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Ceruloplasmin in Wilson's Disease

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Ceruloplasmin in Wilson's Disease Ceruloplasmin in Wilson's Disease Neil A. Holtzman, … , Frank L. Iber, Bonnie M. Gaumnitz J Clin Invest. 1967;46(6):993-1002. https://doi.org/10.1172/JCI105606. Research Article Ceruloplasmin was highly purified from one patient with Wilson's disease and partially purified from a second unrelated patient. The highly purified ceruloplasmin was indistinguishable from normal ceruloplasmin by electrophoresis, tryptic peptide map, oxidase activity, and copper, amino acid, and sugar composition. The partially purified ceruloplasmin was indistinguishable electrophoretically from normal ceruloplasmin. With penicillamine therapy, ceruloplasmin disappeared from the serum of the first patient; it reappeared after the drug was discontinued. The significance of this observation in regard to the basic defect in Wilson's disease is discussed. Find the latest version: https://jci.me/105606/pdf Journal of Clinical Investigation Vol. 46, No. 6, 1967 Ceruloplasmin in Wilson's Disease * NEIL A. HOLTZMAN,t MICHAEL A. NAUGHTON, FRANK L. IBER, AND BONNIE M. GAUMNITZ (From the Departments of Pediatrics, Biophysics, and Medicine, The Johns Hopkins Uni- versity School of Medicine, and The Joseph P. Kennedy Memorial Laboratories, Children's Medical and Surgical Center, The Johns Hopkins Hospital, Baltimore, Md.) Summary. Ceruloplasmin was highly purified from one patient with Wilson's disease and partially purified from a second unrelated patient. The highly purified ceruloplasmin was indistinguishable from normal ceruloplasmin by electrophoresis, tryptic peptide map, oxidase activity, and copper, amino acid, and sugar composition. The partially purified ceruloplasmin was in- distinguishable electrophoretically from normal ceruloplasmin. With peni- cillamine therapy, ceruloplasmin disappeared from the serum of the first pa- tient; it reappeared after the drug was discontinued. The significance of this observation in regard to the basic defect in Wilson's disease is discussed. Introduction Wilson's disease (8) could be explained if, in one pedigree, an amino acid substitution occurs at a Although the concentration of the serum copper point in one of the polypeptide chains, resulting protein ceruloplasmin is decreased in most pa- in a limited alteration of function, whereas in an- tients with Wilson's disease (1), there are several cerulo- other pedigree an amino acid substitution at a objections to the theory that decreased different point results in a more profound dis- plasmin synthesis (2) is the underlying defect. turbance. with un- There are, for instance, several patients Ceruloplasmin accounts for the oxidase activity questionable Wilson's disease who have normal of serum towards several biological aromatic ceruloplasmin levels (3-5). On the other hand, Wilson's amines in vitro (9). However, its function in normal adults unrelated to patients with vivo is still unknown. In previous studies (1, 10, disease, as well as some proven heterozygous lev- 11), insufficient data were presented to determine persons, have persistently low ceruloplasmin if the oxidase activity per milligram of ceruloplas- els without any clinical or chemical manifestations min in sera from patients with Wilson's disease of the disease (6). differs significantly from normal. Furthermore, are with the These findings consistent hypothe- these studies were performed on serum, in which sis that the ceruloplasmin in patients with Wilson's An amino inhibitory factors occur in variable amounts (12), disease is structurally abnormal (7). and therefore may not accurately compare the oxi- acid substitution in a polypeptide chain of cerulo- alter the func- dase activity per mole of pure ceruloplasmin in plasmin, as in other proteins, could Wilson's disease to that of ceruloplasmin in nor- tion, the rate of synthesis or destruction of the The in mal individuals. protein, or both. genetic heterogeneity Structural differences of ceruloplasmin in Wil- * Submitted for publication October 21, 1966; ac- son' disease sera have not been detected either by cepted March 6, 1967. one dimensional electrophoresis (13-15) or by im- This work was supported by U. S. Public Health munolectrophoresis (16). Hirschman, Morell, Service basic science training grant GM-0624 and re- and Scheinberg (17), however, demonstrated a search grant AM-06278 AMP. difference in the electrophoretic mobility of the tAddress requests for reprints to Dr. Neil A. Holtz- man, Dept. of Pediatrics, The Johns Hopkins Hospital, minor component of ceruloplasmin in one patient Baltimore, Md. 21205. with Wilson's disease. The methods employed in 993 994 HOLTZMAN, NAUGHTON, IBER, AND GAUMNITZ the other studies cited would not have detected brane, most dense superiorly, but encircling the such a difference. limbus bilaterally. This report describes a patient with the neuro- No organs or masses were palpable in the ab- logical manifestations of Wilson's disease whose domen. There was no icterus, telangiectasia, serum ceruloplasmin concentration was normal gynecomastia, clubbing, or palmar erythema. when he was first seen. To investigate the pos- Testes were of normal size. sibility that ceruloplasmin was abnormal in this Admission routine hemogram and urinalysis re- patient, we crystallized ceruloplasmin from his vealed no abnormality. Serum bilirubin was less serum and from the sera of normal individuals. than 0.8 mg per 100 ml, serum glutamic oxaloace- The structure of each was extensively studied, and tic transaminase 26 U, serum glutamic pyruvic no differences were detected. Ceruloplasmin was transaminase 14 U, alkaline phosphatase 2.8 Bo- partially purified from another unrelated patient dansky U, albumin/globulin 3.8/4.7 g per 100 ml with Wilson's disease with persistently low levels plasma, uric acid 2.5 mg per 100 ml, and sulfo- of ceruloplasmin. It too was indistinguishable bromophthalein retention 3% 45 minutes after a from normal ceruloplasmin by electrophoresis. dose of 5 mg per kg. Prothrombin time was 50%o Preliminary results of this study were previously of normal but responded to intramuscular vitamin reported (18). K. A low copper diet was started. Two days Case report. E.C. (JHH no. 114-56-16), a 31- after admission, a 24-hour urine sample contained year-old Negro male, was first admitted to The 400 ,ug copper (normal value for this laboratory Johns Hopkins Hospital because of tremor of 2 62 ± 28 /Ag per 24 hours). Serum ceruloplasmin years' duration. There was no family history of (measured by its oxidase activity) was 25 mg per hepatic or neurologic disease or consanguinity. 100 ml, low normal for this laboratory (19). An Serum ceruloplasmin concentration in all seven increase in urinary amino acids, consistent with a of the patient's siblings, as well as his mother, was generalized renal tubular defect, was found. normal. One g per day of D-penicillamine was begun. The patient was employed as a nail maker un- In the second 24 hours, the patient excreted 4,502 til he developed intention tremor of his hands. It MAg copper in the urine. This cupuresis was main- became progressively more severe, even at rest, tained over the next 9 weeks, after which urine and was halted only when he slept or sat on his collections were discontinued. The daily dosage hands. Before his referral to The Johns Hopkins was increased to 4 g. After 3j months of penicil- Hospital, one physician noted glycosuria. The lamine, the serum ceruloplasmin concentration had patient also complained of back pain of several fallen to 8 mg per 100 ml. Three months later years' duration, relieved by lying down. There none was detectable. was no history of anemia, jaundice, ascites, he- After the patient had been receiving penicil- matemesis, melena, or fractures. lamine for 2 months, a closed liver biopsy was On physical examination, the patient had severe, performed. Liver copper was 114 ,ug per g wet flapping, intention tremor of the upper extremities weight (normal value = less than 15 Mug per g wet and a pill-rolling resting tremor of the hands. weight). The biopsy showed moderate fibrosis Facial expression was fixed and speech was slow and regenerating nodules. There was no necrosis. and monotonous with some scanning. Cog wheel There was no clinical improvement for the first rigidity of the upper extremities was present. Re- 9 months on penicillamine therapy, but over the flexes were brisk and symmetrical in the lower ex- next month progressive improvement, with almost tremities and present but difficult to evaluate in complete disappearance of tremor and speech the upper extremities because of the tremor. changes, occurred. The patient felt so well that he Muscle strength was not grossly diminished. Ex- failed to return for medicine until approximately cept for the fine tremors of the tongue, the cranial 1 year after his first admission, when he noted nerves were intact. There was no nystagmus. some recurrence of tremor. He was readmitted The heel to knee test and tandem gait were nor- at this time and aside from some mild intention mal. On slit lamp examination, prominent golden tremor of the upper extremities, where the deep brown deposits were present in Descemet's mem- tendon reflexes were hypoactive, and the persis- CERULOPLASMIN IN WILSON'S DISEASE 995 tent Kayser-Fleischer rings, physical examination was unremarkable. His ceruloplasmin was now 4 mg per 100 ml. D-Penicillamine, 4 g per day, was again started, resulting in the renal excretion of 3,710 jug copper on the second day. A plasmapheresis, yielding 600 ml of heparin- ized plasma, was performed on the patient 1 week after he was started on penicillamine for the first time. A second plasmapheresis, yielding 800 ml of plasma, was performed about 1 year later before penicillamine therapy was reinstituted. There were no ill effects from the procedure. Ceruloplasmin was purified from the plasma TUBE NUMBER obtained. In summary, this 31-year-old male presented with severe intention and resting tremor, fixed facies, and monotonous speech and Kayser- Fleischer rings. He had some hepatic fibrosis and elevated liver and urinary copper. His serum ceruloplasmin concentration was normal but, con- comitant with penicillamine therapy, fell to un- detectable levels.
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