PHENYLKETONURIA

(FLLINGS DISEASE)

Phenylketonuria is the 1st Genetic Disorder

Discovered
Successfully Treated
Generally Tested For

IVAR ASBJRN FLLING

1888-1973

PhD in Medicine from

Kristiania University in Oslo,
Norway
It has been said that: "Flling is
by many considered the most
important medical scientist not
to receive the Nobel Prize for
Physiology or Medicine."

HISTORY
A mother with two mentally retarded children came to Dr. Flling 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 Flling 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

PHENYLKETONURIA
Dr Flling 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.

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. Flling
observed when his dye changed
the urine to a deep green color.

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)

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.

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.

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