Asbjorn Flling Lecture

Heroes of PKUA HistoryHarvey L. Levy, M.D.

Childrens Hospital BostonHarvard Medical School

Boston, Massachusetts USA

Disclosures:I have grants from BioMarin Pharmaceuticals, Inc.

I am receiving an honorarium for this lecture from Serono Symposia International Foundation

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

Two Cases of Phenylpyruvic AmentiaBy L.S. Penrose, M.D. Camb.

Research Medical Officer, Royal Eastern Counties Institution, Colchester

First study of cases of PKU after Fllings report (Penrose recognized PKU as a classic example of Garrods inborn error of metabolism)Lancet 1935; 1: 23-24

Inheritance of Phenylpyruvic AmentiaBy L.S. Penrose, M.D., Camb.

Research Medical Officer, Royal Eastern Counties Institution, Colchester

Phenylpyruvic amentia, more conveniently termed phenylketonuria

(Flling had originally called the disorder oligophrenia phenylpyruvica)

Lancet 1935; 2: 192-194

XXXVIII. Metabolic Studies in PhenylketonuriaBy Lionel Penrose and Juda Hirsch QuastelFrom 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 proteinthe phenylpyruvic acid excretion dropped at onceon day 8 it rosethe patient lost lb. in weight

Biochem J 1937; 31: 266-274

Phenylpyruvic OligophreniaIntroductory Study of Fifty Cases of Mental Deficiency Associated with Excretion of Phenylpyruvic Acid

George A. Jervis, M.D., Ph.DThiells, N.Y. Arch Neurol Psychiatr 1937; 38:944-963

Studies On Phenylpyruvic Oligophrenia 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 Biol Chem 1947; 169: 651-656

Phenylpyruvic Oligophrenia Deficiency of Phenylalanine-Oxidizing System Geoge A. JervisFrom 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 uMPatient VN0WJ0Control I.033II.027III.020Proc Soc Exp Biol Med 1953; 82: 514-515

Phenylketonuria With a Study of the Effect Upon It of Glutamic AcidL.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

Preliminary CommunicationInfluence of Phenylalanine Intake On Phenylketonuria

Dr. L.I. Woolf first drew our attention to the technique of removing phenylalanine from casein hydrolysate and gave further valuable assistanceHorst BickelJohn GerrardEvelyn M. Hickmans Lancet 1953; 2: 812-813

Treatment of Phenylketonuria With a Diet Low in PhenylalanineBy 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. Bickelbut no psychometric measurments were made

Studied 3 cases of diet with psychological testing. All increased in IQ Brit Med J 1955; 1: 57-64.

Phenylalanine ------> TyrosinePAHBH4J Biol Chem 1958;230:931-939

Unanswered Questions in the Primary Metabolic Block in PhenylketonuriaSeymour Kaufmanat the moment, a variant of phenylketonuria in which the cofactor is missing is a real possibility...

The lack of dihydropteridine reductase 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.

Lancet 1975;1:1108-11.

NEJM 1975;293:785-90

NEJM 1978;299:673-679

PKU/BH4 DeficiencyPhenylalanineTyrosinePAHBH4qBH2PTPGTPAlso

Tyrosine DOPADopamine

Tryptophan5-OHTryptSerotonin

Severe MR, Seizures without specific treatment(BH4, neurotransmitter precursors)THBH4TrHBH4

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 Biol Chem 1975; 250; 4777-81

Pediatrics 1963; 32:338-343

N Engl J Med 1963;269:52

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

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

PKU MouseProc Natl Acad Sci USA 1990;87:1965-1967

NEJM 1980; 303:1336-42