⁷, ⁴⁰.

Triggering factors

Unlike the triggering factors for acute hepatic porphyrias, the only known precipitating factor for X-linked protoporphyria (XLP) is sunlight.

X-linked protoporphyria (XLP) in Females

The signs and symptoms of X-linked protoporphyria (XLP) in heterozygous females, the consequence of random X-chromosome inactivation, ranges from as severe as in affected males to asymptomatic. The median age of symptom onset for females with X-linked protoporphyria (XLP) was 11 years. Following sun exposure, symptom onset ranged from within ten minutes to none ³⁵.

X-Linked Protoporphyria life expectancy

People with X-linked protoporphyria (XLP) generally have a life expectancy similar to those without porphyria, except for those with advanced liver disease ¹.

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