Hereditary hyperferritinemia cataract syndrome in three unrelated families of western Greek origin caused by the C39 > G mutation of L-ferritin IRE
Introduction
Hereditary hyperferritinemia–cataract syndrome (HHCS) is clinically characterized by the combination of elevated serum L-ferritin and early onset of bilateral cataracts [1], [2], [3], [4]. Despite the five- to twenty-fold increase in serum L-ferritin levels, no significant effects on body iron metabolism have been observed [4]. Unlike hereditary hemochromatosis, serum iron and transferrin saturation remain normal or low. Hyperferritinemia can persist even in HHCS patients who develop iron deficiency anemia [4], [5].
Hereditary hyperferritinemia–cataract syndrome (OMIM #600886) is transmitted as an autosomal dominant disease resulting from mutations or deletions in the iron responsive element (IRE) of L-ferritin (FTL) gene, located in chromosome 19q13.3–q13.4 [6], [7], [8], [9] (Fig. 1, Fig. 2a).
At least 25 different mutations and deletions spanning the whole IRE structure are reported in families with HHCS. Sporadic cases due to de novo mutations have also been described [10], [11], [12]. Some of the mutations affect the loop that interacts directly with the IRPs, whereas other mutations affect the stems or the bulge of the IRE structure and modify its conformation (Fig. 2b) [13], [14].
The mechanism responsible for the onset of cataract in HHCS is not yet elucidated. Ferritin represents an abundant soluble protein in the lens even in normal conditions and 10–15-fold increase in the lens of HHCS patients was found [4], [15]. Increase in L-ferritin in the lens may affect the solubility of other lens proteins and lead to lens damage [15]. Alternatively, crystalline deposition of L-ferritin itself may trigger cataract development [16]. In HHCS, cataract is probably not congenital and develops in the first few years of life in an age-dependent manner [4].
HHCS has been described in families from diverse geographic areas [5], [17], [18], [19], [20]. Here, we described the first report of HHCS in 3 unrelated Greek families, originating from western Greece, with 19 affected members. Moreover, we identified a relatively rare C39 > G substitution located in the hexanucleotide loop of the L-ferritin IRE. Clinical and laboratory phenotypes of these subjects are described.
Section snippets
Subjects
Three index probands from 3 unrelated families of western Greek origin were referred for evaluation of persistently elevated serum ferritin levels. These probands as well as several members of their pedigrees underwent screening and interviewing for HHCS and other iron overload associated conditions. Clinical information on these subjects was described. Moreover, testing for biochemical markers of iron metabolism and genetic testing for HHCS and hemochromatosis was performed.
Results
Overall, at least 19/70 subjects were identified with HHCS in the 3 kinderships. Genetic testing for HHCS was performed in 9/19 clinically affected members total. All members with HHCS were heterozygotes for a C39 > G mutation in the FTL IRE stem-loop; while unaffected members were wild-type homozygotes (Fig. 3). Seventeen subjects had serum ferritin levels >900 μg/L; 12 subjects were diagnosed with bilateral cataract at an age younger than 40 years, with at least 1 subject at the age of 5
Discussion
This is the first report describing HHCS in Greek families, providing additional evidence for the worldwide distribution of the syndrome. Evidence on the true prevalence of HHCS is very limited. A population-based Australian study estimated a minimum prevalence of approximately 1:200,000 subjects [10]. However, screening of over 3000 blood donors with hyperferritinemia and 13,000 patients with cataract failed to identify mutations of the FTL IRE gene. It is of particular interest that all 3
Acknowledgment
This work was partly supported by the Greek Ministry of Education (Grant “Pythagoras”—EPEAEKII to N.S.).
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2007, Journal of AAPOSCitation Excerpt :Based on these reports, chromosome 19q was implicated as the site most likely to contain the defect responsible for HHCS. Prior reports on HHCS have originated from Western Europe,1,2,4-15 North America,16-20 Australia,21,22 and India.23 These studies have also shown that distinct chromosomal mutations in the iron responsive element of the L-ferritin subunit are responsible for HHCS; these mutations prevent binding of iron (which provides negative feedback) and lead to the unregulated production of ferritin.
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