I idolized a senior named Kate when I was a freshmen in high school. Like me, she played volleyball and tennis and she went out of her way to "show me the ropes" of my new high school. Sometimes, she would give me a ride home after practice and we would stop to get a snack. We had to go to Sonic, though, because she had certain diet restrictions. So, we would get strawberry limeades. Yeah, I know... not what you'd expect when talking about diets.
Kate has phenylketonuria (PKU). She explained the basics of the disease, so I knew she couldn't eat meat, eggs, milk and other foods that had the amino acid phenylalanine in it. If she ate phenylalanine there would be an abnormal accumulation in her brain. You would be surprised at some of the foods that have phenylalanine, like aspartame. So, any foods with NutraSweet/aspartame had to be avoided. A lot of fast food places used NutraSweet, but not Sonic! Hence, the stops for strawberry limeades.
Thankfully, her disease was caught very early. (The blood test where the doctors prick the heel of a newborn tests for PKU) (Lee, 2011). Because she has been on the no-phenylalanine diet since she was a newborn, she did not display the characteristics associated with not following such a diet. These symptoms include delayed mental and social skills, small head size, hyperactivity and jerking movements, mental retardation, seizures, skin rashes, and tremors (Lee, 2011).
Not only did she seem completely normal to me, she was someone to look up to and emulate. So, I always assumed that adhering to the diet and taking special protein supplements without phenylalanine eliminated any problems caused by the disease. In class the other day, though, Dr. JC mentioned that all the necessary amino acids must be present in order to make a protein. This made me question why there aren't more problems associated with the PKU diet. With only 20 amino acids to work with, wouldn't phenylalanine be present in, and therefore necessary for, a lot of the proteins made by our body?
To answer this, I first looked at the genetics and biochemistry of PKU. It is a single gene disorder and an autosomal, recessive disease. It is caused by the absence of the enzyme phenylalanine hydroxylase (Lee, 2011; Campbell, n.d.). Normally, this enzyme breaks down phenylalanine to tyrosine as illustrated below (Campbell). The phenylalanine in affected individuals is converted to phenylpyruvic acid, which is what builds up in the cells of the central nervous system and damages cells (Campbell).
As you can see, there are several pathways that can be affected by this disease. I never knew that Kate's blonde hair and very light skin were due to PKU. Without phenylalanine being converted into tyrosine, which is necessary for the production of the pigment melanin, people suffering from PKU will have light coloring (Campbell).
Without a large list of symptoms occurring in individuals adhering to the strict PKU diet, it seems that phenylalanine is mostly used as a precursor to tyrosine since the most obvious side effects are related to tyrosine deficiency. Phenylalanine either must not be present in most of the proteins our body makes or else there must be redundant pathways that allow for other processes to make up for the lack of phenylalanine (or at least very low levels). This makes sense because looking at it from an evolutionary perspective, it would be more beneficial to be less dependent on an essential amino acid because our bodies cannot make these. Also, the low use of this amino acid may be evident by looking at the genetic code, which shows that only two codons (UUU and UUC) code for phenylalanine.
This disease provides several examples for different topics we are currently learning about. It illustrates how a single gene mutation can have a profound effect; it demonstrates how an alteration of a single component upstream in a pathway can lead to multiple effects, especially when several pathways branch off downstream; and it exemplifies how important it is to screen for diseases and intervene therapeutically as early as possible. Without the early intervention, Kate would not have grown up to be the role model I knew and we would never have had the opportunity to get strawberry limeades together.
References:
Lee, K. (2011). Phenylketonuria (pku). In A.D.A.M. Medical Encyclopedia. Retrieved from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002150/
Campbell, D. (n.d.). Phenylketonuria (pku) detection. Undergraduate biology, Cornell University, Ithaca, NY, Retrieved from http://www.biog1105-1106.org/demos/106/unit06/9d.pku.html
I have heard of PKU before, but Kailey did a great job explaining the disorder with her experience with Kate. I found PKU very interesting so decided to investigate other amino acid disorders caused by genetic abnormalities and came across Hartnup Disease.
ReplyDeleteLike PKU, Hartnup is an autosomal recessive disease in which the mutant gene normally controls transport of neutral amino acids in the small intestine and kidneys. Excessive amounts of amino acids are excreted in the urine and the body thus contains inadequate amounts of amino acids which, as we all know from lecture, are the building blocks of proteins! One major side effect of Hartnup is that tryptophan is not absorbed into the blood and thus nicotinamide is not produced by the body. Nicotinamide is an important and necessary component of NAD+. Hartnup disease can be treated by a diet high in protein and nicotinamide supplements.
Patel AB, Prabhu AS. Hartnup Disease. Indian Journal of Dermatology, 2008, 53(1):31-32. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784584/
After reading this, I wanted to learn more about the evolutionary aspect of essential amino acids that Kailey mentioned. One article I found described the theory that the genes responsible for the synthesis of the amino acids that were readily available for uptake did not have to continue being expressed. This would decrease the selective pressure to keep these genes around. Generations later, when these amino acids were not readily available anymore (due to environmental changes or other evolutionary factors), the biosynthesis genes were not present and so these organisms had to find another way to acquire these amino acids. These are the essential amino acids.
ReplyDeleteGutiérrez-Preciado, A., Romero, H. & Peimbert, M. (2010) An Evolutionary Perspective on Amino Acids. Nature Education 3(9):29
Very interesting read KG! Based on what you mentioned about it being crucial for your friend to have been diagnosed early in life, I wondered whether phenylalanine was in breast milk and found that it is, thus providing further support for early testing. I also read that pregnant women with PKU should be especially aware of avoiding phenylalanine during pregnancy to prevent birth defects. Even if the fetus does not have the mutation for PKU the levels of phenylalanine in the maternal blood supply can be toxic and result in birth defects.
ReplyDeleteA few other things I found interesting... PKU is autosomal recessive and as such pretty rare, yet every child in the U.S. (and many other countries) is screened for it according to Mayo Clinic. This made me reconsider the likelihood of national/universal screening being feasible as discussed Friday in Dr. JC's TBL question.
Additionally, I found it EXCEPTIONALLY interesting that the Mayo Clinic has advice for patients on how to best prepare for their visit with their doctor to discuss their PKU. It essentially advises people to be prepared for their doctor to not have time to discuss their disease with them. "Your appointment time may be limited, so preparing a list of questions can help you make the most of your time with your child's doctor. List your questions from most important to least important in case time runs out." What is healthcare coming to?!!
If you want to read this for yourself to make sure I'm not taking it out of context visit: http://www.mayoclinic.com/health/phenylketonuria/DS00514/DSECTION=preparing-for-your-appointment