Many of us have looked at a bottle of Diet Coke and seen the ominous warning: “Phenylketonurics: Contains Phenylalanine”.  What is this warning and who is it for?  For some people with a rare genetic disease called phenylketonuria the phenylalanine contained within Diet Coke is toxic.  Let’s take a look at what phenylketonuria is and what causes this rare genetic disease.

What is phenylketonuria?

Phenylketonuria (also called PKU) is the name for an [inborn error in metabolism] that prevents the human body from being able to metabolize phenylalanine.  Phenylalanine is an essential amino acid that must be acquired from the diet because human cells cannot make it.  People who have phenylketonuria cannot metabolize phenylalanine into tyrosine and therefore can accumulate large amounts of phenylalanine in their blood and urine.  As phenylalanine accumulates, some of it is converted into other molecules that can cause significant problems, including mental impairment and loss of IQ.

What are the major symptoms of phenylketonuria?

Most patients born with phenylketonuria appear normal at birth and infants may take several months to manifest the intellectual disability that is a hallmark of this disease.  Disease onset may start with vomiting and general irritability along with a red rash.  As phenylalanine accumulates, it is converted by the body into phenylacetate which can produce an unusual ‘musty’ odor that has been described as ‘mousy’ and ‘wolf-like’.  The accumulation of phenylalanine also can inhibit Tyrosinase, an enzyme that controls the production of melanin – because of this, 90% of phenylketonuria patients present with fair skin and hair along with blue eyes.  An impairment of brain function and lowered IQ is one of the most debilitating features of phenylketonuria and many untreated patients will present with IQ’s lower than 50 (significantly impaired).

What causes phenylketonuria?

Phenylketonuria is a genetic disease that occurs from pathogenic variants in the gene Phenylalanine Hydroxylase (PAH).  The PAH gene produces a protein that converts phenylalanine into tyrosine.  Normally, each person has two functional copies of PAH – in order to be diagnosed with Phenylketonuria, both copies of PAH must be defective.  This means that Phenylketonuria is an autosomal recessive disease.  The mechanism of disease in phenylketonuria is called ‘loss of function’ in which the normally active gene is broken by a DNA sequence change – there are hundreds of reported pathogenic changes in PKU, but only seven changes are responsible for many cases of PKU.

How common is phenylketonuria?

Phenylketonuria is a rare disease that affects approximately 1 out of 2,600 to 1:200,000 live births.  The variation in disease frequency is large because the carrier rate varies across different populations.  The highest reported carrier rate is in the Turkish population and the lowest reported rate is in people from Finland.

How can phenylketonuria be treated?

Because phenylketonuria is an inborn error of metabolism, there are interventions available that can help delay or prevent the disease symptoms if the correct diagnosis is made.  There are two main ways to treat phenylketonuria:

  1.  Reduce the amount of phenylalanine that a PKU patient eats.  As a person with PKU eats foods with phenylalanine, they start to accumulate phenylalanine and downstream byproducts.  These levels can rapidly become dangerous.  To prevent this, it is recommended that patients with PKU control their dietary intake of foods rich in phenylalanine.  The recommended target level for blood phenylalanine levels varies depending on the physician, please refer to your health care provider.
  2. Tetrahydrobiopterin (BH4) supplementation.   BH4 is a small molecule that is a cofactor for phenylalanine hydroxylase.  This means that the phenylalanine hydroxylase protein needs BH4 to convert phenylalanine to tyrosine.  In some patients, supplementation of BH4 results in increased levels of phenylalanine hydroxylase activity, this can improve symptoms and in rare cases allow a patient to eat a normal diet!  Tetrahydrobiopterin is sold under the brand name of ‘Kuvan’.

Is DNA testing available for Phenylketonuria?

Yes! DNA testing is available for Phenylketonuria by looking at changes in Phenylalanine hydroxylase and other genes.  Because phenylketonuria is a certain kind of genetic disease, it might be helpful to look at some important factors of clinical DNA testing that you should consider before getting testing.

Common pathogenic DNA variants in Phenylalanine hydroxylase:

The most common cause of Phenylketonuria is by pathogenic DNA changes within the phenylalanine hydroxylase gene.  Variants that cause Phenylketonuria damage the function of phenylalanine hydroxylase and prevent the protein from functioning normally.  To understand more about DNA variants, take a look at our review of DNA changes.  There are many types of variants reported as causative for PKU, including missense, deletions and small insertions.

Here are the seven most common reported variants that may occur in your DNA test for PKU:

DNA Change Protein Change Variant Type Sapropterin (Kuvan) Response
c.1222C>T p.Arg408Trp Missense Rarely
c.1066-11G>A Splicing Rarely
c.194T>C p.Ile65Thr Missense ~89%
c.782G>A p.Arg261Gln Missense ~78%
c.842C>T p.Pro281Leu Missense Rarely
c.1315+1G>A Splicing Rarely
c.473G>A P.Arg158Gln Missense Rarely

Data reproduced from NIH Genereviews (https://www.ncbi.nlm.nih.gov/books/NBK1504/)

What is maternal Phenylketonuria?

Maternal phenylketonuria is a disease that results when a pregnancy exposes a developing baby to elevated levels of phenylalanine.  This can often occur when a pregnant mom who already has PKU has untreated or poorly managed phenylalanine levels.  As phenylalanine accumulates in mom, the developing baby is exposed to toxic levels of phenylalanine.  This can result in altered development of the baby including microcephaly (small head), global developmental delay, congenital heart disease and altered facial development.  To prevent maternal PKU, doctors recommend that women with PKU maintain a low blood phenylalanine level before and after becoming pregnant.

 

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Drew Michael, Ph.D.
Dr. Drew Michael is a Clinical Molecular Geneticist and Clinical Biochemical Genetics fellow. He holds a Ph.D. in Molecular Cell Biology and an M.S. in Biochemistry and Molecular Biology. Dr. Michael has an extensive background in molecular and computational genomics and runs a research program designed to understand the gene regulatory programs which control human development and disease. His diagnostic research is focused on the molecular and biochemical diagnosis of rare human diseases. Outside of science and medicine, he really likes dogs and lives in Washington, D.C. with two german shepherds.