Iron in erythropoietic protoporphyrias: Dr. Jekyll or Mr. Hyde?

Barman-Aksoezen, Jasmin; Schneider‐Yin, Xiaoye; Minder, Elisabeth I.

doi:10.29245/2572-9411/2017/4.1110

Cited by 8 publications

(14 citation statements)

References 28 publications

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“…In addition to the treatment plans discussed earlier, EPP patients, without a FECH mutation, have found beneficial results when treated with iron supplements. 27 , 28 , 32 Iron supplements help clear excess PPIX by driving the metalation reaction catalyzed by FECH. 27 , 28 , 32 However, long-term effects of continual iron supplementation are still being investigated.…”

Section: Developing New Treatments For Epp Patientsmentioning

confidence: 99%

“… 27 , 28 , 32 Iron supplements help clear excess PPIX by driving the metalation reaction catalyzed by FECH. 27 , 28 , 32 However, long-term effects of continual iron supplementation are still being investigated. 32 In addition, treating with iron supplements has only been met with limited success.…”

Section: Developing New Treatments For Epp Patientsmentioning

confidence: 99%

“… 27 , 28 , 32 However, long-term effects of continual iron supplementation are still being investigated. 32 In addition, treating with iron supplements has only been met with limited success. This is likely due to feedback inhibition of iron uptake via the bone morphogenetic protein (BMP) signaling pathway.…”

Section: Developing New Treatments For Epp Patientsmentioning

confidence: 99%

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The role of ClpX in erythropoietic protoporphyria

Whitman

Paw

Chung

2018

Hematology, Transfusion and Cell Therapy

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Hemoglobin is an essential biological component of human physiology and its production in red blood cells relies upon proper biosynthesis of heme and globin protein. Disruption in the synthesis of these precursors accounts for a number of human blood disorders found in patients. Mutations in genes encoding heme biosynthesis enzymes are associated with a broad class of metabolic disorders called porphyrias. In particular, one subtype – erythropoietic protoporphyria – is caused by the accumulation of protoporphyrin IX. Erythropoietic protoporphyria patients suffer from photosensitivity and a higher risk of liver failure, which is the principle cause of morbidity and mortality. Approximately 90% of these patients carry loss-of-function mutations in the enzyme ferrochelatase (FECH), while 5% of cases are associated with activating mutations in the C-terminus of ALAS2. Recent work has begun to uncover novel mechanisms of heme regulation that may account for the remaining 5% of cases with previously unknown genetic basis. One erythropoietic protoporphyria family has been identified with inherited mutations in the AAA+ protease ClpXP that regulates ALAS activity. In this review article, recent findings on the role of ClpXP as both an activating unfoldase and degrading protease and its impact on heme synthesis will be discussed. This review will also highlight the role of ClpX dysfunction in erythropoietic protoporphyria.

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Section: Developing New Treatments For Epp Patientsmentioning

confidence: 99%

Section: Developing New Treatments For Epp Patientsmentioning

confidence: 99%

Section: Developing New Treatments For Epp Patientsmentioning

confidence: 99%

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The role of ClpX in erythropoietic protoporphyria

Whitman

Paw

Chung

2018

Hematology, Transfusion and Cell Therapy

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“…127,128 In contrast, iron substitution can worsen EPP by stimulating the bone marrow enzyme ALAS2. 129 Moreover, mild iron deficiency might protect patients with EPP. Iron substitution in patients with EPP, if necessary, such as in patients with significant anemia, may be considered during the darker seasons when the intensity of sunlight is low.…”

Section: Therapymentioning

confidence: 99%

Clinical Guide and Update on Porphyrias

Stölzel¹,

Doss²,

Schuppan³

2019

Gastroenterology

129

158

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Physicians should be aware of porphyrias, which could be responsible for unexplained gastrointestinal, neurologic, or skin disorders. Despite their relative rarity and complexity, most porphyrias can be easily defined and diagnosed. They are caused by well-characterized enzyme defects in the complex heme biosynthetic pathway and are divided into categories of acute vs non-acute or hepatic vs erythropoietic porphyrias. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficient porphyria) manifest in attacks and are characterized by overproduction of porphyrin precursors, producing often serious abdominal, psychiatric, neurologic, or cardiovascular symptoms. Patients with variegate porphyria and hereditary coproporphyria can present with skin photosensitivity. Diagnosis relies on measurement of increased urinary 5-aminolevulinic acid (in patients with aminolevulinic acid dehydratase deficient porphyria) or increased 5-aminolevulinic acid and porphobilinogen (in patients with other acute porphyrias). Management of attacks requires intensive care, strict avoidance of porphyrinogenic drugs and other precipitating factors, caloric support, and often heme therapy. The non-acute porphyrias are porphyria cutanea tarda, erythropoietic protoporphyria, X-linked protoporphyria, and the rare congenital erythropoietic porphyria. They lead to the accumulation of porphyrins that cause skin photosensitivity and occasionally severe liver damage. Secondary elevated urinary or blood porphyrins can occur in patients without porphyria, for example, in liver diseases, or iron deficiency. Increases in porphyrin precursors and porphyrins are also found in patients with lead intoxication. Patients with porphyria cutanea tarda benefit from iron depletion, hydroxychloroquine therapy, and, if applicable, elimination of the hepatitis C virus. An a-melanocytestimulating hormone analogue can reduce sunlight sensitivity in patients with erythropoietic protoporphyria or Xlinked protoporphyria. Strategies to address dysregulated or dysfunctional steps within the heme biosynthetic pathway are in development.

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“…Obwohl auch bei EPP ein Eisenmangel beobachtet werden kann, kommt es bei einer Eisensubstitution zu einer direkten Induktion der Erythropoese über das geschwindigkeitsbestimmende Enzym (ALAS2). Diese geht mit erhöhter Protoporphyrinbildung und korrespondierend zunehmender Lichtempfindlichkeit einher [22].…”

Section: Merkeunclassified