Hemochromatosis in the Japanese is extremely rare; only 19 cases to date have been described. In 2001 an iron overload disorder was accidentally found in a 56 year old Japanese woman. Investigation of her family revealed two other siblings affected with iron overload.
Four affected family members were subsequently recognized and the genetic mutation identified as autosomal dominant as it spanned two generations. A single point mutation (A49U) was located in the iron responsive element (IRE) motif of H-ferritin mRNA. This gene is called FTH1. This disorder is sometimes called hemochromatosis type 5 or Japanese iron overload.
Other causes of hemochromatosis in the Japanese have also been noted. The C282Y mutation is very rare in the Japanese. However one C282Y homozygote has been found – a 65 year old woman from Kyushu. It is unknown as to whether there is racial admixture in the ancestry of this patient. A screening of over 500 Japanese subjects for C282Y failed to find a single copy of C282Y. Another HFE mutation, Ala176Val, has also been reported. However this patient was a heterozygote. Here digenic inheritance acting with another unknown mutation is possible.
Juvenile hemochromatosis or hemochromatosis type 2 has been identified in the Japanese. Two novel hemojuvelin or HJV mutations, D249H and Q312X, have been reported in three patients from two Japanese families. Of note these patients presented with hemochromatosis that more resembled the classical form than the severe juvenile hemochromatosis that is usually reported with HJV mutations. The patients presented in their fourth and fifth decades as opposed to the usual severe presentation before the age of 30 years. All three patients presented with diabetes mellitus. One patient also had congestive cardiac failure. No HAMP mutations have been reported in the Japanese.
Hemochromatosis type 3 or hemochromatosis due to mutations in Tfr2 has been noted in the Japanese. An AVAQ594-597 deletion was found in a family living on the main island of Japan. Because the AVAQ594-597 deletion was first reported in an Italian family, this indicated a mutation occurring in different ethnic groups. It is likely that this mutation will be found in other ethnicities. Additionally two unrelated patients were found to be homozygous for the novel mutations L490R and V561X in TfR2. All Japanese patients with TfR2 related hemochromatosis showed middle age onset of symptoms of iron overload.
Hemochromatosis type 4 or ferroportin disease has been described in the Japanese. A novel mutation of the FPN1 (SLC40A1) gene, A117G, was found in a 43 year old woman with a severe presentation of the classical form of hemochromatosis. Her transferrin saturation was recorded as high as 92%. She did not have any mutation of HFE, TfR2 or FTH1. Another novel mutation, R489S, was found in a second Japanese family. In contrast, the iron overload in this family presented as mild. Ferroportin disease has been described in Caucasians, Africans and Asians. This suggests that it is one of the more important iron overload syndromes in the world.
Other Japanese patients have been described where the mutant gene has not yet been identified.