Menkes' X-linked disease: prenatal diagnosis and carrier detection

Increased 64Cu uptake into cultured cells is a biochemical marker for mutant cells in Menkes' disease (McKusick 30940). Using this marker selective prenatal diagnosis has been carried out in more than 80 at-risk pregnancies. The 64Cu uptake into cultures from affected male fetuses is however, negatively correlated to the fetal age at amniocentesis. After the 18th week of gestation the risk of false negatives is significant. Using copper uptake into uncloned cultures, a number of obligate and possible carriers showed significantly increased values, but the range of values of obligate carriers considerably overlapped those of the normal controls. All values of normal controls were within a limited range and values above the upper limit in females at risk must, therefore, be caused by mutant cells and establish the carrier diagnosis. However, the extreme skewing of the distribution towards normal values in obligate carriers indicates a strong selection against the mutant cell type and this will hamper the detection of all female carriers in risk families. C-banding heteromorphism of the X-chromosome provides a supplementary carrier detection method. Linkage analysis in five Danish families demonstrated a close physical relationship between the gene for Menkes' disease and the centromere region. By comparative gene mapping (mouse/man) the most likely localization of the gene for Menkes' disease can be suggested to be in band q13 on the long arm of the human X-chromosome. This regional assignment facilitates the choice of appropriate X-specific DNA probes in search for linkage at the DNA level.