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hemochromatosis type 4

MIM.606069 2q32

Tuesday 5 August 2008

Definition: Hemochromatosis type 4 (HFE4) (MIM.606069) is an autosomal dominant disorder, caused by mutation in the SLC40A1 gene (MIM.604653), which encodes ferroportin and maps to 2q32.

Ferroportin-associated iron overload, or hereditary hemochromatosis type 4, was clinically recognized in 1999 and was linked in 2001 to the SLC40A1 gene, which encodes ferroportin, a protein involved in cellular iron export.

Considering the number of reports published since its discovery, ferroportin seems to be a frequent hereditary cause of hyperferritinemia.

Absence of ferroportin activity leads to abnormal retention (and accumulation) of iron, predominantly by reticuloendothelial macrophages in the liver and spleen and to a lesser extent by hepatocytes and possibly enterocytes.

This inappropriate cellular sequestration tends to diminish, rather than augment, the plasma iron pool, reducing the availability of iron for transferrin binding and delivery to the bone marrow.

This feature explains why transferrin-saturation values are low or normal during all but the late stages of the disorder; it also explains the borderline iron-deficiency anemia seen particularly in postmenarchal girls and persons undergoing phlebotomy therapy.

Most cases reported thus far have been phenotypically milder than those involving classic hemochromatosis, possibly because the organ-damaging potential of reticuloendothelial iron deposition is lower than parenchymal iron deposition.

The key to early diagnosis of the disorder is measurement not of transferrin-saturation values but of serum ferritin levels: they may be elevated as early as the first decade of life and often remain high, despite phlebotomy.

Aggressive phlebotomy can provoke or aggravate anemia, so transferrin-saturation values and hemoglobin levels must be closely monitored.

Ferroportin-related iron overload has been documented in numerous ethnic groups, and ferroportin is probably involved in other iron-overload disorders, including one found in sub-Saharan populations (previously attributed exclusively to dietary excess) and one reported in Melanesians