About the Condition

Description/definition:

Hereditary hyperferritinaemia-cataract syndrome (HHCS) is an autosomal dominant disorder associated with a high serum ferritin concentration and the emergence of cataracts in early life.

HHCS was first described in 1995. It was the first example of a genetic alteration resulting in post-transcriptional derepression of protein synthesis.

Cataracts are the only known complication associated with this disorder.

Pathophysiology:

Normal conditions

Within cells, ferritin is comprised of 24 light and heavy subunits, forming a hollow sphere within which excess iron can be stored safely. When intracellular iron concentrations are low – for example, in iron deficiency – the requirement for iron storage is also low. Consequently, iron responsive proteins (IRPs) bind iron regulatory element, preventing translation of ferritin subunits. In states of normal or high iron levels, there is derepression of translation, resulting in increased ferritin protein production.

Hereditary hyperferritinaemia-cataract syndrome (HHCS)

In HHCS, there is a mutation in the iron regulatory element (IRE) in the L-ferritin gene (FTL), which reduces IRP binding and impairs the normal suppression of L-ferritin translation at low intracellular iron concentrations. In other words, there is a disruption in the translational control by iron. Constitutive expression of L-ferritin results in increased serum ferritin concentrations in the absence of iron loading.

Unbalanced formation of ferritin light chains causes free polypeptide to precipitate as crystalline inclusions in lens stroma leading to the formation of punctuate cataracts, which worsen over time. L-ferritin is not known to deposit in any other tissue and hereditary cataracts are the only known clinical manifestation of this protein-aggregation disorder.

Clinical presentation:

From Bowes et al. Lancet. 2014;383:1520.
 

The only known symptom of hyperferritinemia-cataract syndrome is the early onset of ferruginous cataracts:

  • Typically appear between the second and fourth decades of life.
  • Patients may experience glare symptoms that are worse when driving at night or in bright sunlight.
  • Readily identifiable as punctate opacities seen in the red reflex of a dilated pupil using a direct ophthalmoscope.

Diagnosis:

Suspect diagnosis in a patient with:

  • Elevated ferritin in absence of iron overload or inflammation.
  • Presence of bilateral cataracts.
  • Family history of similar disorder.

Confirm diagnosis using DNA sequencing.

Treatment:

The only treatment needed for symptomatic HHCS is cataract surgery.

Genetic counselling is crucial in establishing a prompt diagnosis in at-risk family members, thus avoiding inappropriate biopsy procedures and phlebotomy.

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