Discovery of Phenylketonuria 2

It is now 75 years since a doctor by the name of Asbjorn Folling found a reason for mental retardation in two young children, a sister  (her name was Liv) and a brother (his name was Dag). According to a talk given by Dr. Ivar Folling, son of Asbjorn, a mother of these two children came to see his father to as for advice. Dr. Asbjorn Folling had no reason to believe that he would be able to help these children but he could not reject their mother and agreed to examine them. Their parents were Borgny and Harry Egeland.

Dr. Folling examined both children but found nothing of importance, except for feeble-mindedness.  The girl, at 6 years old, could only say a few words, liked to listen to music, had a whimsy was of moving about, apparently at random. At times she had an enormous appetite, at other times none. The boy, almost 4 years old, could not speak or walk, eat or drink on his own. he was unable to fix his eye on anything, and stool and urine habits were those of a baby. 

Analysis of the urine sample taken from the older child showed no glucose or protein. Dr. Folling then added a few drops of ferric chloride solution (a salt of iron) to an acidified urine sample to test for ketons in the urine, which are abnormal substances that make a red-brown colour with ferric chloride. Instead, the girl’s urine turned dark green colour that faded  in a few minutes. Dr. Folling has never seen that before, but sometimes if the person is on some medication this reaction can give different colours. So the mother was asked to stop giving any medication to her children and bring back another urine sample in a weeks. But when tested, second sample still gave green colour. 

So the next logical step was to isolate and purify the substance that results in this colour. He eventually succeded in obtaining neat crystals with a constnat melting point, a probably sign of purity. 

He then chemically analysied this substance and determined that the material had a material formula of nine carbons, eight hydrogen atoms and three oxygen atoms. It was acidic. On mild oxidation it smelled of benzylaldehyde. And when gently heated with potassium permanganate in alkaline solution, oxalic acid and the characteristic appearance of benzoic acid were obtained as products of stronger oxidation.  From these reaction that give benzaldehyde and benzoic acid, Dr. Folling concluded that the substance had a benzene ring, and was probably phenylpyruvic acid.  To test this he added a known phenylpyruvic acid crystals to the unknown crystals and observed that the melting point did not alter, so they were the same material. 

Dr. Folling then went on to find out if the rest of retardation in children cases were caused by this. Among 430 children he tested, he found 8 with the same abnormality as Egeland children, including two more sibling pairs.  Dr. Folling called the condition “imbecillitas phenylpyruvica”. And in couple more years the name “phenylketonuria” was proposed by Dr. Lionel Penrose, because of the characteristic appearance of the phenylketone, phenylpyruvic acid, in the urine. 

Dr. Folling continued to work in this field, but his later publications are less well known. He observed that the disease had a recessive trait since among the 8 patients there were pairs of siblings.  So he concluded it was a recessive autosomal trait. 

This was how scientific world gained a knowledge of a new disease. For many years PKU (Phenylketonuria) was considered an unfortunate disease of mental retardation for which nothing could be done. But by mid 50s, a special diet food had been developed and soon infants were successfully treated to prevent the mental retardation of Phenylketonuria. For this diet to be a success it had to be started before the onset of mental retardation.