The hereditary hyperferritinaemia-cataract syndrome (HHCS) is characterised by an autosomal dominant cataract and high levels of serum ferritin without iron overload. The cataract develops due to L-ferritin deposits in the lens and its pulverulent aspect is pathognomonic. The syndrome is caused by mutations within the iron-responsive element of L-ferritin. These mutations prevent efficient binding of iron regulatory proteins 1 and 2 to the IRE in L-ferritin mRNA, resulting in an unleashed ferritin translation. This paper reviews all 31 mutations (27 single nucleotide transitions and four deletions) that have been described since 1995. Laboratory test showing hyperferritinaemia, normal serum iron and normal transferrin saturation are indicative for HHCS after exclusion of other causes of increased ferritin levels (inflammation, malignancy, alcoholic liver disease) and should prompt an ophthalmological consultation for diagnostic confirmation. Invasive diagnostics such as liver biopsy are not indicated. HHCS is an important differential diagnosis of hyperferritinaemia. Haematologists, gastroenterologists and ophthalmologists should be aware of this syndrome to spare patients from further invasive diagnosis (liver biopsy), and also from a false diagnosis of hereditary haemochromatosis followed by venesections. Patients diagnosed with HHCS should be counselled regarding the relative harmlessness of this genetic disease, with early cataract surgery as the only clinical consequence.

/pdf/hyperferritinaemia-cataract-syndrome-worldwide-mutations-and-23fl9wt8yt.pdf

Hyperferritinaemia-cataract syndrome: worldwide mutations and phenotype of an increasingly diagnosed genetic disorder.

PURPOSE Hereditary hyperferritinemia cataract syndrome (HHCS) is a rare autosomal dominant hereditary disease, characterized by hyperferritinemia but with absence of body iron excess and early onset of bilateral cataracts. Although 5- to 20-fold increased serum ferritin concentrations have been reported in HHCS patients, data of ferritin levels in aqueous humor have not been obtained. We therefore aimed to investigate the ferritin levels in aqueous humor and serum and further present histological and ultrastructural data of the lens. METHODS During cataract extraction and intraocular lens implantation, aqueous humor and lens aspirate of a 37-year-old HHCS patient were obtained from both eyes. Ferritin levels in serum and aqueous humor were quantitatively analyzed via immunoassays in the HHCS patient and healthy control subjects (n = 6). Lens aspirate in HHCS was analyzed histologically and at the ultrastructural level. Further, genetic mutation screening by polymerase chain reaction and DNA sequencing in blood was performed. RESULTS Serum ferritin levels in the control group were 142.2 ± 38.7 μg/L, whereas in the HHCS patient, this parameter was excessively increased (1086 μg/L). Analysis of ferritin in aqueous humor revealed 6.4 ± 3.8 μg/L in normal control subjects and 146.3 μg/L (OD) and 160.4 μg/L (OS) in the HHCS patient. DNA analysis detected a C>A mutation on position +18, a T>G mutation on position +22, a T>C mutation on position +24, and a T>G polymorphism on position +26 in the iron-responsive element of the light-chain ferritin (L-ferritin) gene. CONCLUSIONS In the HHCS patient, a 23-fold (OD) to 25-fold (OS) increased aqueous humor ferritin level was detected. Therefore, the formation of bilateral cataract in HHCS is most likely a result of elevated aqueous humor ferritin. In addition, a novel mutation in this rare disease in the iron-responsive element of L-ferritin gene is reported.

Aqueous humor ferritin in hereditary hyperferritinemia cataract syndrome.

Background In hereditary hyperferritinaemia-cataract syndrome (HHCS), single nucleic acid alterations in the ferritin light chain (L-ferritin) iron response element (IRE) constitutively derepress ferritin synthesis, resulting in hyperferritinaemia, L-ferritin deposits in the lens of the eye and early bilateral cataract onset. Methods In this study, six German families with putative HHCS were analysed. Clinical diagnosis of HHCS was based on medical history, evaluation of ferritin serum levels, transferrin saturation and clinical ophthalmological examination. Diagnosis was confirmed by polymerase chain reaction (PCR)-based DNA sequencing of the L-ferritin IRE. Results Genetic analysis of the L-ferritin IRE revealed relevant single nucleic acid alterations in each of the affected families. Variants c.-168G > A, c.-168G > U and c.-167C > U were located in the C-bulge region; and variants c.-161C > U and c.-157G > A were located in the hexanucleotide loop of the L-ferritin IRE. Conclusions Family history of hyperferritinaemia and juvenile cataracts are strong indicators of HHCS. Genetic analysis of the L-ferritin IRE is a straightforward procedure to confirm the diagnosis. Accurate diagnosis of hyperferritinaemia can avoid unnecessary treatment by venesection, and focus attention on early cataract detection in offspring at risk.

Hereditary hyperferritinaemia-cataract syndrome (HHCS) - an underestimated condition: ferritin light chain variant spectrum in German families.

Ferritin ist der fur die Entgiftung und Speicherung von Eisen entscheidende Proteinkomplex. Es zahlt zu den Akut-Phase-Proteinen und wird bei Entzundungen und hohem Eisenspiegel induziert. Bei Eisenmangel wird die Synthese unterdruckt. Zur Differenzialdiagnose der Hyperferritinamie mussen laborchemisch Anamien und Entzundungen gesucht werden. Ausserdem ist nach einer Eisenuberladung (Transferrinsattigung, HFE-Genetik und ggf. loslicher Transferrinrezeptor, Ferritinindex) und chronischen Lebererkrankungen (Hepatitis- und Autoimmunserologie, Sonographie, Elastographie) zu suchen. In 90 % ist eine Krankheit ohne Eisenuberladung Ursache der Hyperferritinamie. Eine Eisenuberladung kann bei Hamolyse oder Lebererkrankungen, die zu einem Mangel des „Eisenhormons“ Hepcidin fuhren, auftreten. Eine Leberbiopsie zur Bestimmung des hepatischen Eisenindex ist bei Erkrankungen ohne Eisenuberladung wie dem Hyperferritinamie-Katarakt-Syndrom kontraindiziert. Die genetische Hamochromatose ist eine seltene Ursache fur eine Hyperferritinamie mit primarer Eisenuberladung. Zur Vermeidung von Organschaden erfolgen Phlebotomien, die beim Hyperferritinamie-Katarakt-Syndrom hingegen kontraindiziert sind.

Management der Hyperferritinämie

Hereditary Hyperferritinaemia Cataract Syndrome (HHCS) is a rare autosomal dominant disease characterized by increased serum ferritin levels and early onset of bilateral cataract. The disease is caused by mutations in the Iron-Responsive Element (IRE) located in the 5′ untranslated region of L-Ferritin (FTL) mRNA, which post-transcriptionally regulates ferritin expression. We describe two families presenting high serum ferritin levels and juvenile cataract with novel mutations in the L-ferritin IRE. The mutations were further characterized by in vitro functional studies. We have identified two novel mutations in the IRE of L-Ferritin causing HHCS: the Badalona +36C > U and the Heidelberg +52 G > C mutation. Both mutations conferred reduced binding affinity on recombinant Iron Regulatory Proteins (IPRs) in EMSA experiments. Interestingly, the Badalona +36C > U mutation was found not only in heterozygosity, as expected for an autosomal dominant disease, but also in the homozygous state in some affected subjects. Additionally we report an update of all mutations identified so far to cause HHCS. The Badalona +36C > U and Heidelberg +52 G > C mutations within the L-ferritin IRE only mildly alter the binding capacity of the Iron Regulatory Proteins but are still causative for the disease.

/pdf/novel-mutations-in-the-ferritin-l-iron-responsive-element-2io5t450vg.pdf

Novel mutations in the ferritin-L iron-responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome

We report on a 23-year-old woman who presented with elevated serum ferritin values at our department. She had undergone cataract surgery at the age of 14 and her family pedigree showed hereditary autosomal-dominant cataract. The combination of isolated hyperferritinemia with autosomal-dominant hereditary cataract led to the diagnosis of the hereditary hyperferritinemia cataract syndrome (HHCS) which we now describe in a German family for the first time. HHCS was confirmed by detection of a causal mutation at position 32 within the iron responsive element (IRE) of L-ferritin leading to a guanine to adenine exchange and the pathognomonic star-shaped cataract. This mutation interrupts the post-transcriptional control of L-ferritin. It prevents binding of the iron regulatory protein 1 (IRP1) to the 5alpha untranslated region of L-ferritin resulting in uncontrolled L-ferritin synthesis and high serum ferritin levels independent of the body iron stores. Premature cataract is eventually caused by deposition of L-ferritin crystals in the lens of the eye. Our family shows the typical autosomal-dominant inheritance of HHCS over four generations affecting a total of 17 family members. The causal mutation, star-shaped cataract and typical laboratory configuration were confirmed in five patients. Thus, in gastroenterological practice, HHCS should be added as a differential diagnosis of hyperferritinemia in Germany. Importantly, patients with HHCS can be spared from invasive diagnostics such as liver biopsy.

Das hereditäre Hyperferritinämie-Katarakt-Syndrom – die erste Familie in Deutschland

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Das hereditäre Hyperferritinämie-Katarakt-Syndrom – die erste Familie in Deutschland