Hereditary Hyperferritinaemia Cataract Syndrome

However, mutations in the IRE of the ferritin L subunit mRNA and its gene have been found to be associated with an unusual autosomal dominant disorder, first described in 1995 in two families, one French and one Italian, as the Hereditary Hyperferritinaemia-Cataract Syndrome (HHCS) (Girelli et al., 1995a,b; Bonneau et al., 1995). The condition is characterized by the combination of congenital bilateral cataract and marked elevation of serum ferritin levels (>1000 ^g/l). The hyperfer-ritinaemia was found not to be related to iron overload and entirely due to the increase of the L-subunit, as determined by subunit-specific immunoassay. It was clearly distinguishable from genetic haemochromatosis because of (i) dominant transmission; (ii) lack of any relation with HLA, and (iii) normal to low serum iron and transferrin saturation without evidence of parenchymal iron overload. When patients with the syndrome are subjected to unnecessary phlebotomies, they rapidly develop iron-deficient anaemia (reversed by iron therapy), despite persistently elevated levels of serum ferritin. The initial description of HHCS was rapidly followed by molecular characterization; they were shown to have a single base substitution, the Paris mutation at position 13 (A to G) and the Verona 1 mutation at position 14 (G to C) (Beaumont et al., 1995; Girelli et al., 1995a,b), both in the IRE loop (Figure 7.4). Several other mutations have subsequently been described: in Pavia 1, a single base change in the bulge (G5 to A) and in Pavia 2 two single base changes in the lower stem (Cazzola et al., 1997) are characterized by moderately elevated serum ferritin levels associated with mild cataract and asymptomatic cataract respectively. In Verona 2, a 29 base-pair deletion removes the whole 5' sequence involved in base pairing to form the IRE stem (Girelli et al., 1997) resulting in severe cataract. All of the mutations are assumed, to varying degrees, to affect IRP-binding, and to result in the worst cases in quasiconstitu-tive synthesis of L-subunit ferritin. In a recent study (Allerson et al., 1999) in vitro binding affinity of IRP for HHCS mutant IREs was measured and it was found that decreases in binding affinity correlated with clinical severity. Analysis of ferritins in lympho-blastoid cell lines and in the lenses of subjects with HHCS (Levi et al., 1998) showed that in HHCS cells, L-ferritin levels were up to twenty-times higher than in control cells, with about half of the L-chain assembled in homopolymers which did not incorporate iron. L-Chain accumulation also takes place in the lens, where it may induce cataract formation by altering the equilibrium between other water-soluble proteins, particularly crystallins and/or antioxidant properties. It had been reported that lens epithelial cells actively synthesize ferritin, especially in response to oxidants (McGahan et al., 1994). However, in more recent studies, although high levels of L-ferritin mRNA were found in lenses from guinea pigs and humans (similar to those of major lens crystallins), lens ferritin was undetectable by Western blots (Cheng et al., 2000). The mechanism of cataract formation in HHCS remains obscure, although it seems likely that cataract formation is a direct consequence of cellular L-ferritin overproduction. At the very least, HHCS should be considered as a serious possibility by haematologists in the differential diagnosis of unexplained hyperferritinaemia.

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