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Asbjorn F ö lling Lecture “Heroes of PKU—A History”. Harvey L. Levy, M.D. Children’s Hospital Boston Harvard Medical School Boston, Massachusetts USA. Disclosures:. I have grants from BioMarin Pharmaceuticals, Inc. - PowerPoint PPT Presentation
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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