Updated: Dec 18, 2019
  • Author: Jose A Plaza, MD; Chief Editor: William D James, MD  more...
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The term protoporphyria now encompasses two clinically similar disorders that most often result from hereditary mutations in one of three different genes. The most common is erythropoietic protoporphyria (EPP). It is an inherited disorder caused by partial deficiency in mitochondrial ferrochelatase (FECH), the terminal enzyme of heme biosynthesis. The resultant accumulated excess of its substrate, metal-free protoporphyrin, causes two principal manifestations: (1) an acute cutaneous photosensitivity typically first appearing during childhood and (2) hepatobiliary disease. [1, 2, 3, 4, 5]

The predominant genotype associated with phenotypic expression of EPP is one mutant ferrochelatase allele (FECH) encoding a defective enzyme protein with little or no function, paired with a relatively common polymorphic allele (IVS3-48T>C) with low gene expression that only mildly affects heme synthesis. [6, 7] This type of inheritance has been termed pseudodominant [8, 9] or semidominant, [10] but is often referred to as autosomal recessive [11] in that anomalies in both paired FECH alleles are required for disease expression, even though one alteration causes marked reduction or abrogation of residual enzyme activity while the polymorphism causes little clinically noticeable harm when unpaired with a severely dysfunctional allele. Infrequently, two deleterious FECH mutations are paired in a recessive genotype of EPP that may impart a higher risk for hepatic dysfunction. [12, 13] Rarely, acquired somatic mutation or deletion of a ferrochelatase gene secondary to myelodysplastic or myeloproliferative disorders leads to an adult-onset protoporphyric disorder. [14, 15, 16]

A far less frequent type (< 10%) of hereditary protoporphyria, now recognized as a separate disorder, is X-linked dominant protoporphyria (XLDPP, OMIM 300752), or simply XLP. XLP arises from C-terminal deletions or alterations in the gene encoding the erythroid-specific enzyme 5-aminolevulinic acid synthase-2 (ALAS2), increased function of which leads to overproduction of protoporphyrin. [11, 17] Like EPP, XLP is caused by bone marrow heme synthetic dysfunction, but most often results in a greater ratio of accumulated erythrocyte zinc-protoporphyrin to metal-free protoporphyrin than is typical for EPP. XLP manifests as an acute, childhood-onset, cutaneous photosensitivity indistinguishable from that of EPP, but appears to have a higher risk for hepatic dysfunction. [17] An adult-onset case of XLP in an 89-year-old man with evolving myelodysplasia exhibited somatic mosaicism in erythroid hematopoietic cells associated with an ALAS2 mutation that predicted a C-terminal deletion. [18]

Mutation in a third gene, CLPX, which encodes the mitochondrial AAA+ unfoldase ClpX, has been linked to a familial disorder with biochemical and clinical features of protoporphyria in individuals without either FECH or ALAS2 mutations. [19] ClpX acts to control ALAS activation and degradation during heme synthesis. Defective CLPX leads to increased ALAS post-translational stability, which results in excess accumulation of erythrocyte protoporphyrin. [19]



Protoporphyrin is a lipophilic molecule capable of transformation to excited states by absorption of light energy. Excited-state protoporphyrin mediates photoxidative damage to biomolecular targets in the skin, [20] resulting in immediate phototoxic symptoms variously described as tingling, stinging, or burning that may be followed by the appearance of erythema, edema, and purpura. [1, 20] Excess protoporphyrin is formed during maturation of erythroid cells in the bone marrow and present at the highest levels in reticulocytes and young erythrocytes. [21] Metal-free protoporphyrin escapes from red blood cells into the plasma, from which it is cleared by the liver and secreted into bile. Protoporphyrin-rich bile facilitates gallstone formation. [22] Toxic effects of protoporphyrin deposition in the liver may lead to life-threatening hepatic dysfunction. [22, 23, 24] 99



The cytogenetic location of the ferrochelatase gene is 18q21.3. [25] Loss of activity by as much as 50% as the result of one FECH mutant gene is generally insufficient to cause overt disease when its complementary allele has normal function. [6] FECH genotypes composed of either two mutant alleles (< 1-4% of cases) or one mutation and a variant allele with a specific intronic single nucleotide polymorphism (IVS3-48C) (~82-94% of cases) have been found in most symptomatic individuals. [9, 12, 13, 26, 27] This polymorphism enhances aberrant splicing and rapid degradation of FECH mRNA, with resultant low expression. [7] The allele frequency of this polymorphism varies widely in diverse populations studied, as follows:

  • Japanese - 43.3% [13] ; 45.2% [28]

  • Southeast Asian - 31% [13]

  • White French - 11.3% [13]

  • North African - 2.7% [13]

  • Black West African - < 1% [13]

  • United States - 3.5% [29]

  • South Africans of European descent - 9%

  • United Kingdom - 6.5% [12]

  • Chinese (different regions) - 28-41.4% [30]

  • Swedish - 8% [31]

The pairing of a mutated allele encoding a severely impaired enzyme protein with this low-expressing polymorphic allele typically yields enzyme activity diminished to less than 30% of normal, low enough to cause protoporphyrin accumulation. Individuals with no FECH mutation but who are heterozygous for this polymorphism typically do not have sufficiently diminished FECH activity to cause clinical abnormalities. Individuals with no FECH mutation, but who are homozygous for this polymorphism, may exhibit slightly abnormal erythrocyte protoporphyrin levels and mild photosensitivity. [32]

Adult-onset protoporphyric photosensitivity and increased protoporphyrin levels have been associated with an acquired somatic mutation or deletion of a FECH gene due to myelodysplastic or myeloproliferative disorders. [14, 15, 16]

Eight families were described in 2008 [17] with a protoporphyric disorder indistinguishable clinically from the predominant form of the disease, but without FECH mutations, that is now called X-linked dominant protoporphyria or X-linked protoporphyria (XLDPP, XLP or XLEPP [OMIM 300752]). Two different C-terminal deletions in the gene encoding the erythroid-specific isoform of aminolevulinic acid synthase were identified among these families. The locus for this gene was identified on the X-chromosome, and the inheritance pattern in the families was consistent with X-linked dominant transmission. Both mutations caused a marked increase in activity of ALAS2 that eventuated in large accumulations of erythrocyte metal-free protoporphyrin and zinc-protoporphyrin. Seventeen percent of affected individuals in that study exhibited overt liver disease (40% of affected males), a significantly greater number than the 2-5% of individuals with ferrochelatase-deficient protoporphyria who develop this complication.

Additional cases of XLP and novel associated gain-of-function ALAS2 mutations have subsequently been recognized. [9, 11, 18, 33, 34, 35] A higher prevalence (~10%) of XLP was found among 226 North American individuals with the protoporphyria phenotype; this is 2-5 times greater than observed among Western Europeans previously studied. [11]




United States

Until the recently established registry for protoporphyria sponsored by the American Porphyria Foundation collects sufficient data, accurate enumeration in the United States cannot be provided, but it is probably similar to data from European countries. A study of 226 North American individuals exhibiting the protoporphyria phenotype identified 22 with ALAS2 mutations and 187 with FECH anomalies. [33] The ALAS2/FECH ratio of approximately 10% in this study is greater than ratios reported elsewhere.


Estimates of one EPP case in populations of 75,000-200,000 have been reported for several Western European populations and in the South African population of European ancestry. [3, 36, 37, 38] XLP remains rare but has been identified in increasing numbers. [9, 11, 17, 33, 34, 35, 39]


EPP has been reported most often in people with white heritage, but it has also been reported in persons with Japanese, Chinese, East Indian, or north or central African ancestry. XLP has been identified chiefly among individuals of Western European ancestry but also in an African American and Pacific Islander [11] and a Japanese boy. [34]


EPP and XLP occur in both males and females.


Photocutaneous symptoms usually appear during childhood, [1] but they also may be noted for the first time in adult life. [14, 15, 16, 18, 39] Gallstones may become symptomatic in young adulthood or in middle age. [1] Liver failure and its complications, sufficiently severe to result in liver transplantation and/or death, may develop in children and adolescents as well as adults. [22, 24, 40, 41, 42]



In the absence of hepatic failure, individuals with EPP have normal life expectancies.

Painful cutaneous photosensitivity reduces the sunlight tolerance of individuals with protoporphyria and may influence their lifestyles over entire lifetimes. [1]

An increased prevalence of cholelithiasis in both men and women can result in signs and symptoms of gallstone disease at relatively early ages. [1]

Hepatotoxic effects of excess protoporphyrin deposition have led to liver dysfunction that progressed to life-threatening severity in approximately 2-5% of known cases of protoporphyria. [3]