Molecular epidemiology of erythropoietic protoporphyria in the U.K.

Whatley, Sharon D.; Mason, Nicola G.; Holme, S.A.; Anstey, Alexander Vincent; Elder, George H.; Badminton, Michael Norman

doi:10.1111/j.1365-2133.2010.09631.x

Cited by 57 publications

(86 citation statements)

References 23 publications

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“…In ϳ 5%-10% of EPP families, 2 FECH loss-of-function mutations have been found. 25,41,42 These patients may have a variant EPP phenotype with palmar keratosis. 38 The 2 exon 11 ALAS2 mutations that cause XLP alter the carboxyl-terminal amino acid sequence and result in increased ALAS2 activity and the accumulation of free and zincprotoporphyrins.…”

Section: Diagnosismentioning

confidence: 99%

The porphyrias: advances in diagnosis and treatment

Balwani

Desnick

2012

Blood

218

240

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The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as "acute hepatic," "hepatic cutaneous," and "erythropoietic cutaneous" diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis of the acute hepatic porphyrias, identification of the iron overloadinduced inhibitor of hepatic uroporphyrin decarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, the identification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations in erythroidspecific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic prophyrias. Knowledge of these advances is relevant for hematologists because they administer the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias, perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions in porphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders. (Blood. 2012;120(23):4496-4504)

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Section: Diagnosismentioning

confidence: 99%

The porphyrias: advances in diagnosis and treatment

Balwani

Desnick

2012

Blood

218

240

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“…91 XLDPP was found in 29 families worldwide and in ;2% (United Kingdom) to ;10% (United States) of patients with the EPP phenotype. 90 The diminished ferrochelatase activity in the EPP variant results in reduced heme synthesis, with occasional ringed sideroblasts but without systemic iron overload.…”

Section: E Epp Due To Defects In Fech and Gof Mutations In Alas2 (Xmentioning

confidence: 99%

Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis

Donker

Raymakers

Vlasveld

et al. 2014

Blood

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During recent years, our understanding of the pathogenesis of inherited microcytic anemias has gained from the identification of several genes and proteins involved in systemic and cellular iron metabolism and heme syntheses. Numerous case reports illustrate that the implementation of these novel molecular discoveries in clinical practice has increased our understanding of the presentation, diagnosis, and management of these diseases. Integration of these insights into daily clinical practice will reduce delays in establishing a proper diagnosis, invasive and/or costly diagnostic tests, and unnecessary or even detrimental treatments. To assist the clinician, we developed evidence-based multidisciplinary guidelines on the management of rare microcytic anemias due to genetic disorders of iron metabolism and heme synthesis. These genetic disorders may present at all ages, and therefore these guidelines are relevant for pediatricians as well as clinicians who treat adults. This article summarizes these clinical practice guidelines and includes background on pathogenesis, conclusions, and recommendations and a diagnostic flowchart to facilitate using these guidelines in the clinical setting.

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“…Clinically, it presents with cutaneous photosensitivity symptoms, and in about 2% of patients causes severe liver disease [1,3,6,7]. EPP usually begins to manifest in early childhood, although, as far as we know, another 21 cases of late onset have been described in the literature, associated (50%) or not associated with hematological malignancy (table 1) [5,6,7,8,9,10,11].…”

Section: Discussionmentioning

confidence: 99%

“…In most patients, the disease is due to deficient activity of the FECH enzyme coded by the FECH gene. The disease is transmitted mainly following an autosomal dominant inheritance pattern, although families with autosomal recessive EPP have been described, where the FECH gene mutation is present in both alleles [1,2,3,9]. In addition, recent reports show that in about 2% of patients, protoporphyrin overproduction is due to gain-in-function mutations in the ALAS2 gene which codes for the initial enzyme (5-ALAS) in the heme group biosynthesis [1,4,10].…”

Section: Discussionmentioning

confidence: 99%

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Annular Elastolytic Giant Cell Granuloma Associated to Late-Onset X-Linked Dominant Protoporphyria

et al. 2013

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X-linked dominant protoporphyria (XLDPP) is a genetic disorder that affects the synthesis of the heme group due to an increase in delta-aminolaevulinate synthase 2 (ALAS2) enzyme activity. Moreover, annular elastolytic giant-cell granuloma (AEGCG) is a rare reactive granulomatous dermatosis, usually associated with actinic damage. An 86-year-old man presented with edematous-erythematous lesions in photoexposed areas of the face and on the dorsum of both hands. Protoporphyrin levels in serum and feces were significantly elevated and a heterozygous frameshift mutation in the exon 11 of the ALAS2 gene: c.1706-1709del (p.Glu569GlyfsX24) was identified. Concomitantly, we observed an annular plaque with raised borders on the back of his right hand, clinically and histologically compatible with a diagnosis of AEGCG. Skin lesions disappeared only upon use of a physical sunscreen. We report two rare photodermatoses in an elderly patient and discuss the significance of dermal elastic fiber damage induced by the XLDPP as a main triggering factor of AEGCG.

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Molecular epidemiology of erythropoietic protoporphyria in the U.K.

Abstract: These data define the prevalence and molecular epidemiology of each type of EPP in the U.K.

Cited by 57 publications

References 23 publications

The porphyrias: advances in diagnosis and treatment

The porphyrias: advances in diagnosis and treatment

Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis

Annular Elastolytic Giant Cell Granuloma Associated to Late-Onset X-Linked Dominant Protoporphyria

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