Clinical, biochemical and molecular findings in a series of families with hereditary hyperferritinaemia-cataract syndrome

Hereditary hyperferritinaemia-cataract syndrome (HHCS) is an autosomal domi nant disease caused by mutations in the iron responsive element (IRE) of th e L-ferritin gene. Despite the elucidation of the genetic basis, the overal l clinical spectrum of HHCS has been less well studied as, to date, only in dividual case reports have been described. Therefore, we studied a total of 62 patients in 14 unrelated families, with nine different mutations. No re levant symptoms other than visual impairment were found to be associated wi th the syndrome. A marked phenotypic variability was observed. particularly with regard to ocular involvement (i.e. age range at which cataract was di agnosed in 16 subjects with the C39T: 6-40 years). Similarly, serum ferriti n levels varied substantially also within subjects sharing the same mutatio n (i.e. range for the A40G: 700-2412 mug/l). We followed an HHCS newborn in whom well-defined lens opacities were not detectable either at birth or at I year. The lens ferritin content was analysed in two subjects who underwe nt cataract surgery at different ages, with different cataract morphology. Values were similar and about 1500-fold higher than in controls. These obse rvations suggest that: (i) in HHCS the cataract is not necessarily congenit al; (ii) in addition to the IRE genotype, other genetic or environmental fa ctors may modulate the phenotype, especially the severity of the cataract.