PHENYLKETONURIA

(FØLLING’S DISEASE)Phenylketonuria is the 1st Genetic Disorder

•Discovered

•Successfully Treated

•Generally Tested For

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."

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

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.

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.

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.

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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