A series of reports in the 1960s highlighted nutritional copper deficiencies in infants and children recovering from malnutrition in Peru; since that time, a cascade of additional cases in premature infants, in patients receiving total parenteral nutrition, and in those receiving special diets or unmodified cow milk have been reported. The identification by Danks that Menkes syndrome, a genetically determined defect in copper absorption and utilization, is responsible for the observed clinical manifestations provided further insight into the physiopathologic effects of copper deficiency. New information on the metabolism and physiologic role of copper, plus the identification of additional copper metalloenzymes and improvement in how to determine copper status, has fueled interpretation and speculation on how and why the classic signs of copper deficiency occur, as well as on the possible effects of mild deficiencies. Also under scrutiny are potential interactions between other elements and the effects of other elements, even when given in acceptable amounts, on copper status. There should be no constraints in thinking on other possible effects of impaired copper status in humans. I review some of the history of nutritional copper deficiency in infants and children and attempt to interpret some of the clinical manifestations in light of newly acquired information.

ExtractIn nine infants suffering from protein-calorie malnutrition, significantly low values for muscle mass and cell mass which were proportional were observed. These were 1.02%0.44 kg and 2,295*693 pg, respectively (PtO.OO1). The extracellular volume was disproportionally high relative to creatinine excretion before and after rehabilitation. The major loss of muscle mass was due to loss of cell size rather than cell number.The protein/DNA ratio was 78518.7 (PtO.OO1) prior to rehabilitation and 109.6545.1 (Pt0.001) following rehabilitation. The RNA/DNA ratio was low at 0.96f0.26 (P~0.001) prior to rehabilitation while after rehabilitation the value increased to 1.24f0.14 but was still less than normal (PtO.O1).The levels of Mg and Zn per unit DNA were reduced in muscle prior to rehabilitation. These values were 6.650.7 and 35.6%15.8, respectively (PtO.OO1).The significantly reduced protein/DNA and RNA/DNA ratios after rehabilitation suggest either persistent alteration in mechanisms responsible for protein synthesis or a prolonged period necessary for recovery. Muscle cell number was not reduced for body length after rehabilitation. The mean muscle mass of 1.67f0.64 kg was not significantly different from the normal for body length after rehabilitation.The concentrations of water (39.96% 16.99) and collagen (3.86f2.24) in adipose tissue were elevated (Pt0.01), while that of fat (50.36521.87) was low prior to rehabilitation. The noncollagen protein was constant per gram of tissue in marasmus and following rehabilitation.

ExtractTotal body water (TBW), intracellular (ICW) and extracellular (ECW) spaces, muscle mass and supporting tissue were measured in nine malnourished infants, 5-30 months of age, shortly after, hospitalization, and then following 4-9 months of rehabilitation. Initially all infants had severe growth deficits, height age being 4-64% (average 40 %) and weight age 0-40 % (average 15.6 %) of chronologic age. TBW ranged from 63.5 to 89.3% of body weight and ECW ranged from 38.6 to 50.6% of TBW, suggesting marked losses of cell mass and body fat, with conservation of supporting tissues. Excretory levels of creatinine and hydroxyproline ranged from 31 to 86 mg/24 h and from 10.3 to 28.5 mg/24 h, respectively. During rehabilitation all patients exhibited accelerated growth, height age becoming 28.6-69.1 % (average 58.8 %) of chronologic age; most of the children became moderately obese. With the exception of one infant, who did not gain weight well despite satisfactory linear growth, excretion of creatinine increased 23-1 36 % and excretion of hydroxyproline increased 45-360 % over the initial values. TBW became 54.7-65 % of body weight and ECW 41.8-55.9 % of TBW. Proportionally smaller increases in metabolically active protoplasm, represented by ICW, were experienced in four infants under 11 months (average 25%, than in four of five infants over 11 months of age (average 67.5 %) ; however; these four infants demonstrated proportionately greater gains in ECW (77 versus 36%).Determinations of blood ,sugar, growth hormone and insulin responses to arginine were made in five of these patients and in three additional infants. On admission, the levels of growth hormone in these infants were found to be elevated (1 1.5-18 ng/ml) and did not respond to arginine injection; determination of blood sugar also showed elevated levels (1 19-1 82 mg/ 100 ml) . One to three months later the response was usually normal. Insulin responses, initially and after partial rehabilitation, were almost invariably blunted, with only one child, at 50 days, showing a rise to 45 ng/ml.