Asbjorn Fölling 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.
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 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)
Patient VN
WJ
Control I
II
III
Tyrosine formed uM
0
0
.033
.027
.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.
PAH
Phenylalanine ------>
Tyrosine
BH
4
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
PAH
BH4
Tyrosine
qBH2
PTP
GTP
Also
Tyrosine
TH
BH4
Tryptophan
DOPA
TrH
BH4
Dopamine
5-OHTrypt
Serotonin
Severe MR, Seizures without specific treatment
(BH4, neurotransmitter precursors)
Kaufman
“… Rats pretreated with 6methyltetrahydropterin 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