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Cholesterol Metabolism in Cultured Fibroblasts in Adrenoleukodystrophy

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Cholesterol Metabolism in Cultured Fibroblasts in Adrenoleukodystrophy 540 YAVlN ET AL. REFERENCES AND NOTES fasting. J. Clin. Invest.. 46: 1589 (1967). I I. Smith, A. L., Satterthwaite, H. S., and Sokoloff, L.: Induction of brain I. Appleton, D. B., and De Vivo, D. C.: An animal model for the ketogenic diet. D()-beta-hydroxybutyratedehydrogenase by fasting. Science. 163. 79(1969). Epileps~a,IS: 2 11 (1974). 12. Stern, I., and Shapiro, 8.: A rapid and simple method for the determination of 2. Dekaban, A,: Plasma lipids in epileptic children treated with a high fat diet. Arch. esterified fatty acids and for total fatty acids in blood. J. Clin. Pathol. 6: 15 Neurol., 15: 177 (1966). (1953). 3. De Vivo, D. C., Pagliara, A. S.. and Prensky, A. L.: Ketotic hypoglycemia and 13. Talbot. F. B., Metcalf, K., and Moriarty, M.: Epilepsy. Chemical inestigations the ketogenic diet. Neurology. 23: 640 (1973). of rational treatment by production of ketosis. Amer. J. Dis. Child.. 33: 218 4. Hendley, D. D., Davenport, H. W., and Toman, J. E. P.: Effect of acid-base (1927). changes in experimental convulsive seizures. Amer. J. Physiol., 153: 580 14. Uhlemann, E. R.. and Neims. A. H.: Anticonvulsant properties of the ketogenic (1948). diet in mice. J. Pharmacol. Exp. Ther. 180: 231 (1972). 5. Huggett, A. St. G., and Nixon, D. A.: Use of glucose oxidase, peroxidase, and 15. Wilder, R. M.: Effect of ketonuria on course of epilepsy. Mayo Clin. Bull.. 2: 307 0-dianisidine in determination of blood and urlnary glucose. Lancet, ii. 368 (1921). (1957). 16. Williamson, D. H., Mellanby, J., and Krebs, H. A,: Enzymic determination of 6. Huttenlocher. P. R., Wilbourn, A. J., and Signore, J. M.: Medium-chain D()-beta-hydroxybutyrc acid and acetoacetic acid In blood. Biochem. J., 82. triglycerides as a therapy for intractable childhood epilepsy. Neurology. 21: 90 (1962). 1097 (1971). 17. Zlatkis, A,, Zak, B.. and Boyle, A. J.: A new method for the direct determination 7. Isom. J. B.: Treatment of minor motor seizures with MCT diet. Paper presented of serum cholesterol. J. Lab. Clin. Med.. 41. 486 (1953). at the Annual Meeting of the Child Neurology Society. Mad~son,Wisconsin, 18. Sigma Chemical Co., St. Louis. Mo. October 12, 1974. 19. Calibiochem, La Jolla, Calif. 8. McQuarrie. I.. and Keith. H. M.: Epilepsy in children: Relationship of variations 20. Informed consent was obtained for all subjects in this study. in the degree of ketonemia to occurrence of convulsions in epileptic children on 21. This research was supported by Grants nos. NS-09785 and F. R. 125, National ketogenic diets. Amer. J. Dis. Child. 34. 1013 (1927). Institutes of Health. Public Health Serv~ce. 9. Millichap. J. C., Jones, J D., and Rudis, B. P.: Mechanism of anticonvulsant 22. Requests for reprints should be addressed to: P. R. Huttenlocher, Department of action of ketogenic diet. Amer. J. Dls. Child., 107: 593 (1964). Pediatrics. University of Chicago, Chicago, 111. 60637 (USA). 10. Owen, 0.E., Morgan. A. P.. Kemp. H. G.. er a/.: Brain metabolism during 23. Accepted for publication December 3, 1975. Copyright O 1976 International Pediatric Research Foundation. Inc. Printed in U.S.A Pediat. Res. 10: 540-543 (1976) Adrenoleukodystrophy fibroblast cholesterol Schilder's disease Cholesterol Metabolism in Cultured Fibroblasts in Adrenoleukodystrophy EPHRAIM YAVIN, AUBREY MILUNSKY,'30' G. ROBERT DeLONG, ANDREA H. NASH, AND EDWlN H. KOLODNY Department of Biochemistry, The Eunice Kennedy Shriver Center, Walter E. Fernald State School, Waltham; Departnzents of Pediatrics and Neurologv, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. USA Extract Speculation The basic biochemical defect of X-linked adrenoleukodystrophy These results do not confirm previously reported abnormalities in (sudanophilic leukodystrophy, Schilder's disease) is unknown. To cholesterol metabolism in cultured fibroblasts. Nevertheless, accu- investigate reported abnormalities in cholesterol metabolism in mulating evidence from studies of fatty acid composition of brain vitro, we examined cultured skin fibroblasts of four patients and and adrenal tissues in Schilder's disease indicates the presence of an four normal control subjects. The kinetics of retention and accumu- abnormal series of lonp; chain fatty acids. Studies are now in lation of [14C]cholesterolby these cells was studied. After 3 days of progress to determine whether these possibly unique long chain fatty exposureto tracer amounts of [14C]cholesterol,an apparent steady acids are evident in fibroblasts from patients with Schilder's disease. state between the medium and cellular cholesterol was established. The specific radioactivity expressed per mg of protein was similar for both Schilder and control fibroblasts. After labeling the The association of adrenoleukodystrophy (sudanophilic leuko- pre-existing cellular cholesterol pool, the rate of loss of label was dystrophy, Schilder's disease, or diffuse cerebral sclerosis) and followed up for a 6-day period. About 23% and 14%, respectively, adrenal insufficiency has been recognized for over 50 years (17). of the cellular radioactivity in both Schilder's disease and control This disorder has been clearly delineated as X-linked recessive and cells were released into the medium after the consecutive change separated from the heterogenous group of fatal degenerative with fresh nonlabeled medium. No significant differences in [I4C] leukodystrophies characterized by other modes of inheritance (6, cholesterol rates of uptake or release were observed between control 7, 15, 18, 19). Distinct heterogeneity exists in the X-linked form and Schilder's disease fibroblasts. About 44% of the labeled choles- with variable severity of the adrenal cortical atrophy from terol was present in an esterfied form after incubation in the pres- asymptomatic to overt adrenal crises. The characteristic pathology ence of unheated serum in both Schilder's and control cultures. includes widespread demyelination and gliosis of cerebral and CHOLESTEROL IN ADRENOLEUKODYSTROPHY 54 1 cerebellar white matter with preservation of subcortical U fibers ventricular system and an atrophic process. Spinal fluid was mildly and a relatively normal cerebral cortex (4). xanthochromic at normal pressure and with a protein level of 156 Evidence for abnormalities in cholesterol metabolism in Schild- mg/100 ml. Cerebral spinal fluid measles antibodies and spinal er's disease has been presented. Eto and Suzuki (3) found fluid y-globulin were normal. cholesterol esters with an abnormal fatty acid composition in the Fasting early morning blood cortisol was 0.4-0.6 pg/100 ml, brains of patients with Schilder's disease and other disorders well below the normal range of 5-25 pg/100 ml, and there was no associated with sudanophilic demyelination, probably reflecting rise after adrenocorticotropic hormone (ACTH) stimulation. Elec- nonspecific changes due to abnormal histology. Others reported an trolytes were normal, renin level was 10.6 mg/ml/hr, and testos- abnormal sterol in the white matter of the brain in one patient with terone level was 0.02 /Ig/ 100 ml. A third sibling and both parents sex-linked Schilder's disease (4). Forsyth et al. (5) reported an had normal cortisol levels, although the brother who tanned absolute and relative increase in esterified cholesterol in the brains excessively also had documented adrenocortical insufficiency (case of a number of patients with Schilder's disease. Pathologic studies 3). of the adrenal glands have also revealed distinctive changes in the Progressive neurologic deterioration followed with the develop- adrenal cortex (nests of ballooned, nonsudanophilic cortical cells ment if severe aphasia, bilateral optic atrophy, spastic quadripare- containing cytoplasmic aggregates of birefringent crystals) (16), sis., and.. eventuallv. an unres~onsivebedridden state. The patient's which have been found in other disorders with other abnormalities adrenocortical insufficiency was well controlled with Florinef and in cholesterol metabolism, e.g., Wolman's disease (10). prednisone. The patient died at 10 years of age. Neuropathologic Most recently Burton and Nadler (1) reported abnormal examination (by Dr. H. H. Schaumburg) revealed the typical cholesterol retention and accumulation in cultivated skin fibro- features of adrenoleukodystrophy, the demyelination affecting blasts in Schilder's disease. In contrast, this study documents our large areas of the white matter, especially of the occipital lobes, inability to demonstrate any abnormal kinetics of cholesterol including lesions of the centrum ovale. metabolism in cultured skin fibroblasts. CASE 3 (BC 1027): AGE 13 YEARS CASE REPORTS This patient is the brother of case 2, who was first examined CASE I(PW 1W5): AGE 6.5 YEARS after the diagnosisu of Schilder's and adrenocortical insufficiencv. Growth and development of this patient were normal until 6 Except for generalized pigmentation, he appeared to be a healthy years of age, when visual difficulty with associated lateral rotation 13 year old. In particular, there were no signs of neurologic of the left eye was noticed. Subsequently, bilateral cortical dysfunction. The fasting morning blood cortisol value was 1.6 blindness, left hemiparesis, then right hemiplegia and spasticity pg/100 ml (normal lower limit 5.2 pg/100 ml). Cortisol values resulted. EEG, skull x-rays, cerebrospinal fluid, and arteriogra- after the ACTH stimulation test were unchanged at 1.6 pg/ 100 ml. phy were normal. The pneumoencephalogram suggested central Treatment with Florinef and prednisone
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