When Eating Protein Can be a Death Sentence: PKU

As I prepared to write this blog the intention was to describe PKU, a potentially devastating genetic disorder. Among other ideas, I planned to describe how, in order to come up with a treatment for PKU, Dr. George Jervis experimented on disabled children. He was a research scientist at Letchworth Village, a state institution established as a residence for disabled children and adults. However, I was not going to reveal the fact that my brother was once a resident at that facility.

In writing the blog, however, it seemed disingenuous to omit this personal information. I think my emotional response to Dr. Jervis (evident in the blog) requires an honest explanation, perhaps even an admission that there may be a conflict of interest. I am not a dispassionate reporter in this instance. My awareness of what happened at Letchworth fills me with horror. My brother was loved and valued throughout his life.

An Abandoned Building in Letchworth Village

Image credit: Doug Kerr, from Albany, NY, United States. Used under a CC 2.0 generic license.

PKU: The Hunt for Understanding and Treatment
The term PKU stands for phenyketonuria. This is a genetic condition that is expressed (becomes evident) only when two copies of the affected gene are inherited. Because of this discrete pattern of inheritance, the disorder is described as an autosomal recessive condition.

One of the tragedies of PKU is that parents often don't know they are carriers. They are stunned to learn their offspring suffers from the condition. This will happen only if both parents carry the trait.

Because this disorder, and others, usually lurks hidden, a system of virtually universal newborn screening has developed. (See @cyprianj's blog of 12/28/2021 for an explanation of newborn screening.)

A Newborn is Tested for PKU

Image credit: U. S. Air Force photo, Staff Sgt. Eric T. Sheller. Public domain

PKU is a metabolic disorder. It occurs when a certain enzyme, phenylalanine hydroxylase, is absent. This enzyme ordinarily breaks down phenylalanine, an amino acid. Amino acids are the building blocks of protein, so when people with PKU eat protein, phenylalanine is not processed properly. The amino acid therefore builds up in the individual's body. Some amino acids can cross the blood/brain barrier. Phenylalanine is one of these. Because of its untempered release in the body, the amino acid accumulates in the brain. This accumulation has devastating consequences.

The consequences can be evident very soon after birth, which is why it is essential to catch the disorder before damage is done. The damage may be irreversible.

University of Oslo: PKU First Identified by Asbjørn Følling Here in 1934

Image credit: Mahlum. Used under CC 2.0 license

The mystery of PKU was unraveled by a physician with a background in chemistry and metabolic medicine. The doctor, Asbjørn Følling, agreed to see a distraught mother whose two children were severely affected by a peculiar ailment. The children suffered severe cognitive and physical impairments. The younger child was more profoundly affected than the older child.

Dr. Følling could find nothing in his physical examination of the children that would explain what was causing their symptoms. Finally, on a hunch, he performed a number of tests on their urine. The tests came back with a peculiar result, one Dr. Følling had never see before in a test on urine. To his knowledge, no one else had ever seen it before either. It took the doctor months to identify the substance, which consistently appeared in the children's urine: phenylpyruvic acid.

Here is link to a YouTube video of an interview with Dr. Følling. In the video he describes how he discovered PKU:

The detection of phenylpyruvic acid was a clue that led him and others to wonder if there might be other children who were 'feeble minded' and who also excreted the acid in their urine. Researchers looked at children who had been institutionalized in several facilities. Out of 430 children examined, 8 tested positive for the acid. Not only that, these children tended to have certain physical characteristics in common: broad shoulders, spastic gate, eczema, fair complexion.

With Følling's discovery, the hunt was on in research facilities across the world to find out why the affected children excreted phenylpyruvic acid. How did the children become afflicted, and could there be a treatment? Dr. Følling called the condition he had discovered phenylpyruvic oligophrenia.

Formula for Phenylpyruvic Acid

Image credit: Wikimedia Commons. Public domain.

Despite his findings and quest for answers, Asbjørn Følling did not experiment on children.

At this time, George Jervis worked for the New York State Department of Mental Hygiene. His research department was located in Letchworth Village, a facility where children had been institutionalized. Many of them were 'feeble minded'. At the time, Letchworth Village Administration had a working relationship with the Eugenics Record Office at Cold Spring Harbor. The records of the children at Letchworth were shared with the eugenics lab.

Residence of Charles Davenport, Head of Eugenics Lab at Cold Spring Harbor

Image credit: AdamOxalate. Used under a CC 3.0 license.

Jervis had everything he needed to do research on Følling's phenylpyruvic oligophreniathis. In his 1947 paper Jervis describes the research. While he did work with animals he also used children to find his answer. Here is some of what he wrote. His subjects were adults and children. Some were 'normal' and some were suffering from phenylpyruvic oligophrenia:

They were kept fasting 15 hours before and during the experiment. Dtyrosine (Merck), and phenylpyruvic acid were given by mouth. The dose was 5 gm.; the subjects weighed from 60 to 80 kilos. In three patients who were children, weighing from 20 to 30 kilos, the dose was 4 gm. Finally as a further control, glycine was fed in a dose of 10 gm. to normal individuals and to patients in order to determine whether an increase in Millon-reacting substances could be obtained. Blood was obtained by veni-puncture at the fasting level and at half hour intervals for the first 2 hours following the ingestion of the compound, then at hourly intervals."

Jervis concluded, correctly, from his experiments that phenylpyruvic oligophrenia resulted from an error in the metabolism of phenylalaline. In time, researchers would learn that this 'mistake' occurred because an enzyme, phenylalanine hydroxylase, was not released in the liver as it ought to be.

Structure of Phenylalanine Hydroxylase

Image credit: TimVickers at English Wikipedia. Public domain.

The challenge then became, what to do about it? Obviously afflicted children could not eat protein. Efforts to restrict protein were unsuccessful. After two weeks of a protein-deprived diet, an individual's body stopped looking for external sources of protein and began to break down protein in the person's body. Phenylalaline began once again to build up in the bloodstream.

In time, formulas were devised that would satisfy the body's hunger for protein and yet not add phenylalaline to the diet. The PKU diet became the first "medical food", and the first "dietary therapy for metabolic disease.

Important note: Aspartame contains phenylalaline. Any food containing this artificial sweetener must absolutely be avoided by people on the PKU diet.

The incidence of PKU in the global population varies by country and region. Italy has a relatively high rate, 1:4,500 individuals, Japan a relatively low rate, 1:125,000 individuals. Worldwide, Turkey has the highest incidence and Thailand the lowest incidence. (Unfortunately, no statistics are given for the continent of Africa!!)

PKU Gene Distribution Chart

Image credit:en:User:Cburnett,own work in Inkscape. Used under Creative Commons Attribution-Share Alike 3.0 Unported license

Carrying the Trait May Also Have Consequences
While development of PKU requires an individual to have two copies of the faulty gene, it seems that merely being a carrier may also have consequences. A study at a research facility (Università degli studi della Campania Luigi Vanvitelli) in Naples demonstrated that PKU carriers "...performed worse than HC on immediate verbal recall, on test assessing set-shifting, divided attention, and sensitivity to processing speed".

Conclusion
The story of PKU is a story of hope. It is one instance when a discovery led to a treatment and hope for a previously dismissed population. However, not every ray of sunshine escapes a cloud. The cloud in this case was George Jervis. I know there have been other cases (many) of experimentation on institutionalized children (and adults). In 1950, for example, Jervis "asked Dr. Hilary Koprowski to test" his polio vaccine at Letchworth. Koprowski did that. Jonas Salk tested the first flu vaccine on (adult) mental patients, and the polio vaccine on children at the Polk School (state institution), in Pennsylvania.

As I stated in my first paragraph, my brother was a resident at Letchworth. He was there after Jervis' PKU experiments were completed. Were there other experiments? Who knows. What Jervis' behavior shows is a lack of concern and respect for the people in his charge. It shows a disregard for their value as human beings. I'll end this article, which is about hope and cure, with a picture of the cemetery at Letchworth Village. The institution was closed in 1996, years after the public became aware of scandalous conditions at the institution. Note that the little metal markers are identified with numbers, not names.

Image credit: GeekontheWing CC 4.0 license

Thank you for reading my blog. It's a pleasure to be writing for StemSocial. @cyprianj is 2% beneficiary on the post because I got the idea to write about PKU when I read his blog.

Hive on!

Sources
Accents (paragraph separators and heart): @agmoore

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