Phenylketonuria is a genetic disorder discovered by Dr. Ivar Asbjørn Følling in which the enzyme phenylalanine hydroxylase is deficient, causing an excess buildup of the amino acid phenylalanine. Dr. Følling discovered the condition in the 1930s when he observed two mentally retarded siblings excreting phenylpyruvic acid in their urine, turning it an unusual deep green color with chemical testing. Further research showed the condition was hereditary and could be successfully treated through a diet low in phenylalanine to prevent intellectual disabilities. Newborns are now routinely tested for the disorder to begin dietary treatment early if needed.

1. PHENYLKETO
NURIA
1
Phenylketonuria is the
•Discovered
•Successfully Treated
•Generally Tested For
st
Genetic (FØLLING’S
Disorder
DISEASE)

2. IVAR ASBJØRN FØLLING
• 1888-1973
• PhD in Medicine from
Kristiania University in Oslo,
Norway
• It has been said that: "Følling is
by many considered the most
important medical scientist not
to receive the Nobel Prize for
Physiology or Medicine."

3. HISTORY
A mother with two mentally retarded children came to Dr. Følling and asked for his advice. She was
persistent, and could not accept that there was no explanation for their disability. The feeblemindedness was
beyond doubt. The girl, 7 years of age, could say only a few words, and had a whimsy and purposeless way
of moving about. The 4 year old boy did not walk, he was unable to fix his eyes on anything, and his habits
of eating and of passing urine and stool was that of a baby. Their skin was fair, they had broad shoulders,
stooping figures and the extremities were somewhat spastic. Otherwise routine clinical examination showed
normal findings. A peculiar smell clung to the siblings, and to their urine, which did not contain glucose or
protein. Dr Følling added ferric chloride to the urine, the test for ketones used in those days when examining
diabetic samples. Then a deep green colour appeared, which he had never seen before.
After further testing, He had found that two mentally retarded siblings excreted phenylpyruvic acid in their
urine. It was tempting to speculate of a causal relationship. The next question was: Did other mentally
retarded patients excrete the substance? He therefore examined urine samples from 430 other patients in
institutions for mentally retarded, and 8 of these tested positive.
During the following years he worked with others to elaborate further on the condition. He asked: Is the
condition hereditary, and if so, what is the pattern? The two siblings were suggestive, and among the first 10
patients there were three pairs of siblings. Moreover, three parental pairs were close relatives, and two
parents had seven and five children respectively in their second marriages, all healthy children. They
therefore conducted a new study, and found that in 22 families there were additional 18 affected and 86
healthy siblings. This fitted an autosomal recessive trait

4. PHENYLKETONURIA
• Dr Følling wrote a paper on excretion of phenylpyruvic
acid (a phenylketone) and suggested that the name of
the condition should be “oligophrenia phenylpyrouvica”.
• Later the term phenylketonuria has been adopted.

5. WHAT HAPPENS:
Phenylalanine is an essential
amino acid that is metabolized in
the liver by the enzyme
phenylalanine hydroxylase
(PAH).
When there is a mis-sense
mutation on the long arm of
chromosome 12, the PAH
enzyme is unable to function
properly.
As you can see in the top left of
the diagram, the phenylalanine
is changed by PAH into tyrosine.
If the PAH is unable to function,
excess phenylalanine builds up
and is changed into
phenylpyruvic acid. This
phenylpyruvic acid is expelled in
the urine and is what Dr. Følling
observed when his dye changed
the urine to a deep green color.

6. SYMPTOMS INCLUDE:
• Spasticity (stiff or rigid muscles)
• Severe Mental Retardation
• Hypo(less than normal)pigmentation of hair, skin, and iris
• Gait Abnormalities
• Behavioral Abnormalities (hyperactivity, aggression, and
social withdrawal)

7. TREATMENTS:
Phenylketonuria can be successfully treated if identified
early. Most hospitals test for elevated phenylalanine at
birth with a simple blood test. If the test results are positive
then immediate action must be taken to allow proper
development.
A diet low in phenylalanine, by restricting the intake of
natural proteins, is essential and meat, cheese, bread,
fish, and milk must be avoided. Taking supplements of
other needed proteins is also required since they are not
obtained through diet.
Carefully following this diet can allow a relatively normal
development. However, those with phenylketonuria still
have documented difficulties and are slightly ‘slower’
then their unaffected companions.

8. GENETIC INHERITANCE
Phenylketonuria only occurs
in homozygous recessive
individuals. One ‘normal’
allele is able to make
enough PAH enzyme to
break down all need
phenyalanine. The gene for
PAH is on the long arm of
chromosome 12 and so this
makes the mutation
recessive autosomal.

9. “
MAY THE ODDS BE EVER IN YOUR
FAVOR!
The percentage of people who have phenylketonuria varies depending upon
country.
1 in 2600
Turkey
1 in 15,000 USA
1 in 25,000 Latin America
1 in 70,000 Japan
1 in 200,000 Thailand
”

10. “
MAY THE ODDS BE EVER IN YOUR
FAVOR!
The percentage of people who have phenylketonuria varies depending upon
country.
1 in 2600
Turkey
1 in 15,000 USA
1 in 25,000 Latin America
1 in 70,000 Japan
1 in 200,000 Thailand
”