SummaryCopper (Cu) metabolism was selectively studied in seven infants with Menke's steely-hair syndrome (SHS). A daily oral regimen of CuS04 (584 pg Cu/kg) and L-histidine (100 mg/kg) in three infants produced an increase in serum Cu concentrations ranging from 33-95% of normal, but without the formation of ceruloplasmin. Cohn serum protein fractionation after oral CU/L-histidine loading showed a disproportionate accumulation of Cu in the albumin fraction (V). The electron spin resonance spectrum of fraction V showed a heightened signal for the S H S patients, suggesting that an increased concentration of a radical Cu species is present after oral loading. The Sephadex G-150 chromatographic profile of serum fraction V in SHS did not differ significantly from controls. These results suggest that, in SHS, Cu absorbed in the presence of L-histidine is in an abnormal complex involving albumin, which does not allow for holoceruloplasmin biosynthesis. Cu and ceruloplasmin concentrations in the cord blood specimen of an infant who went on to develop SHS were normal, a finding which may account for the transient period of seemingly normal development after birth in SHS patients. An almost &fold difference in mean Cu concentration was observed in SHS fibroblasts compared to controls. Fibroblast Cu concentration was elevated in one of two possible maternal heterozygotes, a finding which may permit diagnosis of the carrier state for some SHS heterozygotes. SpeculationThe basic defect in SHS may be an abnormality in an intracellular Cu binding or transport protein, which is present in multiple tissues. This suggestion is supported by data from intestine and skin fibroblasts and may, in part, explain the common failure of simple Cu replenishment to alter the clinical course of SHS.In 1972, Danks et al. (3) demonstrated a deficiency in the intestinal absorption of Cu in SHS and suggested that a general dysfunction in Cu containing enzymes might account for the keratin and collagen abnormalities, cerebrovascular disease, scorbutic bone changes, and hypothermia commonly seen in the disorder. Although Cu deficiency, as reflected by the low levels of serum Cu and ceruloplasmin, has been found to be a universal feature of the disease, emerging evidence suggests that defective intestinal absorption of the metal may be only part of a more widespread disorder of Cu transport and/or binding. Danks et al. (3) found that erythrocyte Cu concentrations were normal in four SHS infants, suggesting a preferential retention of Cu by red blood cells. Elevated Cu concentrations have also been demonstrated in liver (5, 16), skin fibroblasts (4, 14), amniotic fluid cells (19), and small intestine (2, 3) in the disorder. Excessive urinary (1 1) and fecal (6) excretion of Cu has been reported in SHS, along with unresponsiveness of Cu metalloenzymes (12). Replenishment of Cu deficiency through parenteral supplementation has not yielded impressive clinical results. At best, there is a mild subjective improvement (2, 3, 6) or a partial arrest of sy...