return to normal, the number of insulin receptors 

 on the cell increases, and sensitivity to the effects 

 of insulin becomes normal. 



Application of these new procedures has led to 

 the discovery that receptors play a role in at least 

 several other disease states. In uncontrolled dia- 

 betic acidosis, part of the resistance to insulin 

 treatment is due to a decrease in the tightness 

 with which receptors bind insulin. Elevated levels 

 of adrenal steroid hormones, whether natural or 

 administered, often cause alterations in the cell 

 receptors which result in derangements of blood 

 glucose and impaired responsiveness to insulin. 



The therapeutic implications of this research 

 may extend beyond insulin to all types of hormon- 

 al diseases, even including major diseases of oth- 

 er organ systems such as coronary artery disease 

 and several forms of cancer in which hormones 

 play a significant role. 



Elucidation of Mechanisms of Enzyme Action 

 Through Study of Enzyme Deficiency 

 Diseases 



Since the middle 1960's, Dr. Roscoe Brady and 

 his co-workers in NINCDS have been working to 

 understand the causes of a group of 10 inherited 

 metabolic disorders known as lipid storage diseas- 

 es or lipidoses. Each of these disorders is char- 

 acterized by a specific enzyme defect which pro- 

 duces an accumulation of fatty substances called 

 lipids in various parts of the body. 



Starting with Gaucher's disease. Dr. Brady and 

 his associates had discovered by 1965 that the 

 accumulation of a lipid called glucocerebroside 

 was due to a deficiency of an enzyme required for 

 the normal disposal of the lipid. Soon after dis- 

 covering the metabolic defect in Gaucher's dis- 

 ease. Dr. Brady succeeded in developing a diag- 

 nostic test for the disease by assaying for the 

 enzyme in small samples of blood. The new test 

 opened a whole new era in genetic counseling; it 

 not only could be used to identify patients and 

 unaffected carriers of the defective gene, but sub- 

 sequently was adapted to monitor the condition of 

 unborn children at risk, and permitted the antena- 

 tal detection of affected fetuses. 



Within a year of the discovery of the enzyme 

 deficiency in Gaucher's disease. Dr. Brady and 

 his colleagues showed that another lipid storage 

 disease — Niemann-Pick disease — was caused by a 

 genetic deficiency of the enzyme sphingomyeli- 

 nase. These discoveries suggested hypotheses for 

 the specific metabolic defects in all of the other 

 lipid storage diseases. The hypotheses were sub- 

 stantiated for Fabry's disease in 1967 and for Tay- 

 Sachs disease in 1969. By 1973, the enzyme defi- 

 ciencies of the remaining lipid storage diseases 



had been uncovered as well, and tests had been 

 developed to diagnose affected individuals and 

 identify familial carriers of the genes that cause 

 the diseases. 



The hereditary nature of these disorders has 

 made the development of procedures for identify- 

 ing carriers an important goal. Effective genetic 

 counseling is now possible for all of these disor- 

 ders because of diagnostic procedures that have 

 been developed. This past year Dr. Brady's group 

 succeeded in synthesizing two clinically important 

 compounds which can be used for the diagnosis 

 of patients and the detection of carriers of Nie- 

 mann-Pick disease and Krabbe's disease. A third 

 compound has also been developed recently 

 which is useful for the diagnosis of Gaucher's 

 disease. These measurements may be done in 

 conventional hospital chemistry laboratories. Prior 

 to these developments, diagnostic procedures for 

 Krabbe's and Niemann-Pick required the use of 

 radioactive compounds, and they could only be 

 performed in specialized laboratories equipped 

 with radioactive counting facilities. 



In 1973, Dr. Brady and his associates launched 

 a revolutionary treatment for Fabry's disease. 

 They were able temporarily to reverse the effects 

 of the metabolic defect in two patients with Fa- 

 bry's disease by injecting a purified preparation of 

 the missing enzyme into the patients' bodies. This 

 procedure marked the first enzyme replacement 

 therapy for a genetic disorder that has yielded 

 beneficial results. In 1974, injections of the en- 

 zyme missing in Gaucher's disease were given to 

 two patients with that disorder and again encour- 

 aging results were obtained. These successes sug- 

 gest that enzyme replacement therapy may offer 

 hope of effective treatment for some of these in- 

 curable genetic disorders. Although more work i. 

 needed to determine the long-range effects of 

 enzyme replacement in hereditary diseases, the 

 revolutionary demonstration that patients with 

 enzyme deficiency disorders can be benefited by 

 supplementation with purified exogenous enzyme 

 is a landmark of medical achievement. 



Another group of hereditary metabolic disor- 

 ders that has received much attention at NIH is 

 the mucopolysaccharide storage disorders. The 

 work of Dr. Elizabeth Neufeld and her associates 

 in NIAMDD has revolutionized the conceptual 

 and experimental approaches to these metabolic 

 derangements. In each disease, there is a deficien- 

 cy of one of the many enzymes that work togeth- 

 er to break down mucopolysaccharides, chemical 

 substances belonging to the carbohydrate family. 

 Identification of the biochemical defect in Hur- 

 ler's syndrome and Hunter's syndrome — the two 

 most common of these disorders— has far-reaching 



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HEALTH, EDUCATION AND WELFARE 



