Hyperferritinemia-cataract syndrome is a disorder characterized by an excess of an iron storage protein called ferritin in the blood (hyperferritinemia) and tissues of the body. A buildup of this protein begins early in life, leading to clouding of the lenses of the eyes (cataracts). In affected individuals, cataracts usually develop in infancy, rather than after age 60 as typically occurs in the general population. Cataracts that are not removed surgically cause progressive dimming and blurriness of vision because the clouded lenses reduce and distort incoming light.

Although the hyperferritinemia in this disorder does not usually cause any health problems other than cataracts, the elevated ferritin levels in the blood can be mistaken for a sign of certain liver disorders. These conditions result in excess iron in the body and may be treated by blood-drawing. However, individuals with hyperferritinemia-cataract syndrome do not have an excess of iron, and with repeated blood draws will develop reduced iron levels leading to a low number of red blood cells (anemia). Therefore, correct diagnosis of hyperferritinemia-cataract syndrome is important to avoid unnecessary treatments or invasive test procedures such as liver biopsies.

Hyperferritinemia-cataract syndrome is caused by mutations in the FTL gene. This gene provides instructions for making the ferritin light chain, which is one part (subunit) of the protein ferritin. Ferritin is made up of 24 subunits formed into a hollow spherical molecule. The 24 subunits consist of varying numbers of the ferritin light chain and another subunit called the ferritin heavy chain, which is produced from another gene. The proportion of the two subunits varies in different tissues.

Ferritin stores and releases iron in cells. Each ferritin molecule can hold as many as 4,500 iron atoms inside its spherical structure. This storage capacity allows ferritin to regulate the amount of iron in cells and tissues.

The mutations that cause hyperferritinemia-cataract syndrome are found in a segment of the gene called the iron responsive element (IRE). The IRE normally can attach (bind) to a protein called the iron regulatory protein (IRP). When this binding occurs, the activity (expression) of the FTL gene is stopped to prevent too much ferritin light chain from being produced. This normally occurs when iron levels are low, because under those circumstances less ferritin is needed to store the iron. Mutations in the IRE segment of the FTL gene prevent it from binding with IRP, interfering with the mechanism by which ferritin production is matched to iron levels and resulting in excess ferritin being formed.

Normal Function

The FTL gene provides instructions for making the ferritin light chain, which is one part (subunit) of a protein called ferritin. Ferritin is made up of 24 subunits formed into a hollow spherical molecule. The 24 subunits consist of varying numbers of the ferritin light chain and another subunit called the ferritin heavy chain, which is produced from another gene. The proportion of the two subunits varies in different tissues.

Ferritin stores and releases iron in cells. Each ferritin molecule can hold as many as 4,500 iron atoms inside its spherical structure. This storage capacity allows ferritin to regulate the amount of iron in cells and tissues. Iron is needed for the body to produce red blood cells.

Health Conditions Related to Genetic Changes

Hyperferritinemia-cataract syndrome

At least 31 mutations in the FTL gene have been identified in people with hyperferritinemia-cataract syndrome. Individuals affected by this disorder have an excess of ferritin in the blood (hyperferritinemia) and tissues of the body. A buildup of this protein begins early in life, leading to clouding of the lenses of the eyes (cataracts) in infancy.

The mutations that cause hyperferritinemia-cataract syndrome are found in a segment of the gene called the iron responsive element (IRE). The IRE normally can attach (bind) to a protein called the iron regulatory protein (IRP). When this binding occurs, the activity (expression) of the FTL gene is stopped to prevent too much ferritin light chain from being produced. This normally occurs when iron levels are low, because under those circumstances less ferritin is needed to store the iron. Mutations in the IRE segment of the FTL gene prevent it from binding with IRP, interfering with the mechanism by which ferritin production is matched to iron levels and resulting in excess ferritin being formed.

Neuroferritinopathy

At least four mutations in the FTL gene have been identified in people with neuroferritinopathy, a disorder in which iron gradually accumulates in the brain. These mutations all affect an area of the gene known as exon 4. The most common mutation detected in people with this disorder inserts the DNA building block (nucleotide) adenine between positions 460 and 461 in the gene sequence. Researchers believe that most families with this mutation descend from a common ancestor who lived in northwest England before 1800. Three other known mutations are each found in a single individual or family affected by neuroferritinopathy.

Mutations in the FTL gene that cause neuroferritinopathy are believed to reduce ferritin's ability to store iron, resulting in the release of excess iron in nerve cells (neurons) of the brain. The cells may respond by producing more ferritin in an attempt to handle the free iron. Excess iron and ferritin accumulate in the brain, particularly in certain regions that help to control movement (basal ganglia), resulting in the movement problems and other neurological changes seen in neuroferritinopathy.

Other Names for This Gene

• ferritin L subunit
• ferritin L-chain
• ferritin light polypeptide-like 3
• ferritin, light polypeptide
• FRIL_HUMAN
• L apoferritin
• MGC71996
• NBIA3

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Signs and symptoms of hyperferritinemia cataract syndrome includes early onset (childhood to early adulthood) cataract. Apart from cataracts, the syndrome causes no symptoms. The condition does not cause iron to be stored in body tissues. Lab tests show high levels of ferritin in the blood, however iron and transferrin saturation levels are normal. Once the syndrome is diagnosed, treatment involves regular eye exams and cataract surgery if needed. Currently there are no treatments to stop or slow the cataracts.

Hyperferritinemia-cataract syndrome has been estimated to occur in 1 in 200,000 individuals.