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X-linked erythropoietic protoporphyria(XLDPP; XLEPP)

MedGen UID:
394385
Concept ID:
C2677889
Disease or Syndrome
Synonyms: ERYTHROHEPATIC PROTOPORPHYRIA, X-LINKED; Erythropoietic Protoporphyria, X-Linked Dominant; X-Linked Protoporphyria
SNOMED CT: X-linked dominant erythropoietic protoporphyria (1197360001)
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Source: Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
 
Gene (location): ALAS2 (Xp11.21)
 
Monarch Initiative: MONDO:0010420
OMIM®: 300752
Orphanet: ORPHA443197

Disease characteristics

Excerpted from the GeneReview: X-Linked Protoporphyria
X-linked protoporphyria (XLP) is characterized in affected males by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within minutes of sun/light exposure and may be accompanied by swelling and redness. Blistering lesions are uncommon. Pain, which may seem out of proportion to the visible skin lesions, may persist for hours or days after the initial phototoxic reaction. Photosensitivity is lifelong. 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. An unknown proportion of individuals with XLP develop liver disease. Except for those with advanced liver disease, life expectancy is not reduced. The phenotype in heterozygous females ranges from asymptomatic to as severe as in affected males. [from GeneReviews]
Authors:
Manisha Balwani  |  Robert Desnick  |    view full author information

Additional descriptions

From OMIM
X-linked erythropoietic protoporphyria (XLEPP) is a metabolic disorder of heme biosynthesis characterized by onset in early childhood of severe photosensitivity associated with decreased iron stores and increased erythrocyte zinc- and metal-free protoporphyrin. Some patients may develop liver disease or gallstones (summary by Ducamp et al., 2013). For a discussion of genetic heterogeneity of erythropoietic protoporphyria, see EPP1 (177000).  http://www.omim.org/entry/300752
From MedlinePlus Genetics
Porphyria is a group of disorders caused by abnormalities in the chemical steps that lead to heme production. Heme is a vital molecule for all of the body's organs, although it is most abundant in the blood, bone marrow, and liver. Heme is a component of several iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood).

The porphyrias can also be split into erythropoietic and hepatic types, depending on where damaging compounds called porphyrins and porphyrin precursors first build up in the body. In erythropoietic porphyrias, these compounds originate in the bone marrow. Erythropoietic porphyrias include erythropoietic protoporphyria and congenital erythropoietic porphyria. Health problems associated with erythropoietic porphyrias include a low number of red blood cells (anemia) and enlargement of the spleen (splenomegaly). The other types of porphyrias are considered hepatic porphyrias. In these disorders, porphyrins and porphyrin precursors originate primarily in the liver, leading to abnormal liver function and an increased risk of developing liver cancer.

Researchers have identified several types of porphyria, which are distinguished by their genetic cause and their signs and symptoms. Some types of porphyria, called cutaneous porphyrias, primarily affect the skin. Areas of skin exposed to the sun become fragile and blistered, which can lead to infection, scarring, changes in skin coloring (pigmentation), and increased hair growth. Cutaneous porphyrias include congenital erythropoietic porphyria, erythropoietic protoporphyria, hepatoerythropoietic porphyria, and porphyria cutanea tarda.

Other types of porphyria, called acute porphyrias, primarily affect the nervous system. These disorders are described as "acute" because their signs and symptoms appear quickly and usually last a short time. Episodes of acute porphyria can cause abdominal pain, vomiting, constipation, and diarrhea. During an episode, a person may also experience muscle weakness, seizures, fever, and mental changes such as anxiety and hallucinations. These signs and symptoms can be life-threatening, especially if the muscles that control breathing become paralyzed. Acute porphyrias include acute intermittent porphyria and ALAD deficiency porphyria. Two other forms of porphyria, hereditary coproporphyria and variegate porphyria, can have both acute and cutaneous symptoms.

Environmental factors can strongly influence the occurrence and severity of signs and symptoms of porphyria. Alcohol, smoking, certain drugs, hormones, other illnesses, stress, and dieting or periods without food (fasting) can all trigger the signs and symptoms of some forms of the disorder. Additionally, exposure to sunlight worsens the skin damage in people with cutaneous porphyrias.  https://medlineplus.gov/genetics/condition/porphyria

Clinical features

From HPO
Cholelithiasis
MedGen UID:
3039
Concept ID:
C0008350
Disease or Syndrome
Hard, pebble-like deposits that form within the gallbladder.
Iron deficiency anemia
MedGen UID:
57668
Concept ID:
C0162316
Disease or Syndrome
Anemia caused by low iron intake, inefficient iron absorption in the gastrointestinal tract, or chronic blood loss.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Increased erythrocyte protoporphyrin concentration
MedGen UID:
868608
Concept ID:
C4023007
Finding
Concentration of protoporphyrins in erythrocytes above the upper limit of normal.
Cutaneous photosensitivity
MedGen UID:
87601
Concept ID:
C0349506
Pathologic Function
An increased sensitivity of the skin to light. Photosensitivity may result in a rash upon exposure to the sun (which is known as photodermatosis). Photosensitivity can be diagnosed by phototests in which light is shone on small areas of skin.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVX-linked erythropoietic protoporphyria

Professional guidelines

PubMed

Dickey AK, Naik H, Keel SB, Levy C, Beaven SW, Elmariah SB, Erwin AL, Goddu RJ, Hedstrom K, Leaf RK, Kazamel M, Mazepa M, Philpotts LL, Quigley J, Raef H, Rudnick SR, Saberi B, Thapar M, Ungar J, Wang B, Balwani M; Porphyrias Consortium of the Rare Diseases Clinical Research Network
J Am Acad Dermatol 2023 Dec;89(6):1227-1237. Epub 2022 Aug 27 doi: 10.1016/j.jaad.2022.08.036. PMID: 36041558Free PMC Article
Balwani M
Mol Genet Metab 2019 Nov;128(3):298-303. Epub 2019 Jan 24 doi: 10.1016/j.ymgme.2019.01.020. PMID: 30704898Free PMC Article
Whatley SD, Badminton MN
Ann Clin Biochem 2013 May;50(Pt 3):204-16. doi: 10.1177/0004563212473278. PMID: 23605133

Recent clinical studies

Etiology

Balwani M, Bonkovsky HL, Levy C, Anderson KE, Bissell DM, Parker C, Takahashi F, Desnick RJ, Belongie K; Endeavor Investigators
N Engl J Med 2023 Apr 13;388(15):1376-1385. doi: 10.1056/NEJMoa2208754. PMID: 37043653
Phillips JD
Mol Genet Metab 2019 Nov;128(3):164-177. Epub 2019 Apr 22 doi: 10.1016/j.ymgme.2019.04.008. PMID: 31326287Free PMC Article
Balwani M
Mol Genet Metab 2019 Nov;128(3):298-303. Epub 2019 Jan 24 doi: 10.1016/j.ymgme.2019.01.020. PMID: 30704898Free PMC Article
Ramanujam VS, Anderson KE
Curr Protoc Hum Genet 2015 Jul 1;86:17.20.1-17.20.26. doi: 10.1002/0471142905.hg1720s86. PMID: 26132003Free PMC Article
Lecha M, Puy H, Deybach JC
Orphanet J Rare Dis 2009 Sep 10;4:19. doi: 10.1186/1750-1172-4-19. PMID: 19744342Free PMC Article

Diagnosis

Dickey AK, Naik H, Keel SB, Levy C, Beaven SW, Elmariah SB, Erwin AL, Goddu RJ, Hedstrom K, Leaf RK, Kazamel M, Mazepa M, Philpotts LL, Quigley J, Raef H, Rudnick SR, Saberi B, Thapar M, Ungar J, Wang B, Balwani M; Porphyrias Consortium of the Rare Diseases Clinical Research Network
J Am Acad Dermatol 2023 Dec;89(6):1227-1237. Epub 2022 Aug 27 doi: 10.1016/j.jaad.2022.08.036. PMID: 36041558Free PMC Article
Stölzel U, Doss MO, Schuppan D
Gastroenterology 2019 Aug;157(2):365-381.e4. Epub 2019 May 11 doi: 10.1053/j.gastro.2019.04.050. PMID: 31085196
Balwani M
Mol Genet Metab 2019 Nov;128(3):298-303. Epub 2019 Jan 24 doi: 10.1016/j.ymgme.2019.01.020. PMID: 30704898Free PMC Article
Ramanujam VS, Anderson KE
Curr Protoc Hum Genet 2015 Jul 1;86:17.20.1-17.20.26. doi: 10.1002/0471142905.hg1720s86. PMID: 26132003Free PMC Article
Lecha M, Puy H, Deybach JC
Orphanet J Rare Dis 2009 Sep 10;4:19. doi: 10.1186/1750-1172-4-19. PMID: 19744342Free PMC Article

Therapy

Ogasawara A, Ogawa K, Ide R, Ikenaga Y, Fukunaga C, Nakayama S, Tsuda M
Eur J Clin Pharmacol 2023 Jun;79(6):801-813. Epub 2023 Apr 15 doi: 10.1007/s00228-023-03476-6. PMID: 37060458Free PMC Article
Balwani M, Bonkovsky HL, Levy C, Anderson KE, Bissell DM, Parker C, Takahashi F, Desnick RJ, Belongie K; Endeavor Investigators
N Engl J Med 2023 Apr 13;388(15):1376-1385. doi: 10.1056/NEJMoa2208754. PMID: 37043653
Heerfordt IM, Lerche CM, Philipsen PA, Wulf HC
Biomed Pharmacother 2023 Feb;158:114132. Epub 2022 Dec 14 doi: 10.1016/j.biopha.2022.114132. PMID: 36525819
Balwani M
Mol Genet Metab 2019 Nov;128(3):298-303. Epub 2019 Jan 24 doi: 10.1016/j.ymgme.2019.01.020. PMID: 30704898Free PMC Article
Manceau H, Gouya L, Puy H
Curr Opin Hematol 2017 May;24(3):198-207. doi: 10.1097/MOH.0000000000000330. PMID: 28118224

Prognosis

Ventura P, Brancaleoni V, Di Pierro E, Graziadei G, Macrì A, Carmine Guida C, Nicolli A, Rossi MT, Granata F, Fiorentino V, Fustinoni S, Sala R, Pinton PC, Trevisan A, Marchini S, Cuoghi C, Marcacci M, Corradini E, Sorge F, Aurizi C, Savino MG, Cappellini MD, Pietrangelo A
Eur J Dermatol 2020 Oct 1;30(5):532-540. doi: 10.1684/ejd.2020.3880. PMID: 33021473
Yasuda M, Chen B, Desnick RJ
Mol Genet Metab 2019 Nov;128(3):320-331. Epub 2018 Nov 30 doi: 10.1016/j.ymgme.2018.11.012. PMID: 30594473Free PMC Article
Whatley SD, Badminton MN
Ann Clin Biochem 2013 May;50(Pt 3):204-16. doi: 10.1177/0004563212473278. PMID: 23605133
Whatley SD, Mason NG, Holme SA, Anstey AV, Elder GH, Badminton MN
Br J Dermatol 2010 Mar;162(3):642-6. Epub 2010 Jan 22 doi: 10.1111/j.1365-2133.2010.09631.x. PMID: 20105171
Lecha M, Puy H, Deybach JC
Orphanet J Rare Dis 2009 Sep 10;4:19. doi: 10.1186/1750-1172-4-19. PMID: 19744342Free PMC Article

Clinical prediction guides

Ogasawara A, Ogawa K, Ide R, Ikenaga Y, Fukunaga C, Nakayama S, Tsuda M
Eur J Clin Pharmacol 2023 Jun;79(6):801-813. Epub 2023 Apr 15 doi: 10.1007/s00228-023-03476-6. PMID: 37060458Free PMC Article
Ventura P, Brancaleoni V, Di Pierro E, Graziadei G, Macrì A, Carmine Guida C, Nicolli A, Rossi MT, Granata F, Fiorentino V, Fustinoni S, Sala R, Pinton PC, Trevisan A, Marchini S, Cuoghi C, Marcacci M, Corradini E, Sorge F, Aurizi C, Savino MG, Cappellini MD, Pietrangelo A
Eur J Dermatol 2020 Oct 1;30(5):532-540. doi: 10.1684/ejd.2020.3880. PMID: 33021473
Phillips JD
Mol Genet Metab 2019 Nov;128(3):164-177. Epub 2019 Apr 22 doi: 10.1016/j.ymgme.2019.04.008. PMID: 31326287Free PMC Article
Yasuda M, Chen B, Desnick RJ
Mol Genet Metab 2019 Nov;128(3):320-331. Epub 2018 Nov 30 doi: 10.1016/j.ymgme.2018.11.012. PMID: 30594473Free PMC Article
Balwani M, Naik H, Anderson KE, Bissell DM, Bloomer J, Bonkovsky HL, Phillips JD, Overbey JR, Wang B, Singal AK, Liu LU, Desnick RJ
JAMA Dermatol 2017 Aug 1;153(8):789-796. doi: 10.1001/jamadermatol.2017.1557. PMID: 28614581Free PMC Article

Recent systematic reviews

Heerfordt IM, Philipsen PA, Lerche CM, Wulf HC
Exp Dermatol 2023 Jul;32(7):1042-1047. Epub 2023 Apr 13 doi: 10.1111/exd.14809. PMID: 37052136
Heerfordt IM, Lerche CM, Philipsen PA, Wulf HC
Biomed Pharmacother 2023 Feb;158:114132. Epub 2022 Dec 14 doi: 10.1016/j.biopha.2022.114132. PMID: 36525819

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