7/22/2019 History of PKU

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Celebrating 75 Years Since the Discovery of PKU

 By Virginia Schuett, editor, National PKU News

Birmingham Children’s Hospital in England,

in collaboration with Dr. Horst Bickel using

an idea first 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 first identified as thesyndrome 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 hydrolyzedmilk protein to be low in

phenylalanine, is the first

commercially available

low phe formula for the

treatment of PKU to be

approved by the FDA in

the US.

1960 A filter 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 field 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. Fölling receives the first 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.

 Asbjörn Fölling, one of Norway’s first physiciansto apply chemistry to medicine. He calls it

“imbecillitas phenylpyruvica”

 because of the serious mental

retardation found in the first

two children identified with the

disorder, Liv and Dag Egeland

( pictured with their parents at

right ), and the phenylpyruvic

acid in the urine. Dr. Fölling

later finds 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 defines 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 Office 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 newbornsusing 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 Treatmen

of PKU begins, involving 16 clinics and studyin

211 children over a period of 16 years; the studyultimately confirms the value of early treatmen

and low blood phe levels.

1983 The human phenylalanine hydroxylas

gene is isolated and cloned by Dr. Savio Woo

at Baylor College of Medicine in Texas, paving

the way for carrier identification and importa

PKU gene therapy research.

1984 Again led by Dr. Richard Koch, TheInternational Maternal PKU Study begins,

involving 91 clinics in the US, Canada and

Germany; it ultimately documents that levels of

6 mg/dl during pregnancy produce good result1990 A genetically altered mouse is engineer

to have PKU by Dr. David McDonald and Dr

 Alexandra Shedlovsky at the University of

 Wisconsin’s McArdle Laboratories in Madiso

This “PKU mouse model” gives researchers a

 vital tool for carrying out experiments that ar

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 U

“Treatment for Life” is emphasized.

2007 BioMarin’s Kuvan (sapropterin

dihydrochloride), a synthetic version of a

natural cofactor for the enzyme missing or

malfunctioning in PKU, is the first drug (a pi

approved by the FDA to lower blood phe leve

in some people with PKU.

2009 BioMarin clinical trials begin for

studying an enzyme replacement therapy for

PKU using pegylated phenylalanine ammoni

lyase (PEG-PAL) injections.

 Liv (left), age 7, and Dag, age 4, the first children

diagnosed with PKU by Dr. Fölling, with their

 parents, Dag and Borgny Egeland, Norway, 1934.

 Dr. Asbjörn Fölling.

Volume 2NumberFall 200

News And Information About Phenylketonuria