Menkes disease is a lethal-X linked recessive disorder associated with copper metabolism disturbance. We have recently mapped two chromosome breakpoints related to this disease in a 1 megabase yeast artificial chromosome contig at Xq13.3. We now report the construction of a phage contig and the isolation of candidate partial cDNAs for the Menkes disease gene. The candidate gene expresses an 8 kb message in all investigated tissues, and deletions were detected in 16% of 100 unrelated Menkes patients. The deduced partial protein sequence shared the GMTCXXC motif with bacterial metal resistance operons, suggesting a potential heavy metal binding protein. These findings should lead to more accurate prenatal diagnosis of this severe disease and a better understanding of the cellular homeostasis of essential heavy metals.

We have recently described the identification of a second IDS locus (IDS-2) located within 90 kb telomeric of the IDS gene (Bondeson et al. submitted). Here, we show that this region is involved in a recombination event with the IDS gene in about 13% of patients with the Hunter syndrome. Analysis of the resulting rearrangement at the molecular level showed that these patients have suffered a recombination event that results in a disruption of the IDS gene in intron 7 with an inversion of the intervening DNA. Interestingly, all of the six cases with a similar type of rearrangement showed recombination between intron 7 of the IDS gene and sequences close to exon 3 at the IDS-2 locus implying that these regions are hot spots for recombination. Analysis by nucleotide sequencing showed that the inversion is caused by recombination between homologous sequences present in the IDS gene and the IDS-2 locus. No detectable deletions or insertions were observed as a result of the recombination event. The results in this study have practical implications for diagnosis of the Hunter syndrome.

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We have calculated the incidence of Menkes disease for Denmark, France, The Netherlands, the United Kingdom and West Germany, based on known Menkes patients born during the time period 1976-87. Considering live-born Menkes patients, the combined incidence for these five countries is 1 Menkes patient per 298,000 live-born babies. If the number of affected aborted fetuses are taken into account, the incidence is 1 Menkes per 254,000 live-born babies. This incidence, which is 2-4 times lower than earlier published incidence figures, places Menkes disease as an extremely rare disease. The mutation rate for Menkes disease is estimated to be 1.96 x 10(-6), based on the number of isolated Menkes cases born during the time period 1976-87 and the total number of newborn males during this time.

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