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of heme biosynthesis: X-linked sideroblastic anemias and the ..

inherited disorders of heme biosynthesis include the porphyrias and X-linked sideroblastic anemia.

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Disorders of Heme Biosynthesis: X-Linked Sideroblastic ..

Severe cutaneous photosensitivity begins in early infancy in most cases. The disease may be recognized in utero as a cause of nonimmune hydrops fetalis. The skin over light-exposed areas is friable, and bullae and vesicles are prone to rupture and infection (). Skin thickening, focal hypopigmentation and hyperpigmentation, and hypertrichosis of the face and extremities are characteristic. Secondary infection and bone resorption may lead to disfigurement of the face and hands. The teeth are reddish brown and fluoresce on exposure to long-wave ultraviolet light. Hemolysis is probably the result of the marked increase in erythrocyte porphyrins and leads to splenomegaly. A later-onset, milder form of the disease has been reported., However, several of these later-onset patients had a myeloid malignancy (usually myelodysplastic disorder) and were found to have normal erythrocyte URO-synthase activity, and no germline URO-synthase (UROS) or GATA1 mutations; this entity was termed erythropoietic uroporphyria, presumably because only a minor clone of uroporphyric cells had somatic UROS mutations causing the uroporphyrinogen I accumulation and the late-onset phenotype.

Disorders of heme biosynthesis: X‐linked sideroblastic anemia and the ..

All of the genes encoding the heme biosynthetic enzymes have been cloned and mutations of these genes are responsible for a group of human disorders designated the porphyrias and for X-linked sideroblastic anemia.

Disorders of heme biosynthesis: X-linked sideroblastic anemia ..

Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias.

The porphyrias are a group of eight disorders of haem biosynthesis characterised by overproduction of haem precursors secondary to partial enzyme deficiencies or, in one porphyria, gain of function of the rate‐controlling enzyme of the pathway in erythroid cells. Patients suffer from acute neurovisceral attacks, always associated with overproduction of porphyrin precursors, skin lesions caused by photosensitisation by porphyrins or both together. All are inherited, apart from sporadic porphyria cutanea tarda. The three porphyrias in which acute attacks occur (acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) and familial porphyria cutanea tarda are low penetrance autosomal dominant disorders and one is an X‐linked disorder. All others are autosomal recessive. Enzyme activities in the autosomal recessive porphyrias and in the homozygous variants of other porphyrias are usually less than 20% of normal.

Anderson KE, Sassa S, Bishop D and Desnick RJ (2001) Disorders of heme biosynthesis: X‐linked sideroblastic anemia and the porphyrias. In: Scriver CR, Beaudet AL, Sly WS and Valle D, (eds); Childs B, Kinzler KW, Vogelstein B (assoc eds). The Metabolic and Molecular Bases of Inherited Disease, 8th edn, pp. 2961–3062. New York: McGraw‐Hill.

Porphyrin and Heme Synthesis and Bilirubin Metabolism

Disorders of heme biosynthesis:X-linked sideroblastic anemia and the porphyrias

The inborn errors of heme biosynthesis, the porphyrias, are metabolic disorders, each resulting from the deficiency of a specific enzyme in the heme biosynthetic pathway (; )., These enzyme deficiencies are inherited as autosomal dominant, autosomal recessive, or X-linked traits, with the exception of the most common porphyria, porphyria cutanea tarda (PCT), which usually is sporadic. Notably, these are disorders in which environmental, physiologic, and genetic factors interact to alter the normally tight regulation of heme biosynthesis and cause disease.

Hematologists often are involved in the diagnosis and/or treatment of these diseases, which as a group can be difficult to diagnose and are considered by many physicians as confusing and complex. Here we present a simplified approach to their classification and focus on the recent advances in understanding their pathogenesis, gene-based diagnoses, identification of their molecular genetic heterogeneity, and currently approved and experimental therapies. We also briefly highlight relevant aspects of heme biosynthesis, including the role of the housekeeping and erythroid-specific 5-aminolevulinate synthase genes (ALAS1 and ALAS2), the mechanism of inhibition of uroporphyrinogen decarboxylase (URO-decarboxylase) activity in sporadic and familial PCT, and the recent recognition that ALAS2 gain-of-function mutations cause X-linked protoporphyria (XLP).

Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias
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The porphyrias are relatively rare disorders ..

N2 - Most iron in mammalian systems is routed to mitochondria to serve as a substrate for ferrochelatase. Ferrochelatase inserts iron into protoporphyrin IX to form heme which is incorporated into hemoglobin and cytochromes, the dominant hemoproteins in mammals. Tissue-specific regulatory features characterize the heme biosynthetic pathway. In erythroid cells, regulation is mediated by erythroid-specific transcription factors and the availability of iron as Fe/S clusters. In non-erythroid cells the pathway is regulated by heme-mediated feedback inhibition. All of the enzymes in the heme biosynthetic pathway have been crystallized and the crystal structures have permitted detailed analyses of enzyme mechanisms. All of the genes encoding the heme biosynthetic enzymes have been cloned and mutations of these genes are responsible for a group of human disorders designated the porphyrias and for X-linked sideroblastic anemia. The biochemistry, structural biology and the mechanisms of tissue-specific regulation are presented in this review along with the key features of the porphyric disorders.

X-linked sideroblastic anemia ..

AB - Most iron in mammalian systems is routed to mitochondria to serve as a substrate for ferrochelatase. Ferrochelatase inserts iron into protoporphyrin IX to form heme which is incorporated into hemoglobin and cytochromes, the dominant hemoproteins in mammals. Tissue-specific regulatory features characterize the heme biosynthetic pathway. In erythroid cells, regulation is mediated by erythroid-specific transcription factors and the availability of iron as Fe/S clusters. In non-erythroid cells the pathway is regulated by heme-mediated feedback inhibition. All of the enzymes in the heme biosynthetic pathway have been crystallized and the crystal structures have permitted detailed analyses of enzyme mechanisms. All of the genes encoding the heme biosynthetic enzymes have been cloned and mutations of these genes are responsible for a group of human disorders designated the porphyrias and for X-linked sideroblastic anemia. The biochemistry, structural biology and the mechanisms of tissue-specific regulation are presented in this review along with the key features of the porphyric disorders.

. Disorders of Heme Biosynthesis: The Porphyrias | …

The porphyrias are a group of inherited disorders resulting fromenzyme defects in the heme biosynthetic pathway. Depending on thespecific enzyme involved, various porphyrins and their precursorsaccumulate in different specimen types. The patterns of porphyrinaccumulation in erythrocytes and plasma and excretion of the hemeprecursors in urine and feces allow for the detection anddifferentiation of the porphyrias.

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