Two novel mutations in the L ferritin coding sequence associated with benign hyperferritinaemia unmasked by glycosylated ferritin assay

Abstract

Investigating persistent hyperferritinaemia without apparent iron overload is challenging. Even when inflammation, cirrhosis, Still's disease, fatty liver and malignancy are excluded, there remains a group of patients with unexplained hyperferritinaemia for whom rare forms of haemochromatosis (ferroportin disease) are a consideration. Preliminary results suggest that abnormal percentage glycosylation of serum ferritin is seen in some cases of genetically determined hyperferritinaemia. Serum ferritin is normally 50-81% glycosylated, but low glycosylation (20-42%) prevails in hereditary hyperferritinaemia cataract syndrome. This contrasts with hyperglycosylation (>90%) associated with the benign hyperferritinaemia related to missense L ferritin (p.Thr30Ile) mutation. Here, we describe two novel missense L ferritin variants also associated with hyperglycosylation, p.Gln26Ile and p.Ala27Val. Ferritin glycosylation, a comparatively simple measurement, can identify patients for DNA sequencing as hyperglycosylation (>90%) is associated with benign hyperferritinaemia and mutant L ferritin chain.

A novel deletion in the iron-response element of the L-ferritin gene, causing hyperferritinaemia cataract syndrome

“…4 There are also missense mutations in the coding region of FTL (p.Thr30Ile, p. Gln26Ile and p.Ala27Val) known to cause hyperferritinaemia associated with hyperglycosylation of ferritin, without iron overload or cataracts. 7,8 HHCS normally follows an autosomal dominant pattern of inheritance. Cases of de novo mutation are also known, which have been referred to as 'nonhereditary hyperferritinemia cataract syndrome' by Cao et al 9 or more simply 'hyperferritinaemia cataract syndrome'.…”

How should hyperferritinaemia be investigated and managed?

“…The cataracts may be asymptomatic but can be diagnosed in children [68,69]. Some L-ferritin mutations can cause benign hyperferritinaemia without cataracts but with a very high glycosylation of SF, compared to low glycosylation of SF in HHCS [70,71]. There is no iron overload in HHCS.…”

Extreme hyperferritinaemia; clinical causes

“…More recently the literature reports hereditary hyperferritinaemias such as hereditary hyperferritinaemia/cataract syndrome (HHCS) and benign hyperferritinaemia (BH) have been identified which are associated with a normal serum iron and transferrin saturation 6–13. Measurement of percentage glycosylated ferritin may be of use in distinguishing these conditions as hyperglycosylation (>90%) suggests BH and low glycosylation (20–42%) indicating HHCS 13. However, this is a specialist assay and not routinely available.…”