centrations and decreased concentrations of copper in the liver and brain (Danks 1995). The morphological changes of the disease start in utero and are fully manifested during the perinatal period (Vulpe and Packman 1995). Premature birth and being small for gestational age are frequent characteristics of Menkes patients. Hypothermia, prolonged jaundice, feeding difficulties, and diarrhea can occur in the neonatal period (Horn et al. 1992). Developmental delays are apparent around the third month, as shown by abnormal head movement and the absence of a smiling response. Therapy-resistant convulsions also occur (Horn et al. 1992). There is no evidence that maternal copper status influences the development or expression of Menkes disease in the infant.
The primary genetic defect in Menkes disease is in the protein ATP7A, a membrane-bound Cu-ATPase that regulates the outward flow of copper ions from the interior to the exterior of the cell (Chelly et al. 1993; Mercer et al. 1993; Vulpe et al. 1993). For this reason, Menkes patients accumulated copper in the intestinal cells. Skin fibroblasts from patients with Menkes disease accumulate large amounts of copper when grown for 3 to 5 days in essential growth medium, demonstrating that the primary defect is detectable at the cellular level (Goka et al. 1976; Horn 1976). Thus, copper accumulation by fibroblasts has been used to confirm prenatal and postnatal diagnosis of Menkes disease. Unlike normal fibroblasts, fibroblasts from Menkes patients became growth-sensitive in very-low-to-medium copper concentrations during a 7-day exposure (Rayner and Suzuki 1994). No significant differences are detectable in copper accumulation by cells established from Menkes patients with different allelic variants of the disease. Thus, the severity of the phenotype cannot be determined by in vitro copper uptake assays (Masson et al. 1997).
In the case of mucosal epithelia, the ATPase transports the copper ions into the serosal capillaries as part of the absorption mechanism across the gut. Studies with animal models and isolated cell cultures suggest that the neurodegeneration is caused by a failure of the ATPase that normally transports copper, resulting in reductions in the activity of select copper-dependent enzymes (Kodama 1993; Yoshimura et al. 1995; Qian et al. 1997; Qian et al. 1998).
Efforts to treat Menkes disease by giving the patients parenteral copper in the form of copper histidine, copper acetate, or copper EDTA have had little success to date. None of these agents prevents neurological damage, although they can increase serum copper concentrations and ceruloplasmin activity. The age when copper administration begins seems to be of some consequence. In one study, a Menkes patient with a splice acceptor site mutation in a non critical region was treated with copper histidine beginning on day 8 of life. Head growth, myelination of neurons in the brain, and neurodevelopment were all normal in the patient. A half broth-