The PKU Story - just one enzyme missing

 

A woman with two retarded children came in 1934 to visit a shy Norwegian doctor, Dr. Ivar Følling, who had a background in chemistry. Behind their retardation, the mother guessed something was wrong with their metabolism --she had noticed a strange odor around the children.

He did many tests. In their urine Dr. Følling found a compound that is not found in normal humans. Now he had to figure out what it was.

He extracted crystals of the substance, crystals which all had the same melting point - a sign to him that the substance was all of a kind. He then figured out its atomic composition, and identified the substance as Phenylpyruvic Acid. But was it the cause, or a sign of the cause of the retardation, or was it just incidently related?

Other people with retardation were located and tested. Those that had the same substance in their urine shared a set of physical characteristics: fair complexion, with a tendency to eczema, broad shoulders, a stooping figure and spastic gait.

What does it mean that there is so much Phenylpyruvic acid in the urine? Knowing some of the metabolic pathways, Dr. Følling hypothesized that the sufferers were unable to break down the amino acid phenylalanine into another amino acid, tyrosine. A liver enzyme was missing, that is, an enzyme that operates in the liver, one of the last places for breaking down compounds, phenylalanine hydroxylase (PAH). Because it is not being broken down, phenylalanine builds up.

Now Phenylketonuria (PKU) is known as a genetic disorder which prevents the normal use of protein food, because one of the amino acids, phenylalanine, cannot be broken down. We know exactly where on DNA PAH is mapped, and know hundred or so mutations that lead to failure of the enzyme. Without the enzyme a compound builds up that is toxic.

PKU victims do best on a low protein diet. They eat a special diet using substitutes for the normal food proteins, and can lead normal, productive lives.

 

See the full story of the discovery of PKU , by Følling's son Dr. Asbjørn.

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