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• W1815518647 abstract "Ferroportin disease is an autosomal dominant form of inherited iron overload resulting from mutations in the ferroportin gene (SLC40A1). Occasionally, mutations in ferroportin lead to a form of inherited iron overload that is clinically indistinguishable from adult onset HFE-linked haemochromatosis. This is caused by ‘gain-of-function’ mutations that render ferroportin (fpn) resistant to hepcidin action (type 4b haemochromatosis). These patients have elevated serum ferritin and transferrin saturation, and a susceptibility to iron-induced organ damage. More commonly, however, ferroportin mutations are ‘loss-of-function’ mutations that ultimately disrupt the export of intracellular iron (De Domenico et al, 2005), leading to a characteristic phenotype of highly elevated ferritin levels with normal or slightly elevated transferrin saturation. This is usually referred to as ‘Ferroportin disease’ (type 4a haemochromatosis). Iron deposition occurs predominantly in macrophages, and affected patients do not usually develop iron-induced organ damage (Devalia et al, 2002). Here, we present a family with a novel mutation in the SLC40A1 gene leading to a type 4a haemochromatosis phenotype (ferroportin disease). The proband is a 58-year-old Caucasian male who was referred to our department for investigation of hyperferritinaemia. The patient was well and had no other significant comorbidities. His serum ferritin at presentation was 4123 μg/l with a transferrin saturation of 32%. His full blood count (FBC) showed a normal haemoglobin concentration with normal red cell indices. There was no known family history of iron overload. HFE gene analysis revealed a normal genotype (C282C, H63H). Because the patient had elevated liver function enzymes (alanine transaminase [ALT] = 82 i/u per litre) he underwent a liver biopsy, which showed grade 4 reticulo-endothelial haemosiderosis (Fig 1). The biopsy also showed steatohepatitis which was felt to be the cause of his elevated ALT levels. Perl’s stain showing grade 4 haemosiderosis in hepatic macrophages (arrow). The patient’s SLC40A1 gene was subjected to mutation analysis. High Resolution Melting Analysis (HRMA) revealed a mutation in exon 5 of SLC40A1 and the variant melt was sequenced using a Beckman CEQ8000 sequencer. A heterozygous missense mutation was detected as a result of a single base substitution (c.470 A>C) resulting in a change in the amino acid at codon 157 from Asp (GAT) to Ala (GCT). The mutation was designated: p.D157A (Fig 2A). This mutation is novel, however, another mutation at codon 157: p.D157G had been recorded as a cause of ferroportin disease (Hetet et al, 2003). Identification of the novel p.D157A mutation. (A) Electropherogram showing the presence of heterozygous c.470 A>C on exon 5 of the SLC40A1 gene. (B) HRMA of the family DNA (indicated) and comparing it with a normal control (thin arrow) and DNA of the common SLC40A1 mutation, V162del (thick arrow). After counselling and consenting, the patient’s daughter was screened and was also found to have an elevated serum ferritin of 1404 μg/l with a transferrin saturation of 18%. Her FBC was normal with normal red cell indices, and her liver function tests were entirely normal. SLC40A1 analysis revealed the same mutation (Fig 2B). The patient was started on a cautious venesection programme, with removal of 400 ml blood on 21 occasions. His ferritin levels fell to 2537 μg/l (c. 40% reduction). However, his venesections were becoming increasingly difficult to perform due to a progressive fall in haemoglobin and poor patient tolerance. A T2* magnetic resonance imaging (MRI) scan, at that stage, showed no evidence of cardiac or hepatic iron loading. In view of the normal T2* MRI it was decided to withhold the venesections and take a watchful approach to his management. T2* MRI of the proband’s daughter also revealed no evidence of cardiac or hepatic iron loading, and she is currently being managed expectantly. Many mutations have been implicated as causing ferroportin disease, and most of these mutations have been traced to exon 5 of the SLC40A1 gene (Lee & Beutler, 2009). The disease should be suspected in patients presenting with hyperferritinaemia and normal transferrin saturation. Genetic screening is available and has the potential of accurately identifying these patients. It may also help in counselling and screening their family members. As the disease often leads a benign course, a proper diagnosis can also help avoid unnecessary and prolonged venesection programmes. We thank Dr Lisa Mears for reporting the liver biopsy and providing a digital image of the patient’s hepatic iron stain." @default.
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• W1815518647 date "2010-05-20" @default.
• W1815518647 modified "2023-10-17" @default.
• W1815518647 title "A novel missense mutation c.470 A>C (p.D157A) in the SLC40A1 gene as a cause of ferroportin disease in a family with hyperferritinaemia" @default.
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• W1815518647 doi "https://doi.org/10.1111/j.1365-2141.2010.08137.x" @default.
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