Celebrating 75 Years Since the Discovery of PKU

By Virginia Schuett, editor, National PKU News

Birmingham Childrens Hospital in England,
in collaboration with Dr. Horst Bickel using
an idea rst proposed by the British Dr. Louis
Woolf in 1949. The reduced phe milk protein
is given to a child with PKU over a period of 6
months and shown to cause improvements in
mental development and behavior. This leads to
recognition that early treatment is crucial for the
best outcome.
1957 Maternal PKU is rst identied as the
syndrome that results when women with high
blood phe levels have babies. The high en utero
phe levels cause mental retardation and a variety
of other problems.
1957 The Wet Diaper Test for PKU is
developed in Oregon by Dr. Willard Centerwall.
This test for excretion of high levels of phenyl-
pyruvic acid allows diagnosis of PKU, but it is
not accurate for some time after birth.
1958 Lofenalac (Mead
Johnson), a formula
made from hydrolyzed
milk protein to be low in
phenylalanine, is the rst
commercially available
low phe formula for the
treatment of PKU to be
approved by the FDA in
the US.
1960 A lter paper screening test for PKU is
developed by Dr. Robert Guthrie in Buffalo, NY,
and becomes known as the Guthrie Test. This
inexpensive and accurate bacterial inhibition
test run on a small spot of blood makes mass
screening for PKU possible at birth, to prevent
its harmful effects.
1961 A eld trial of newborn screening
for PKU is begun in the US on nearly one
million infants using the Guthrie Test and
demonstrates the feasibility of mass screening.
1962 Dr. Flling receives the rst Joseph
P. Kennedy International Award in Mental
Retardation from then-President John F.
Kennedy at the White House.
This year we celebrate the 75th anniversary of the
discovery of PKU, a small but important chapter
in the history of medicine. To commemorate
what was such a crucial discovery for all of us, I
wanted to outline other landmark events along
the way that have shaped PKU treatment and
thus for each of us in the PKU community have
shaped our own individual lives.
1934 PKU is discovered in Norway by Dr.
Asbjrn Flling, one of Norways rst physicians
to apply chemistry to medicine. He calls it
imbecillitas phenylpyruvica
because of the serious mental
retardation found in the rst
two children identied with the
disorder, Liv and Dag Egeland
(pictured with their parents at
right), and the phenylpyruvic
acid in the urine. Dr. Flling
later nds that the abnormal
amounts of phenylpyruvic acid
in the urine of these children
is caused by their inability to
metabolize phenylalanine,
and suggests the autosomal
recessive genetic nature of the
disorder.
1935 The name imbecillitas
phenylpyruvica is changed to
phenylketonuria, as suggested
by Dr. Lionel Penrose, an eminent British
medical geneticist, because of the characteristic
appearance of the phenylketone, phenylpyruvic
acid, in the urine. He further denes the
chemical basis of the disorder in years to come.
1937 PKU is found to be caused by abnormal
functioning of the enzyme phenylalanine
hydroxylase by Dr. George Jervis, Director of
the Institute for Basic Research of the New
York State Ofce of Mental Retardation and
Developmental Disabilities.
1951 First diet treatment for PKU is developed
in the laboratory of Dr. Evelyn Hickmans at
1963 Mass screening of newborns
using the Guthrie Test begins.
Dr. Guthrie travels the US to advocate for
newborn screening laws to be enacted.
1967 By this time, 37 states have mandatory
newborn screening laws for PKU. Led by
Richard Koch, Los Angeles, California, The
National Collaborative Study for the Treatment
of PKU begins, involving 16 clinics and studying
211 children over a period of 16 years; the study
ultimately conrms the value of early treatment
and low blood phe levels.
1983 The human phenylalanine hydroxylase
gene is isolated and cloned by Dr. Savio Woo
at Baylor College of Medicine in Texas, paving
the way for carrier identication and important
PKU gene therapy research.
1984 Again led by Dr. Richard Koch, The
International Maternal PKU Study begins,
involving 91 clinics in the US, Canada and
Germany; it ultimately documents that levels of 2-
6 mg/dl during pregnancy produce good results.
1990 A genetically altered mouse is engineered
to have PKU by Dr. David McDonald and Dr.
Alexandra Shedlovsky at the University of
Wisconsins McArdle Laboratories in Madison.
This PKU mouse model gives researchers a
vital tool for carrying out experiments that are
impossible or unethical in humans.
1993 National PKU Treatment Guidelines
and Standards are developed at a National
Institutes of Health Consensus Conference to
make PKU treatment more uniform in the US.
Treatment for Life is emphasized.
2007 BioMarins Kuvan (sapropterin
dihydrochloride), a synthetic version of a
natural cofactor for the enzyme missing or
malfunctioning in PKU, is the rst drug (a pill)
approved by the FDA to lower blood phe levels
in some people with PKU.
2009 BioMarin clinical trials begin for
studying an enzyme replacement therapy for
PKU using pegylated phenylalanine ammonia
lyase (PEG-PAL) injections.
Liv (left), age 7, and Dag, age 4, the rst children
diagnosed with PKU by Dr. Flling, with their
parents, Dag and Borgny Egeland, Norway, 1934.
Dr. Asbjrn Flling.
Volume 21
Number 2
Fall 2009
News And Information About Phenylketonuria