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

Abstract

Summary. Hereditary hyperferritinaemia±cataract syndrome (HHCS) is an autosomal dominant disease caused by mutations in the iron responsive element (IRE) of the lferritin gene. Despite the elucidation of the genetic basis, the overall clinical spectrum of HHCS has been less well studied as, to date, only individual case reports have been described. Therefore, we studied a total of 62 patients in 14 unrelated families, with nine different mutations. No relevant symptoms other than visual impairment were found to be associated with the syndrome. A marked phenotypic variability was observed, particularly with regard to ocular involvement (i.e. age range at which cataract was diagnosed in 16 subjects with the C39T: 6±40 years). Similarly, serum ferritin levels varied substantially also within subjects sharing the same mutation (i.e. range for the A40G: 700± 2412 mg/l). We followed an HHCS newborn in whom welldefined lens opacities were not detectable either at birth or at 1 year. The lens ferritin content was analysed in two subjects who underwent cataract surgery at different ages, with different cataract morphology. Values were similar and about 1500-fold higher than in controls. These observations suggest that: (i) in HHCS the cataract is not necessarily congenital; (ii) in addition to the IRE genotype, other genetic or environmental factors may modulate the phenotype, especially the severity of the cataract.

Clinical features and molecular analysis of seven British kindreds with hereditary hyperferritinaemia cataract syndrome

“…Similar findings have been noted in the probands of other kindreds with HHCS 16 and this raises the possibility that overexpression of L-ferritin may have a more subtle effect on iron metabolism in this disorder. However, serum L-ferritin is commonly measured only in individuals with clinically suspected iron deficiency suggesting that this finding may reflect selection bias.…”

“…However, female bias was also evident among the affected family members in our series. Previous short series from other centres have shown no sex bias in HHCS 16,23 and the reasons for the female preponderance among subjects from our series remain unclear.…”

“…However, serum L-ferritin is commonly measured only in individuals with clinically suspected iron deficiency suggesting that this finding may reflect selection bias. Family members with HHCS in this, and other series 16 showed no consistent evidence of iron deficiency so this abnormality is unlikely to be part of the HHCS phenotype. Selection bias may also explain the high frequency of young female subjects within our probands.…”

“…Our study therefore provides independent conformation of the findings of the previous European case series of HHCS that comprised 62 affected individuals. 16 L-ferritin is a widely used marker of body iron load because its rate of synthesis is closely regulated by the availability of iron in the tissues through the IRP-IRE system. 2,3 Therefore, increased serum L-ferritin concentration usually indicates iron overload.…”

“…16 In order to characterise further the clinical phenotype of HHCS and to examine the relationship of disease severity to specific mutations in FTL, we have analysed the clinical features of seven kindreds with HHCS from the United Kingdom.…”