Genetic disorders of iron overload and the novel "ferroportin disease".

A positive iron balance inevitably leads to iron overload. 1 Excluding red blood cell transfusion, iron loading usually reflects an altered mucosal regulation of iron absorption, observed both in genetic conditions not associated with anemia and in iron-loading anemias. 2,3 The best characterized form of genetic iron overload is a common recessive HLA-linked disorder, initially called idiopathic hemochromatosis and more recently reported as hereditary or genetic hemo-chromatosis. 4 Patients with this disorder have excessive iron absorption combined with decreased macrophage iron retention, and undergo progressive parenchymal iron loading with appearance of clinical manifestations in the fifth decade of life, predominantly in males. 5 In 1996, HFE was identified as the HLA-related hemochromatosis gene by posi-tional cloning. 6 For years, hereditary hemochromatosis has been considered by most investigators as a single genetic entity, and also as a typically WASP disorder, presumably of Celtic origin. While few reports denying this have appeared in the past two decades, several molecular studies in the last few years have definitely shown that the one-disease dogma is totally untrue. A large body of evidence clearly indicates that, although the HFE-related condition is highly prevalent in Caucasians, on a worldwide basis hereditary hemochromatosis must be considered a genetically heterogeneous syndrome of parenchymal iron overload with variable prevalence in different ethnic groups and with variable clinical expression. HFE-related genetic hemochromatosis in Caucasians (HFE, OMIM 235200) Most patients with HFE-related genetic hemo-chromatosis are homozygous for a Cys282→Tyr (C282Y) mutation and others are compound het-erozygotes for C282Y and a second mutation, His63→Asp (H63D). Homozygosity for C282Y is found in more than 90% of North European 9 and more than 80% of American patients of European origin clinically diagnosed as having genetic hemo-chromatosis. 10 Several studies have shown lower frequencies (64-76%) for C282Y homozygosity in severely iron-loaded patients belonging to populations of Southern Europe 11-13 or including individuals of such origin. 14 According to Beutler et al. 15 the pen-etrance of the C282Y mutation is low, with less than 1% of homozygotes developing frank clinical hemo-chromatosis. Additional HFE mutations have been reported. For instance, Mura et al. 16 described the S65C missense substitution in a study of a large series of hemochro-matosis probands and controls. The S65C substitution accounted for 7.8% of hemochromatosis chromosomes that were neither C282Y nor H63D. Other uncommon HFE exon and intron mutations may be occasionally discovered among hemochromatosis patients who have atypical HFE genotypes. For instance, …