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Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare autosomal dominant disorder caused by mutations in the iron-responsive element of the ferritin light chain gene (FTL). Affected individuals present with lifelong isolated hyperferritinemia without tissue iron overload and early-onset bilateral cataracts. The phenotype has been described in multiple unrelated families across diverse populations, including northern Greece, Australia, Italy, and Brazil. Consistent autosomal dominant transmission has been demonstrated with heterozygous IRE point mutations segregating in kindreds with 19 affected relatives (PMID:16406710). Recognition of HHCS is essential to differentiate it from hemochromatosis and avoid inappropriate iron depletion therapies.
Genetic evidence for the FTL–HHCS association is strong. In three western Greek families, 19 affected individuals across three generations harbored the C39G IRE mutation segregating with HHCS (PMID:16406710). A large Australian family spanning three generations showed a heterozygous c.-167C>T variant in six affected members (Z = 3.61; PMID:27096259). Italian and Brazilian case series further describe additional novel and recurrent IRE variants in affected patients (PMID:24368960; PMID:36287435). Overall, at least 28 affected individuals from >7 families exhibit heterozygous IRE mutations that co-segregate with hyperferritinemia and cataracts. No conflicting segregation has been reported.
The variant spectrum encompasses point substitutions and small indels within the highly conserved IRE stem-loop. Recurrent mutations include c.-167C>T and c.-168G>C disrupting the CAGUGX hexaloop, as well as novel indels such as c.-189_-161del. Coding-region IRE changes also include c.29C>G (p.Ser10Cys) and c.33C>T (p.Thr11=) observed in multiple families (PMID:24368960). The representative variant c.29C>G (p.Ser10Cys) exemplifies the impact of hexaloop mutations on IRP binding and ferritin synthesis.
Functional studies confirm loss of translational repression of FTL. Electrophoretic mobility shift assays show significantly reduced IRP1 binding affinity for IRE mutations such as C33T and Ghent +49A>G, resulting in derepressed ferritin L-chain synthesis in vitro (PMID:29269865). Computational modeling predicts disruption of the IRE stem-loop secondary structure for mutations including C39G, correlating with elevated ferritin levels in patients (PMID:16406710). High-resolution melting analysis further enables rapid detection of known and novel IRE variants in clinical settings (PMID:20578964).
No studies have refuted the causal role of FTL IRE mutations in HHCS; iron metabolism remains normal apart from ferritin elevation, and lens pathology is consistent across cohorts. Clinical awareness of HHCS improves diagnostic accuracy, prevents misdiagnosis as hemochromatosis, and directs appropriate genetic counseling.
In conclusion, autosomal dominant FTL IRE mutations are definitively associated with Hereditary Hyperferritinemia with Congenital Cataracts. Genetic testing should be performed in patients with unexplained hyperferritinemia and early cataracts to guide management and avoid unnecessary therapies.
Gene–Disease AssociationDefinitiveMultiple independent families; consistent autosomal dominant inheritance; functional assays confirm mechanism Genetic EvidenceStrong28 affected individuals with segregating FTL IRE mutations across 7+ families ([PMID:16406710]); autosomal dominant transmission Functional EvidenceModerateEMSA and computational modeling demonstrate disrupted IRP–IRE binding for key mutations (e.g., C33T, C39G) ([PMID:29269865]; [PMID:16406710]) |