Hyperferritinemia With Or Without Cataract

A number sign (#) is used with this entry because hyperferritinemia with or without cataract (HRFTC) is caused by heterozygous mutation in the iron-responsive element (IRE) in the 5-prime noncoding region of the ferritin light chain gene (FTL; 134790) on chromosome 19q13.

Some patients, born in consanguineous families, may carry homozygous mutations, but they do not appear to have a more severe phenotype (Giansily-Blaizot et al., 2013; Luscieti et al., 2013).

Clinical Features

Girelli et al. (1995) studied 2 Italian families in which a combination of congenital nuclear cataract and elevated serum ferritin not related to iron overload was transmitted as an autosomal dominant trait. Affected individuals had normal serum iron and transferrin saturation, but high serum ferritin. Red cell counts were normal and venesection rapidly resulted in iron deficiency anemia. Both families had lived in northern Italy for many generations, and both had instances of male-to-male transmission of the trait. Studies with monoclonal antibodies demonstrated no ferritin H subunit in either normal subjects or those with hyperferritinemia, but elevation of the ferritin L subunit in those with elevated serum ferritin. No relationship between high serum ferritin and HLA type was found. Girelli et al. (1995) noted that the FTL and MP19 (154045) genes map to 19q.

Bonneau et al. (1995) reported cosegregation of dominantly inherited cataract with an abnormally high level of serum ferritin in a 3-generation pedigree and suggested 2 possibilities: that the cataract-hyperferritinemia syndrome is a disorder of ferritin metabolism leading to lens opacity, or that it is a contiguous gene syndrome involving the L-ferritin gene and the gene encoding lens membrane protein MP19 on 19q.

Giansily-Blaizot et al. (2013) reported a 54-year-old woman of Canadian descent who presented with unexplained hyperferritinemia and microcytic anemia. Medical history revealed that she was diagnosed with bilateral cataracts at age 35 years. Several family members, including both possibly consanguineous parents and 2 sibs, had visual impairment or known cataracts, but these individuals were not available for examination. Genetic analysis identified a homozygous mutation in the FTL gene (134790.0009). Homozygous mutations are very unusual in this disorder, but the patient's phenotype was similar to that of heterozygous mutation carriers. Giansily-Blaizot et al. (2013) speculated that the mutation, which does not occur at the highly conserved region in the bulge or upper stem of the iron response element of the FTL gene, may have milder effects than other mutations, even in the homozygous state.

Luscieti et al. (2013) reported a Spanish family with HHCS. The proband, who was born of consanguineous parents, was a 54-year-old woman with a 10-year history of hyperferritinemia and cataracts since 18 years of age. She had no signs of iron overload; serum iron, transferrin saturation, and liver functional tests were normal. A sister and cousin had a similar disorder. Family history revealed an affected deceased uncle and an affected deceased father. The proband's deceased mother was never diagnosed with cataracts, but had severe myopia. Three children of the proband and her sister also showed signs of the disorder. Genetic analysis identified a homozygous mutation (+36C-U; 134790.0020) in the proband and her sister, whereas the affected children and the cousin were heterozygous for the mutation. The individuals with the homozygous mutations were not significantly more affected than heterozygotes. In vitro studies showed that the mutation caused a mild reduction in the binding of iron regulatory proteins. The report indicated that genotype/phenotype correlations in this disorder are difficult to establish due to inter- and intraindividual variability.

Inheritance

The transmission pattern of hyperferritinemia with cataract in the families reported by Girelli et al. (1995) and Bonneau et al. (1995) was consistent with autosomal dominant inheritance. Some patients, born in consanguineous families, may carry homozygous mutations, but this does not appear to result in a more severe phenotype (Giansily-Blaizot et al., 2013; Luscieti et al., 2013).

Molecular Genetics

In affected members of the family with bilateral cataract and high serum ferritin reported by Bonneau et al. (1995), Beaumont et al. (1995) identified a point mutation in the IRE in the 5-prime noncoding region of the ferritin light chain gene (134790.0001). The synthesis of ferritin, the iron-storing molecule, is regulated at the translational level by iron through interaction between a cytoplasmic protein denoted iron regulatory protein (IRP) or IRE-binding protein (100880; 147582), and a conserved nucleotide motif present in the 5-prime noncoding region of all ferritin mRNAs, the IRE. The IRE region forms a stem-loop structure; when the supply of iron to the cells is limited, IRP binds to IRE and represses ferritin synthesis. Beaumont et al. (1995) noted that this was the first mutation affecting the IRP-IRE interaction and the iron-mediated regulation of ferritin synthesis. They suggested that excess production of ferritin in tissues is responsible for the hyperferritinemia and that intracellular accumulation of ferritin leads to cataract.

In 3 Australian pedigrees with hereditary hyperferritinemia-cataract syndrome, McLeod et al. (2002) identified mutations in the FTL gene. One of the mutations was the same as that identified by Beaumont et al. (1995); see 134790.0001.

Camaschella et al. (2000) reported a father and daughter with 'modest' hyperferritinemia and a mutation in the IRE of FTL (51G-C; 134790.0009) who had no history of visual impairment. Upon slit lamp examination, bilateral fine lenticular changes were observed in both subjects. Computational analysis predicted that the 51G-C substitution would alter the conformation of the stem loop without modifying the residues involved in direct contact with IRPs, and functional analysis showed that the mutation reduced, but did not abolish, binding to IRPs. Camaschella et al. (2000) stated that these findings supported a direct relationship between the structural effect of IRE mutations and phenotypic expression of HHCS, and indicated an association between the level of l-ferritin expression and severity of cataract.

Girelli et al. (2001) studied a total of 62 patients in 14 unrelated families with 9 different mutations in the FTL gene. No relevant symptoms other than visual impairment were found to be associated with the syndrome. Marked phenotypic variability was observed, particularly with regard to ocular involvement; in 16 subjects with the 39C-T mutation in the FTL gene (134790.0007), age at diagnosis for cataract ranged from 6 to 40 years. Similarly, serum ferritin levels varied substantially between subjects sharing the same mutation. One infant lacked cataracts at birth and at age 1 year, suggesting that the cataract is not necessarily congenital. Ferritin content of the lens removed at surgery in 2 family members was about 1,500-fold higher than in controls. The cataract as viewed by slit-lamp was described as a 'pulverulent' cataract in some patients and as a 'sunflower' cataract in others. Girelli et al. (2001) presented a pedigree of an affected 4-generation family with a 29-bp deletion (134790.0005) in the FTL gene that removed most of the IRE.

In affected members of a family with hyperferritinemia-cataract syndrome, Campagnoli et al. (2002) identified a heterozygous mutation in the FTL gene (134790.0012). Two sisters in the last generation developed cataracts at age 18 months, earlier than most reported cases. The authors suggested that the early onset rules out the possibility that cataracts in this syndrome are due to age-accumulation of ferritin.

In a healthy 52-year-old woman who was a control subject in a genetic study of hyperferritinemia-cataract syndrome, Cremonesi et al. (2004) identified a heterozygous mutation in the ATG start codon of the FTL gene, predicted to disable protein translation and expression. She had no history of iron deficiency anemia or neurologic dysfunction. Hematologic examination was normal except for decreased serum ferritin. The findings suggested that L-ferritin has no effect on systemic iron metabolism and also indicated that neuroferritinopathy is not a consequence of haploinsufficiency of L-ferritin, but likely results from gain-of-function mutations in the FTL gene.

Kannengiesser et al. (2009) analyzed the FTL gene in 91 probands with hyperferritinemia, including 25 familial cases and 66 isolated cases. Some patients were referred for early-onset cataract, but none had an IRE mutation in FTL exon 1; however, heterozygosity for a missense mutation in the N terminus (T30I; 134790.0017) was identified in 12 familial and 5 isolated probands, 1 of whom had bilateral cataract. The mutation segregated with disease in the 10 families that underwent cosegregation analysis. There were significant fluctuations in serum ferritin levels, both over time in a given individual and between affected individuals within the same family. No characteristic clinical symptoms were found in the 37 mutation-positive individuals, although 4 complained of joint pain and 3 of asthenia. Serum ferritin hyperglycosylation ranging from 90 to 99% (normal range, 50 to 80%) was observed in 9 mutation-positive individuals tested.

Genotype/Phenotype Correlations

In 7 kindreds from the United Kingdom with hyperferritinemia-cataract syndrome containing 49 individuals with premature cataract, Lachlan et al. (2004) found that the severity of the clinical phenotype was variable both within and between kindreds and showed no clear relationship with FTL genotype, confirming the findings reported by Girelli et al. (2001) in a European case series.