Hereditary Hypochromic Anemia with Transfusion Hemosiderosis Treated with Pyridoxine

Bishop, Ronald C.; Bethell, Frank H.

doi:10.1056/nejm195909032611004

Cited by 46 publications

(23 citation statements)

References 7 publications

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“…1 The defect results in hyperferremia and potential death from hemochromatosis. In some cases, XLSA can be partially rescued by supplementation with pyridoxine, 51 which is the cofactor of ALAS2. 52 Despite disruption to heme biosynthesis and an increase in mitochondrial Fe loading, no neuropathy was observed in this disease, in contrast to that found in XLSA/A (see "X-linked sideroblastic anemia with ataxia (XLSA/A)").…”

Section: X-linked Sideroblastic Anemiamentioning

confidence: 99%

Iron trafficking in the mitochondrion: novel pathways revealed by disease

Napier

Ponka

Richardson

2005

Blood

250

201

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It is well known that iron (Fe) is trans- IntroductionSince its discovery, the mitochondrion has been known as an essential and dynamic component of cellular biochemistry. The complexity of the mitochondrion has been gradually revealed by the study of a variety of genetic diseases associated with its function. Thus far, it is clear that Fe plays a crucial role in many facets of mitochondrial metabolism and the consequences of disruption to these pathways are catastrophic. Therefore, it would seem clear that the mitochondrion, a site of dynamically active electron transport and redox activity, would possess sufficient measures for the safe trafficking and metabolism of Fe. However, until recently, knowledge of the Fe metabolism of the mitochondrion has been largely confined to the heme synthesis pathway (for review, see Ponka 1 ), and very little was understood concerning the trafficking and storage of Fe in this organelle.The recent discovery of a plethora of mitochondrial proteins believed to be involved in Fe metabolism has resulted in a marked increase of research in this field. Key proteins identified include frataxin, ATP-binding cassette protein B7 (ABCB7), and the more recently discovered mitochondrial ferritin. These discoveries have provided evidence to support the hypothesis that the mitochondrion is a distinct compartment of Fe metabolism. However, despite these new data, the Fe trafficking pathways within the mitochondrion remain unclear, and in this review we will attempt to analyze and integrate the most recent findings in this intriguing field. Iron transport, storage, and homeostatic regulationBefore discussing the most recent results regarding mitochondrial Fe metabolism, we will first provide a brief overview of the well-characterized molecular pathways of cellular Fe trafficking and utilization. Iron is transported within the serum bound to the Fe-binding protein, transferrin (Tf), 2-4 that binds to the transferrin receptor 1 (TfR1; Figure 1). The receptor binds 2 molecules of Fe-loaded Tf, 5 resulting in receptor-mediated endocytosis of the Tf-TfR1 complex (for reviews, see Morgan, 2 Richardson and Ponka, 3 and Hentze et al 4 ). A reduction in endosomal pH 2,3,6 mediates the release of Fe from Tf. 2,7 A protein known as the natural resistance-associated macrophage protein 2 (Nramp2) 8 was subsequently demonstrated to be the long sought-after exporter of Fe ϩ2 from endosomes. [9][10][11] This molecule is now known as divalent metal ion transporter 1 (DMT1) but has also been denoted as the divalent cation transporter 1 (DCT1) or solute carrier family 11a member 2 (Slc11a2).Within the cytosol, Fe can be stored in a large multimeric protein known as ferritin. 12 The storage of Fe in this molecule protects the cells from the damaging effects of free Fe and also keeps it sequestered in a bioavailable form. Since Fe is such an important but potentially toxic metal, its uptake, storage, and mobilization pathways are tightly regulated. This homeostatic control mechanism is largely controlled by RNA-bi...

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Section: X-linked Sideroblastic Anemiamentioning

confidence: 99%

Iron trafficking in the mitochondrion: novel pathways revealed by disease

Napier

Ponka

Richardson

2005

Blood

250

201

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“…The therapeutic trials were performed only in the boy who, in addition to the usual hematinics, received sufficient pyridoxine (17)(18)(19)(20) and oral liver extract (21) to exclude any potential benefit from these substances. Moreover, a tryptophan loading test performed before the administration of pyridoxine failed to reveal any abnormal tryptophan metabolites, such as 3-hydroxykynurenine or anthranilic acid.…”

Section: Therapeutic Trialsmentioning

confidence: 99%

Iron Deficiency Anemia Associated with an Error of Iron Metabolism in Two Siblings *

Shahidi¹,

Nathan²,

Diamond³

1964

J. Clin. Invest.

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“…The other cases of pyridoxine-responsive anaemia in which similar studies have been done tend to show a varying degree of shortening of the 'T for plasma-iron clearance and an impairment of red-cell iron utilization which may be marked (3) or moderate (15 ). H a v a r d (ii) described a case with similar ferrokinetics to some of ours, which had a similar "complete" response to pyridoxine therapy, while it is of interest to note that those cases showing abnormal patterns of iron handling had an "incomplete" response, their haemoglobin levels usually remaining below io G%.…”

Section: Discussionmentioning

confidence: 81%