Asbjorn F ö lling Lecture “Heroes of PKU—A History”

1. Asbjorn Fölling Lecture“Heroes of PKU—A History” Harvey L. Levy, M.D. Children’s Hospital Boston Harvard Medical School Boston, Massachusetts USA

2. Disclosures: I have grants from BioMarin Pharmaceuticals, Inc. I am receiving an honorarium for this lecture from Serono Symposia International Foundation

4. . Bewley T Psychiatric Bulletin 2000;24:469-469

5. Two Cases of Phenylpyruvic Amentia By L.S. Penrose, M.D. Camb. Research Medical Officer, Royal Eastern Counties’ Institution, Colchester First study of cases of PKU after Fölling’s report (Penrose recognized PKU as a classic example of Garrod’s inborn error of metabolism) Lancet 1935; 1: 23-24

6. Inheritance of Phenylpyruvic Amentia By L.S. Penrose, M.D., Camb. Research Medical Officer, Royal Eastern Counties’ Institution, Colchester “…Phenylpyruvic amentia, more conveniently termed phenylketonuria…” (Fölling had originally called the disorder “oligophreniaphenylpyruvica”) Lancet 1935; 2: 192-194

8. XXXVIII. Metabolic Studies in PhenylketonuriaBy Lionel Penrose and Juda Hirsch Quastel From the Biochemical Laboratory, Cardiff City Mental Hospital, and the Research Department, Royal Eastern Counties’ Institution, Ltd., Colchester “If phenylketonurics are unable properly to metabolize a constituent of the protein of the diet, it was thought likely that if protein intake could be reduced to a minimum…” “…the diet contained less than half the usual amount of protein…the phenylpyruvic acid excretion dropped at once…on day 8 it rose…the patient lost ½ lb. in weight…” Biochem J 1937; 31: 266-274

9. Phenylpyruvic OligophreniaIntroductory Study of Fifty Cases of Mental Deficiency Associated with Excretion of Phenylpyruvic Acid George A. Jervis, M.D., Ph.D Thiells, N.Y. Arch Neurol Psychiatr 1937; 38:944-963

10. Studies On PhenylpyruvicOligophrenia The Position of the Metabolic Error By George A. Jervis (From the Research Department, Letchworth Village, New York State Department of Mental Hygeine, Thiells) “The data here presented, showing that no increase of Millon-reacting substances (tyrosine) occurs in the blood of patients on administration of phenylalanine, indicate that the organism of the patient is unable normally to bring about the hydroxylation of phenylalanine.” J BiolChem 1947; 169: 651-656

11. PhenylpyruvicOligophrenia Deficiency of Phenylalanine-Oxidizing System Geoge A. Jervis From the Research Department, N.Y. State Department of Mental Hygiene, Letchworth Village, Thiells, N.Y. Table I. Conversion of Phenylalanine to Tyrosine in 2 Phenylketonurics and 3 Controls (2 mL phenylalanine added to each) Tyrosine formed uM Patient VN 0 WJ 0 Control I .033 II .027 III .020 ProcSocExpBiol Med 1953; 82: 514-515

13. Phenylketonuria With a Study of the Effect Upon It of Glutamic Acid L.I. Woolf and D. G. Vulliamy From the Hospital for Sick Children, Great Ormond Street, London “Glutamic acid feeding is said to depress the blood level of other amino-acids (Christiansen, Streicher, and Elbinger, 1948)…Encouraging reports of treatment of mental defect with glutamic acid…” “The blood phenylalanine concentration does not seem to be much altered by glutamic acid fed…” Arch Dis Child 1951; 26: 487-494

14. Preliminary Communication Influence of Phenylalanine Intake On Phenylketonuria “Dr. L.I. Woolf first drew our attention to the technique of removing phenylalanine from casein hydrolysateand gave further valuable assistance” Horst Bickel John Gerrard Evelyn M. Hickmans Lancet 1953; 2: 812-813

15. Treatment of Phenylketonuria With a Diet Low in Phenylalanine By L.I. Woolf, Ph.D., B.Sc., Ruth Griffiths, M.A., Ph.D., and Alan Moncrieff, C.B.E., M.D., F.R.C.P (From The Hospital for Sick Children, Great Ormond Street, London) “it is known that (protein hydrolysates) can be freed from phenylalanine, tyrosine, and tryptophan by passing through a column of charcoal (Schramm and Primosigh, 1943). This was suggested by one of us (L.I.W.) to Dr. H. Bickel…but no psychometric measurments were made…” Studied 3 cases of diet with psychological testing. All increased in IQ Brit Med J 1955; 1: 57-64.

20. PAH Phenylalanine ------> Tyrosine BH4 J Biol Chem 1958;230:931-939

21. Unanswered Questions in the Primary Metabolic Block in PhenylketonuriaSeymour Kaufman “…at the moment, a variant of phenylketonuria in which the cofactor is missing is a real possibility...” “The lack of dihydropteridinereductase is a possible variant. Presumably, the consequences of lacking this enzyme might be the same as a lack of the cofactor” In: Phenylketonuria and Allied Metabolic Diseases (edited by Anderson JA, Swaiman KF). Washington: U.S. Government Printing Office, 1967; pp. 205-13.

22. Lancet 1975;1:1108-11.

23. NEJM 1975;293:785-90

24. NEJM 1978;299:673-679

25. PKU/BH4 Deficiency Phenylalanine Tyrosine PAH BH4 qBH2 PTP Also Tyrosine DOPA Dopamine Tryptophan 5-OHTrypt Serotonin Severe MR, Seizures without specific treatment (BH4, neurotransmitter precursors) GTP TH BH4 TrH BH4

26. Kaufman “… Rats pretreated with 6- methyltetrahydropterin showed enhanced phenylalanine hydroxylase activity in liver slices…” “… This finding opens up the possibility of treating phenylketonurics who still possess some residual phenylalanine hydroxylase activity with a tetrahydropterin…” Milstien S, Kaufman S. J BiolChem 1975; 250; 4777-81

28. Pediatrics 1963; 32:338-343

30. N Engl J Med 1963;269:52

31. Guthrie R. The origin of Newborn Screening. Screening 1992;1:5-15.

32. Am J Obstet Gynecol 1972;113:121-8.

33. PKU Mouse Proc Natl Acad Sci USA 1990;87:1965-1967

35. NEJM 1980; 303:1336-42