PKU: An exploration of a metabolic disease

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Phenylketonuria (fee-null-keet-o-noo-ria), mercifully also known as “PKU” (pee – kay – you) is a disorder in which phenylalanine, an essential amino acid, is not broken down as it normally would be by an enzyme (phenylalanine hydroxylase) and thus accumulates (in the form of phenylpyruvic acid) in the body. Normally, Phenylalanine hydroxylase coverts phenylalanine into tyrosine, another amino acid, which has a number of different functions.

This is bad because buildup of phenylpyruvic acid has several negative effects, the most important being to interfere with normal development of neural tissues.

In the US and elsewhere (I do not know how widely, but presumably wherever “western medicine” is practiced widely) newborns are tested for PKU and if they test positive steps are taken to avoid negative effects. This involves restricting the intake of phenylalanine until adulthood, then later in life, restrictions on the intake of this amino acid in women who become pregnant.

Phenylalanine is common in animal tissues (including milk) but not in plant tissues. Therefore, the “treatment” for this condition is a kind of strict vegetarian diet. Also, PKU people should not consume Aspartame (e.g. Nutrasweet) because phenylalanine is a major component in this sugar-substitute.

The PKU “system” is very useful and instructive because several aspects of evolutionary biology can be explored using from this perspective. Thus, we only have to learn the gory details (like how to pronounce phenylalanine!) of one system, and this gets us to a wealth of interesting knowledge. The PKU story, or at least my version of it, touches on the early evolution of life on the Earth, how metabolic systems work, the essence of the “Nature-Nurture Dichotomy Falsehood” and allows us to touch on population genetics and the concept of balanced polymorphisms. We can even explore other metabolic conditions as well.

Phenylalanine and Metabolic Processes

This diagram (click the thumbnail for a larger version) shows Phenylalanine’s place in the broader metabolic arena in simplified form. Each word represents a molecule, and each arrow represents the transformation of a molecule into a different molecule. Most of these arrows actually represent an enzyme, which is coded for by a particular gene, that makes this transformation. Thus, if the gene for that enzyme does not function in the cells in which this is supposed to happen (e.g. in the liver) the transformation does not occur. The red bars represent some of the known examples of an allele (variant of a gene) coding for an enzyme that does not function and thus causes a medical condition.

If the enzyme that normally converts phenylalanine into tyrosine is not present, the phenylalanine transforms instead into Phenylpyruvic Acid and builds up in the body, and via the bloodstream interferes with neural development, and causes condition known as PKU.

Notice that tyrosine is normally converted through a couple of steps in to melanin. If this process is interfered with, the result is albinism (lack of melanin pigment). But what if a person has PKU and thus does not convert phenylalanine into tyrosine? Would that result in albinism? Not really but sort of. A person with a normal metabolic pathway from tyrosine to melanin will still produce melanin because phenylalanine conversion to tyrosine is not the only way to get tyrosine. Other sources of tyrosine will still be present, so there will still be melanin. However, the total amount of tyrosine available for eventual conversion into melanin is reduced, so PKU children are often born with blue eyes and lighter skin and hair than expected.

Failure to convert homogenistic acid into maleylacetoacetate is another inherited disease called Alkaptonuria, a rare condition that causes urine to turn black on exposure to the air and other effects, including early (adult) onset of a certain kind of arthritis.

These examples are typical of many inherited conditions.

Most genes (in humans) are inherited in functioning form from both parents (there are some genes where the copy inherited from one of the parents is turned off, and there are genes on the X and Y chromosomes that are inherited from only one parent in males). In some cases, one of the genes does not function normally, or does not function at all. If a person inherits a functioning gene from one parent and a non-functioning allele for that gene from the other parent, this may result in less metabolic conversion than needed and thus cause an effect, but in other cases, having only one functioning gene is sufficient. The latter is the classic “recessive genetic condition.” In these cases, a heterozygote … a person with one working copy and one non-functioning copy … is a “carrier” of the disorder. If two carriers reproduce, there is a chance that an offspring will carry two non-functioning alleles, and thus has the disorder. As far as I know, a person who is a heterozygote for the PKU allele (the “broken” version of the gene that codes for the enzyme that breaks down phenylalanine to tyrosine) does not have any symptoms of PKU. However, it is sometimes the case that heterozygosity is associated with some condition that is subtle, and eventually gets noticed by medical researchers. In the case of PKU, there are some effects of heterozygosity. This is fairly complex and I’ll address it in another post.

Now, consider this question: What kind of disease is PKU? It is reasonable to conclude, since it is caused by an allele for an important gene that codes for an ineffective enzyme (or no enzyme at all), that PKU is a genetic disease. However, it is also the case that PKU is caused by the ingestion of phenylalanine by having a certain diet. What if the genetic condition that leads to PKU arose in a primate that ate mostly leaves and fruit, and hardly ever consumed any animal tissue? PKU would not typically be a disease in this primate because they would never consume phenylalanine . If an individual in this species had nothing else to eat but animal products and was thus forced through starvation to do something it would normally not do, then it would suffer the effects of PKU. In this sense, PKU is not a genetic disease, but rather, an environmental disease … in this case, phenylalanine is a poison that has negative effects when consumed in quantity by a juvenile primate of this hypothetical species.

This may seem like I’m just playing with words, but consider an alternative example. People enjoy a wide range of plant tissues, especially leaves, that have wonderful aromatic flavors or a kind of edgy bitterness. Spinach, basil, thyme, sage and many other spices come to mind. However, many of the molecules that provide these plant tissues with the qualities we enjoy are actually evolved products to limit herbivory by insects. In this case, one species’ culinary enjoyment is another species’ poison. We don’t say that the insects that are put off by these molecules have a genetic disease. We say that these molecules act as poisons for those insects. An insect that eats a bunch of basil and dies from it is an insect that died from consuming poison.

Another example may be the molecule(s?) in chocolate that are poisonous to dogs, but apparently not to humans. There is probably not an adaptive reason that chocolate is a poison for dogs, but since dogs are mainly carnivores and evolved in temperate climates, dogs would have no evolved adaptation to manage the cocoa plant’s anti-insect adaptations. Since humans are omnivorous primates, and primates evolved in the tropics, we may expect humans to have a number of ways, metabolically, to consume a wide range of tropical plant insect-deterring molecules.

In fact, I would expect animals that very rarely eat meat to very commonly have the inability to break down molecules such as phenylalanine that are only found in meat in any quantity.

From this perspective, PKU can easily be understood as an environmental disease, or a poison, just like any of the other poisons (like strychnine) found in nature. Yet, we also know that in humans only a homozygote for this allele will suffer the effects of this poison. In this sense, PKU is definitely an environmental disease, and it is also definitely a genetic condition. It is not really sufficient or accurate to claim that it is, say, 50% environmental and 50% genetic. People without the genetic condition simply don’t have this disease even if they eat huge quantities of meat, and people with the genetic condition who eat no phenylalanine don’t get “half” of the disease.

So, PKU is 100% genetic. And it is 100% environmental.

Does that make your head hurt? It should. But how to we fix this? I will examine this issue again in an upcoming post, but for now, consider this: If you want to know if a particular “trait” is caused by “nature” (genes) or “nurture” (the environment), and more specifically, what percentage of the trait is caused by each of these sources, then maybe you are actually asking the wrong question. Maybe the requirement of calculating a percentage of nature vs. nurture, or genes vs. environment is incompatible with the synergy between different causal sources.

What percentage of the sound of two hands clapping is caused by each hand?

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1 thought on “PKU: An exploration of a metabolic disease

  1. L-Phenylalanine is biologically converted into L-tyrosine, another one of the DNA-encoded amino acids. L-tyrosine in turn is converted into L-DOPA, which is further converted into dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). The latter three are known as the catecholamines.,^*^

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