Nicc In The Tyrol And Germany

Between 1900 and 1974, a group of 138 infants from the Austrian province of Tyrol suffered from childhood liver cirrhosis (13,33). All of the children with symptoms died before the age of 3 yr. The clinical features of the fatal liver cirrhosis observed in the Tyrol showed striking similarities to ICC and ICT. Although the hepatic copper content was not determined in these children, the hepatic morphology was characteristic of ICC/ICT. The high levels of dietary copper were attributed to the formula milk used for feeding the infants; it was routinely prepared in untinned copper and brass vessels until the early 1970s. The disappearance of the disease after 1974 coincided with a change in baby feeding practices and the replacement of untinned copper and brass kitchen vessels. These observations further supported the significant role played by copper cooking utensils. However, the fact that 231 siblings remained healthy although they had been exposed to the same copper-enriched diet as the 138 diseased children implied a genetic predisposition. Segregation analysis suggested that the disease was transmitted as an autosomal recessive disorder, involving equal numbers of both sexes (13). The social and geographical isolation of this population probably led to a high rate of consanguineous marriages (possibly unrecognized as such), resulting in an increased frequency of homozygous offspring (13).

The families affected by Tyrolean NICC were found to be related to each other and they all lived in a rural area of approx 2500 km2 (13). Back in 1780, the entire population of this area comprised


High affinity Cu uptake

High affinity Cu uptake

cell membrane

Cliu cell membrane


nuclear membrane

Human homologs:


yeast Ctrl -> human CTR1 (5q) yeast Atx1 -> human AT0X1 (9q)

yeast Ccc2-> human Wilson disease protein (ATP7B; I3q) yeast Fet3 -> human ceruloplasmin (CP, 3q)

Fig. 1. A simplistic scheme of copper transport into the secretory pathway in yeast. Before the copper ions are taken up by the high-affinity copper transporter Ctr1, the copper II ions are reduced to copper I ions. Inside the cell, copper is transported by the copper chaperone (Atx1) to Ccc2 in the trans-Golgi network, where it is incorporated into ferroxidase (Fet3). In humans, homologous genes have been identified for Ctrl, Atxl, Ccc2, and Fet3. It is anticipated that these human genes will exhibit very similar functions. For an overview, see ref. 35.

approx 17,500 inhabitants, increasing to 57,030 inhabitants by 1995 (T. Müller, personal communication). A part of the large Tyrolean NICC pedigree (13) containing the nuclear families A, B, C, and I (34) could be linked to a common ancestor 10 generations ago. These 4 families came from a small, isolated village, which comprised 2230 individuals in 1760 and 5196 in 1996. The village population presumably expanded only by reproduction rather than by migration of people into the community. Because many people left this rural area because there was insufficient work, the expansion of the population must have been greater than suggested by the numbers given above. Nevertheless, the gene pool is unlikely to have received new mutations in the NICC genes.

A similar large cluster of NICC families has been found in northern Germany (18). Five families with eight NICC cases were identified in Emsland, northern Germany, in a well-defined rural area. Pedigree analysis showed that the families were linked to a common ancestor many generations ago (at least eight). Copper water pipes were suggested as the source of high copper concentrations in tap water. Like the Tyrolean cases, the infants were not breast-fed but fed with formula milk prepared with tap water (18). In addition, the inheritance pattern of NICC in the Emsland families was consistent with an autosomal recessive inheritance of the disease.

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