Common local founder effects for Wilson's disease and hereditary hemochromatosis; mutation studies of a large family.

UNLABELLED: Wilson's disease (WND) and hereditary hemochromatosis (HH) are two metal loading diseases of copper and iron, respectively, and are both recessively inherited. In central Sweden, where HH is common, 9 Wilson kindred (14 members) were identified. Aims of the study were to test whether nine WND families shared a common origin, a common mutation and if carrying HFE mutations affected their phenotype. RESULTS: The nine families were traced through 13 generations to a common founder origin in the mid-seventeenth century. Despite identity of descent, four different ATP7B mutations appeared with homozygosity in four, with two different mutations, W779X and T977M. There were three compound heterozygotes, W779X/T977M, R1319X/H1069Q and one T977M combined with a new, previously not described mutation, probably of Finnish origin. The founder family also included 26 descendant kindred (55 members) with HH as shown by HFE mutations. This admixture coincided with a migration out of the original parish into hemochromatosis-rich localities. One WND patient had iron overload (serum ferritin 672 µg/l and raised liver enzymes), but lacked HFE mutations. In another family with serious hemochromatosis (two sons dying from bronze diabetes), the coinheritance of congenital spherocytosis was probably the cause rather than an additional effect of WND. CONCLUSIONS: WND though a rare disease may become aggregated like HH in certain areas due to local founder effects. Despite extensive pedigree studies leading back to the local founder family, the authors were unable to find a single defining mutation of the ATP7B gene.

Hemorrhagic colitis induced by trientine in a 51-year-old patient with Wilson's disease waiting for liver transplantation: A case report.

BACKGROUND: Wilson's disease (WD) is a rare inherited disorder of copper metabolism. Treatment consists of chelating agents, but side effects are common. We describe a patient who developed colitis during trientine treatment leading to decompensation of liver cirrhosis. CASE SUMMARY: A healthy 51-year-old woman was diagnosed with liver cirrhosis due to decompensation with ascites. Etiologic evaluation raised suspicion of hereditary hemochromatosis because of compound heterozygosity HFE p.C282Y/p.H63D, and phlebotomy was started. Re-evaluation showed low ceruloplasmin, increased urinary copper excretion and the presence of Kayser-Fleischer rings. WD was confirmed by genetic analysis. Because of decompensated cirrhosis, she was referred for liver transplant evaluation. Simultaneously, treatment with trientine was initiated. Liver function initially stabilized, and the patient was not accepted for a liver transplant. Shortly after this, she developed severe hemorrhagic colitis, most probably a side effect of trientine. During that episode, she decompensated with hepatic encephalopathy. Because of a second decompensating event, she was accepted for liver transplantation, and an uneventful transplantation was carried out after clinical improvement of colitis. CONCLUSION: Despite WD being a rare disorder, it is important to consider because it can present with a plethora of symptoms from childhood to an elderly age. Colitis should be recognized as a serious adverse drug reaction to trientine treatment that can result in decompensated liver disease.

Was the C282Y mutation an Irish Gaelic mutation that the Vikings helped disseminate? HLA haplotype observations of hemochromatosis from the west coast of Sweden.

UNLABELLED: The HLA-related hemochromatosis mutation C282Y is thought to have originated in Ireland in a person with HLA-A3-B14 and was spread by Vikings. Irish people with two HLA-A3 alleles had a high risk of hemochromatosis. In this study, from west Sweden, we wanted to test these hypotheses. METHODS: HFE mutations in controls, bone marrow donors with HLA-A3/A3 and patients with hemochromatosis. HLA haplotypes, extended haplotype analysis and pedigree studies. RESULTS: The allelic C282Y frequency 0.04, (CI 0.01-0.07) was lower (P < 0.001) in Sweden than in Ireland 0.10 (CI 0.08-0.11), and Swedish bone marrow donors with HLA-A3/A3 (n = 77) had a low risk of hemochromatosis. HLA haplotypes available from 239/262 (91.5%) proband patients homozygous for C282Y showed a dominance of A3-B7 and A3-B14 both in linkage disequilibrium with controls (P < 0.001). Pedigree studies extended into the 17th century supported a local founder effect of A3-B14 in the county of Bohuslän. The A3-B14 haplotype may well be the original and A3-B7 the result of centromeric recombinations. The haplotype diversity and recombination events were not different from a Celtic series. These findings do not support the hypothesis of the C282Y mutation being of an Irish Celtic origin. CONCLUSIONS: The C282Y frequency shows a west to east decline from Ireland through the north of Europe. Vikings may have been involved in the spread of C282Y, but the mutation is probably older and may have been spread in Europe by earlier seafarers.