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Raised serum ferritin concentration in hereditary hyperferritinemia cataract syndrome is not a marker for iron overload.

Yin D, Kulhalli V, Walker AP - Hepatology (2014)

Bottom Line: Hyperferritinemia and bilateral cataracts are features of the rare hereditary hyperferritinemia cataract syndrome (HHCS; OMIM #600886).HHCS is an autosomal dominant condition caused by mutations which increase expression of the ferritin light polypeptide (FTL) gene.We report a patient with HHCS who was misdiagnosed and treated as having hemochromatosis, in whom a heterozygous c.-160A>G mutation was identified in the iron responsive element (IRE) of FTL, causing ferritin synthesis in the absence of iron overload.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology (HUST), Wuhan, P.R. China; Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, UCL, London, UK.

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(A) Pedigree showing autosomal dominant inheritance of hyperferritinemia with cataracts. Solid symbol, affected; open symbol, unaffected, gray symbol, unknown; arrow, proband (P). (B) Sequence chromatogram of the FTL gene from the proband (upper panel) and his mother (lower panel), showing the heterozygous c.-160A>G mutation (arrow; Reference Sequence NM_000146.3). (C) IRE prediction of wild-type FTL mRNA showing the mutation site (arrow) in the apical loop which binds IRPs. Bioinformatic analysis of c.-160A>G mutant FTL did not predict an IRE. (D) Schematic diagram showing how the c.-160A>G mutation causes loss of normal IRE-IRP-mediated repression of FTL expression at low intracellular iron concentrations, causing unregulated L-ferritin synthesis, in the absence of iron overload, in HHCS.
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fig01: (A) Pedigree showing autosomal dominant inheritance of hyperferritinemia with cataracts. Solid symbol, affected; open symbol, unaffected, gray symbol, unknown; arrow, proband (P). (B) Sequence chromatogram of the FTL gene from the proband (upper panel) and his mother (lower panel), showing the heterozygous c.-160A>G mutation (arrow; Reference Sequence NM_000146.3). (C) IRE prediction of wild-type FTL mRNA showing the mutation site (arrow) in the apical loop which binds IRPs. Bioinformatic analysis of c.-160A>G mutant FTL did not predict an IRE. (D) Schematic diagram showing how the c.-160A>G mutation causes loss of normal IRE-IRP-mediated repression of FTL expression at low intracellular iron concentrations, causing unregulated L-ferritin synthesis, in the absence of iron overload, in HHCS.

Mentions: A 43-year-old Caucasian man was hospitalized following exposure to formaldehyde. His hemoglobin, serum iron concentration, total iron binding capacity (TIBC), and transferrin saturation were within the laboratory reference ranges but his serum ferritin concentration was elevated (1650 μg/L; reference range 25-300 μg/L). Serum transaminase activities, copper, ceruloplasmin, and lead concentrations were normal. A liver biopsy showed normal liver architecture and no evidence of iron overload. There was no history of alcohol abuse. He did, however, have a family history of hemochromatosis in a pattern suggestive of autosomal dominant inheritance (Fig. 1A) and a personal history of bilateral rheumatoid factor negative arthritis affecting his ankles and knees which had resolved spontaneously after 6 months and of bilateral cataract removal the previous year. A diagnosis of hemochromatosis was made on the basis of the strong family history and the presence of persistent hyperferritinemia despite the absence of evidence of iron overload. Venesection (450 mL) was performed monthly for 6 months but was stopped when the patient became symptomatic with a microcytic, iron deficient anemia in the absence of any other source of bleeding; at this time his hemoglobin was 10.0 g/dL (12.5-17.5 g/dL), transferrin saturation 4% (20%-55%) while his serum ferritin remained elevated at 1,728 μg/L. Venesection was stopped; he was treated with iron supplements until he was iron replete; his serum ferritin concentrations remained elevated throughout.


Raised serum ferritin concentration in hereditary hyperferritinemia cataract syndrome is not a marker for iron overload.

Yin D, Kulhalli V, Walker AP - Hepatology (2014)

(A) Pedigree showing autosomal dominant inheritance of hyperferritinemia with cataracts. Solid symbol, affected; open symbol, unaffected, gray symbol, unknown; arrow, proband (P). (B) Sequence chromatogram of the FTL gene from the proband (upper panel) and his mother (lower panel), showing the heterozygous c.-160A>G mutation (arrow; Reference Sequence NM_000146.3). (C) IRE prediction of wild-type FTL mRNA showing the mutation site (arrow) in the apical loop which binds IRPs. Bioinformatic analysis of c.-160A>G mutant FTL did not predict an IRE. (D) Schematic diagram showing how the c.-160A>G mutation causes loss of normal IRE-IRP-mediated repression of FTL expression at low intracellular iron concentrations, causing unregulated L-ferritin synthesis, in the absence of iron overload, in HHCS.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4296220&req=5

fig01: (A) Pedigree showing autosomal dominant inheritance of hyperferritinemia with cataracts. Solid symbol, affected; open symbol, unaffected, gray symbol, unknown; arrow, proband (P). (B) Sequence chromatogram of the FTL gene from the proband (upper panel) and his mother (lower panel), showing the heterozygous c.-160A>G mutation (arrow; Reference Sequence NM_000146.3). (C) IRE prediction of wild-type FTL mRNA showing the mutation site (arrow) in the apical loop which binds IRPs. Bioinformatic analysis of c.-160A>G mutant FTL did not predict an IRE. (D) Schematic diagram showing how the c.-160A>G mutation causes loss of normal IRE-IRP-mediated repression of FTL expression at low intracellular iron concentrations, causing unregulated L-ferritin synthesis, in the absence of iron overload, in HHCS.
Mentions: A 43-year-old Caucasian man was hospitalized following exposure to formaldehyde. His hemoglobin, serum iron concentration, total iron binding capacity (TIBC), and transferrin saturation were within the laboratory reference ranges but his serum ferritin concentration was elevated (1650 μg/L; reference range 25-300 μg/L). Serum transaminase activities, copper, ceruloplasmin, and lead concentrations were normal. A liver biopsy showed normal liver architecture and no evidence of iron overload. There was no history of alcohol abuse. He did, however, have a family history of hemochromatosis in a pattern suggestive of autosomal dominant inheritance (Fig. 1A) and a personal history of bilateral rheumatoid factor negative arthritis affecting his ankles and knees which had resolved spontaneously after 6 months and of bilateral cataract removal the previous year. A diagnosis of hemochromatosis was made on the basis of the strong family history and the presence of persistent hyperferritinemia despite the absence of evidence of iron overload. Venesection (450 mL) was performed monthly for 6 months but was stopped when the patient became symptomatic with a microcytic, iron deficient anemia in the absence of any other source of bleeding; at this time his hemoglobin was 10.0 g/dL (12.5-17.5 g/dL), transferrin saturation 4% (20%-55%) while his serum ferritin remained elevated at 1,728 μg/L. Venesection was stopped; he was treated with iron supplements until he was iron replete; his serum ferritin concentrations remained elevated throughout.

Bottom Line: Hyperferritinemia and bilateral cataracts are features of the rare hereditary hyperferritinemia cataract syndrome (HHCS; OMIM #600886).HHCS is an autosomal dominant condition caused by mutations which increase expression of the ferritin light polypeptide (FTL) gene.We report a patient with HHCS who was misdiagnosed and treated as having hemochromatosis, in whom a heterozygous c.-160A>G mutation was identified in the iron responsive element (IRE) of FTL, causing ferritin synthesis in the absence of iron overload.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology (HUST), Wuhan, P.R. China; Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, UCL, London, UK.

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Related in: MedlinePlus