This rare disorder is inherited as a sex-linked recessive trait. In most of the cases known to us, birth was premature. Poor feeding and failure to gain weight, instability of temperature (mainly hypothermia), and seizures become apparent in early infancy. The hair is normal at birth but the secondary growth is lusterless and depigmented and feels like steel wool; hairs break easily and under the microscope they appear twisted (pili torti). Radiologic examination shows metaphysial spurring, mainly of the femurs, and subperiosteal calcifications of the bone shafts. Arteriography discloses tortuosity and elongation of the cerebral and systemic arteries and occlusion of some. The combination of intracerebral hemorrhage and metaphysial bone spurs, which may be interpreted as “corner fractures,” has led in some cases to the erroneous diagnosis of child abuse. There is no discernible neurologic development, and rarely does the untreated child survive beyond the second year. Three of our cases were examined postmortem (Williams et al). There was a diffuse loss of neurons in the relay nuclei of the thalamus, the cerebral cortex, and the cerebellum (granule and stellate cells) and of dendritic arborizations of residual neurons of the motor cortex and Purkinje cells.
The manifestations of this disease are attributable to one of numerous known mutations in a copper- transporting adenosine triphosphatase (ATPase), ATP7A, that is attributed to a failure of absorption of copper from the gastrointestinal tract and a profound deficiency of tissue copper (Danks et al). Furthermore, because copper fails to cross the placenta, a severe reduction of copper in the brain and liver is evident from birth. In this sense, the abnormality of copper metabolism is the opposite of that in Wilson disease. A relationship between Wilson and Menkes disease is nonetheless evident at a genetic level as they arise from genes encoding two different copper-transporting proteins that are both ATPases. The situation, however, may be more complex, as samples of intestinal tissue show a buildup of copper that indicates the problem is in mobilization of copper from the gut to the bloodstream. Other copper-dependent enzymes show impaired function, such as cytochrome oxidase. For the purposes of early diagnosis, Kaler and colleagues have taken advantage of the reduced activity of another copper-dependent enzyme, dopamine–b-hydroxylase, to detect increased plasma levels of its substrates (dopamine and dihydroxyphenylacetic acid [DOPAC]), as well as reduced levels of the enzyme products (norepinephrine and dihydroxyphenylglycol [DHPG]). The ratio of dopamine to norepinephrine and dihydroxyphenylacetic acid to dihydroxyphenylglycol proved, in their study, to be the most sensitive and specific for early detection. This has allowed the neonatal identification of cases in families with affected children and resulted in normal neurodevelopment in a few children who were treated with copper beginning in the first weeks of life. This same group has suggested that only those mutations in ATP7A that allow for some residual copper transport activity are associated with better outcomes.
Parenteral administration of cupric salts, usually in the form of copper histidine administered subcutaneously twice daily by the parents, restores the serum and hepatic copper and may allow normal development in a few children as noted above but it does not materially influence the neurologic symptoms if treatment is started later. However, even early treated cases showing limited neurodevelopment survive and show some neurologic advance, unlike the past experience in which few survived beyond 5 or 6 years.
Diagnosis of Inherited Metabolic Diseases of Infancy