Asbjorn Fölling Lecture

“Heroes of PKU—A History”

Harvey L. Levy, M.D.

Children’s Hospital Boston Harvard Medical School

Boston, Massachusetts USA

Bewley T Psychiatric Bulletin 2000;24:469-469 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 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 “oligophrenia phenylpyruvica”)

Lancet 1935; 2: 192-194

XXXVIII. Metabolic Studies in Phenylketonuria By 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 Phenylpyruvic Oligophrenia Introductory 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 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. 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 Proc Soc Exp Biol Med 1953; 82: 514-515

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 Preliminary Communication

Influence 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 assistance” Horst Bickel John Gerrard Evelyn M. Hickmans Lancet 1953; 2: 812-813

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.

Phenylalanine ------PAH > Tyrosine BH4

J Biol Chem 1958;230:931-939 Unanswered Questions in the Primary Metabolic Block in Phenylketonuria Seymour Kaufman “…at 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 Deficiency

Phenylalanine Tyrosine PAH

BH4

PTP qBH2

Also GTP

TH Tyrosine BH DOPA Dopamine 4 Tryptophan TrH 5-OHTrypt Serotonin BH 4 Severe MR, Seizures without specific treatment

(BH4, neurotransmitter precursors) 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 Mouse

Proc Natl Acad Sci USA 1990;87:1965-1967

NEJM 1980; 303:1336-42