Alterations in copper and collagen metabolism in Menkes' syndrome and a new subtype of Ehlers-Danlos syndrome

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Abstract
Cultured fibroblasts of 13 patients with the Menkes syndrome and 2 with a new subtype (type IX) of the Ehlers-Danlos syndrome (E-D IX patients) showed many very similar abnormalities in their Cu and collagen metabolism. Both cell types had markedly increased Cu concentrations and 64Cu incorporation, and this cation accumulated in metallothionein or a metallothionein-like protein, as previously established for Menkes cells. Histochemical staining indicated that Cu was distributed diffusely throughout the cytoplasm in both cell types, this location being consistent with the accumulation in metallothionein. Both fibroblast types also had markedly low lysyl oxidase activity and distinctly increased extractability of newly synthesized collagen, whereas no abnormalities were present in cell viability, duplication rate, prolyl 4-hydroxylase activity or collagen synthesis rate. A high negative correlation (P < 0.001) was found in the pooled group of Menkes and E-D IX cells between cellular Cu concentration (r = 0.804) or 64Cu incorporation (r = 0.863) and the logarithm of lysyl oxidase activity. There was also a high positive correlation (P < 0.001) between cellular Cu concentration and incorporation (r = 0.869). One of the 2 E-D IX patients also had similar changes in lysyl oxidase activity and collagen extractability in the skin biopsy specimen, suggesting that the abnormalities observed in cultured cells are similar to those present in vivo. The only distinct abnormality found in the cells of the parents of the E-D IX patients was an increased 64Cu incorporation in those of the mother, this finding being consistent with X-linked inheritance of the disorder.