Studies of Lipids, Lipoproteins, and Apolipoproteins in Menkes' Disease

864 BLACKETT ET AL. pulmonary arterial hypertension produced by distension of the main pulmonary artery (MPA) in the conscious dog. Circulation 48: 114 17. Linday LA, Levin AR, Klein AA, Reidenberg MM, Engle MA 1980 Effect of vasodilators on left-to-right shunts in infants and children. Pediatr Res 14447 18. Lusk G 1909 The Science of Nutrition. WB Saunders Co, Philadelphia 19. Miach PJ, Dausse JP, Meyer P 1978 Direct biochemical demonstration of two types of a-adreno-receptor in rat brain. Nature 274:492 20. Miller RR, Awan NA, Maxwell KS, Mason DT 1977 Sustained reduction of cardiac impedance and preload in congestive heart failure with the antihypertensive vasodilator prazosin. N Engl J Med 297:303 21. Nakazawa M, Takao A, Chon Y, Shimizu T, Kanaya M, Momma K 1983 Significanceof systemic vascular resistance in determining the hemodynamic effects of hydralazine on large ventricular septal defects. Circulation 68:420 22. Nuwayhid CR, Brinkman CS, Bevan JA, Assali NS 1975 Systemic and pulmonary hemodynamic responses to adrenergic and cholinergic agonists during fetal development. Biol Neonate 26:301 PEDIATRIC 'RESEARCH 23. Oates HF, Graham RM, Stoker LM, Stokes GS 1976 Haemodynamic effects of prazosin. Arch Int Pharmacodyn 224239 24. Rubin U,Peter RH 1980 Oral hydralazine therapy for primary pulmonary hypertension. N Engl J Med 302:69 25. Rudolph AM 1965 The effects of postnatal circulatory adjustments in congenital heart disease. Pediatrics 36:763 26. Rudolph AM, Auld PAM 1960 Physical factorsaffecting normal and serotoninconstricted pulmonary vessels. Am J Physiol 1982346 27. Steel RDG, Tonie JH 1960 Principles and Procedures of Statistics. McGrawHill Book Co. New York 28. Synhorst DP, Lauer RM, Doty DB, Brody MJ 1976 Hemodynamic effects of vasodilator agents in dogs with experimental ventricular septal defects. Circulation 54:472 29. Talner NS 1971 Congestive heart failure in the infant. Pediatr Clin Am 18: 101 1 30. Tanenbaum H, Pfaff W 1963 Effect of pressor amines on experimental intracardiac shunts and valvular regurgitation. Dis Chest 44485 Vol. 18, No. 9, 1984 Printed in U.S.A. ' Copyright O 1984 lntemational Pediatric Research Foundation, Inc. Studies of Lipids, Lipoproteins, and Apolipoproteins in Menkes' Disease P. R. BLACKETT, D. M. LEE, D. L. DONALDSON, J. D. FESMIRE, W. Y. CHAN, J. H. HOLCOMBE, AND 0 . M. RENNERT Department of Pediatrics, Universityof Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73129 [P. R. B., D. L. D., W. Y. C., J. H. H., 0 . M. R.] and Laboratory of Lipid and Lipoprotein Studies, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 [D. M. L., J. D. F.] Summary Three patients with Menkes' disease, an inherited disorder of copper transport, were studied to determine whether the copper deficiency was associated with a lipoprotein disorder. Hypocuprinemia was documented in all three cases. Two patients had severe copper and ceruloplasmin deficiencies, whereas the third patient had a less severe deficiency. Hypertriglyceridemia was observed in the first patient, and elevations in triglyceride, cholesterol, apolipoprotein B (ApoB), and apolipoprotein GI11 (ApoC-111) occurred predominantly in the very low density lipoprotein fraction (VLDL). This patient had normal lipoprotein lipase activity but mild glucose intolerance. The second patient had a borderline high cholesterol level with normal plasma triglycerides and apolipoproteins, whereas the third patient appeared to have normal total cholesterol but slightly higher triglycerides with elevated plasma apolipoprotein E (ApoE). No striking differences were observed in the chemical composition of all lipoprotein subfractions between patients and controls except that the neutral lipid content of VLDL was higher in patients than in controls. The ApoB was initially normal in molecular weight but degraded faster than the controls during storage. The appearance of the major low density lipoprotein (LDL) fraction of the first two patients was opaque white, in contrast to clear yellow in the third patient and in the age- and diet-matched controls. This abnormal appearance of LDL in Received December 7, 1982; accepted February 7, 1984. Reprint requests may be addressed to P. R. Blackett, M.D., University of Oklahoma, Health Sciences Center, OCMH-2B25 1, P.O. Box 2690 1, Oklahoma City, OK 73 190. This work was supported in part by Program Project HL-23181 and Grant HD16730 from the Department of Health, Education, and Welfare. these patients was associated with low plasma levels of Bcarotene and ceruloplasmin. These findings suggest that decreased serum copper levels may be associated with lipid and lipoprotein abnormalities and may enhance lipid peroxidation of LDL accounting for the color change. The increase in neutral lipids and the damaging effects on lipoprotein-transported substances may lead to atherosclerosis. Abbreviations EEG, electroencephalogram PIS ratio, polyunsaturated to saturated fatty acid ratio VLDL, very low density lipoproteins LDL, low density lipoproteins HDL, high density lipoproteins VHDL, very high density lipoproteins Apo, apolipoprotein GSH, glutathione SDS, sodium dodecyl sulfate Copper is an essential dietary component (13) and is known to be present in many plant and animal tissues (13). Clinical evidence of deficiency was first observed in animals and many of the clinical manifestations have been related to low tissue activities of copper enzymes such as tyrosinase, lysyl oxidase, lactase, ascorbic acid oxidase, cytochrome oxidase, uricase, monoamine oxidase, and dopamine-P-hydroxylase(3 1). Clinical effects of copper deficiency are manifested as widespread derangements in tissues such as skin, bone, connective tissue, red blood cells and the central nervous system. In addition, increased tortuosity of arterial wall tissues may be attributed to defective DISEASE inter- and intramolecular cross-linking of elastin and collagen molecules (28, 35). Following the suggestion that copper deficiency and a low ratio of serum copper to zinc may lead to increased mortality due to coronarv atherosclerosis ( 16). Allen and Klevav ( 11 studied plasma cholesterol concentrations in copper-defi&ent'rats. The plasma cholesterol concentration of the rats was 230% that of pair fed controls, and the difference was apparent even when cholesterol-free diets were fed to both groups. Increased incorporation of [3H]mevalonateinto total plasma lipids, cholesterol, and cholesterol esters was subsequently demonstrated in the deficient rats, suggesting that increased cholesterol synthesis was occumng (1). In view of these findings, we have studied the effects of copper deficiency on human plasma lipoproteins in three cases of Menkes' disease (9, 26), a sex-linked recessively inherited disorder of copper transport (2, 9, 37). CASE REPORTS Case 1. R. S., a 3160-g baby boy, was born at full term to a 16-year-old prima gravida. At 5 days of age, he was noted (...truncated)