What is Phenylketonuria?
Phenylketonuria (PKU) is a genetic disorder that affects the body’s ability to process a specific amino acid called phenylalanine, which is a building block of proteins. This is usually because of changes or mutations in the gene that provides instructions for making an enzyme known as phenylalanine hydroxylase (PAH). This enzyme is responsible for converting phenylalanine into another amino acid, tyrosine. But when there’s a problem with this enzyme, phenylalanine can accumulate and become harmful.
PKU belongs to a group of medical conditions referred to as “toxic accumulation-IEMs.” This is when the body has too much of an amino acid or its byproducts, which can be harmful. If there’s a mutation in an enzyme like PAH, it usually requires two copies of the mutated gene (one from each parent) for the disorder to take place. That’s because having just one functioning copy of the gene is usually enough to prevent the disease.
There’s a specific compound called tetrahydrobiopterin (BH4) that plays a critical role in the PAH enzyme’s activity. PAH, which is primarily found in the liver, uses BH4 to help it convert phenylalanine into tyrosine.
PKU is characterized by high levels of phenylalanine and low levels of tyrosine in the blood. Newborns with PKU often seem normal at first, with symptoms only appearing after several months. These can include a musty smell from the skin and urine, light skin, skin inflammation or eczema, seizures, shaking, and overactive behavior.
What Causes Phenylketonuria?
Phenylketonuria, or PKU, is caused by over 1,000 different mutations. The most common one is when a particular protein segment in the body known as arginine, usually abbreviated as Arg, gets replaced with another one called tryptophan or Trp at a specific location (position 408 to be exact). This is technically referred to as the Arg408Trp mutation.
These mutations in the PAH gene that lead to PKU generally result in reduced PAH activity or reduced PAH expression. This causes an increase in the levels of a substance known as Phenylalanine (Phe) in the blood while lowering Tyrosine (Tyr) levels. Phe is an important amino acid in the body, and its change to Tyr is usually well-controlled to allow for enough protein production, yet keeping the levels low enough so it won’t be harmful.
The Arg408Trp mutation leads to what’s known as “classic” PKU, where there are more than 1200 units of Phe in the blood. Less severe mutations can result in a milder form of PKU, where there are Phe levels between 600 to 1200 units in the blood or even milder conditions where the Phe levels are less than 600 units.
Most people with PKU have two different PKU variants, causing them to become “compound heterozygotes.” This means they can have two severe alleles (severe/severe) or one severe and one mild allele (severe/mild).
It’s also possible that some milder PAH gene variants produce an enzyme variant that has lower attraction for BH4 (an essential nutrient in the body) and/or a variant with increased stability and lifespan due to BH4 binding. Almost half of the people with PKU do experience at least a 30% decrease in blood Phe levels when given BH4 supplements orally, even when they already have normal levels of BH4.
Risk Factors and Frequency for Phenylketonuria
Phenylketonuria (PKU) is a condition that occurs in about 1 out of every 15,000 people in the United States. However, this rate can vary among different ethnic groups. It is more common in Caucasian and Native American populations and less common in African American, Hispanic, and Asian populations. Globally, the frequency of PKU differs greatly. An example is Turkey, where PKU occurs in a notably high rate of 1 out of every 4,000 live births.
Signs and Symptoms of Phenylketonuria
In the U.S., a condition known as PKU (Phenylketonuria) is typically identified in newborns through screening tests. Once detected, a special diet is set up with the help of a dietitian and a genetics or metabolism specialist. Sometimes, milder forms of PKU can be overlooked if the mother leaves the hospital too soon or the newborn hasn’t had any protein yet. Symptoms like delayed development, small head size, lighter skin and hair color, hyperactivity, seizures, and a distinct musty odor can become more noticeable if the condition is not treated. However, children who are diagnosed and treated early are less likely to show these symptoms. The long-term care for PKU involves sticking to the special diet, regular blood tests to check phenylalanine and tyrosine levels, and regular assessments to check for any learning problems.
- Usually identified in newborns through screening tests
- Dietary adjustments made with specialists
- Milder forms might be overlooked if early hospital discharge or lack of protein intake
- Untreated PKU symptoms include delayed development, small head size, lighter skin and hair color, hyperactivity, seizures, and musty odor
- Early diagnosis and treatment can prevent symptoms
- Long-term care involves dietary adherence, regular blood tests, and cognitive assessments
Testing for Phenylketonuria
In the United States, a condition called PKU (phenylketonuria) is detected in newborns by state-run screening programs. This test measures the ratio of two chemicals, Phenylalanine (Phe) and Tyrosine (Tyr), in a small blood sample obtained from a heel prick. The blood is then placed on a special type of filter paper and analyzed through a process known as tandem mass spectrometry (MS/MS), which helps identify and quantify the molecules in the blood. This test is usually conducted 1 or 2 days after birth.
Newborns with PKU often seem normal at birth, with the first signs of the condition only becoming evident after several months. It’s important to note that some babies may show high Phenylalanine levels as a result of another condition called BH4 deficiency, not PKU. BH4 deficiency is a rare metabolic disorder that also causes increased Phenylalanine levels in the blood.
To understand if parents are carriers for PKU, commercial genetic testing services (like 23andme.com) can be used. These tests seek out specific changes or variations in your genes, known as single nucleotide polymorphisms (SNPs), that could indicate a carrier status for PKU, especially for those of Northern European descent. If both parents are found to be carriers of a PKU variation, their child has a 25% chance of having PKU.
Treatment Options for Phenylketonuria
Early diagnosis of classic PKU (phenylketonuria – a genetic disorder that increases levels of an amino acid in the body) can be managed by following a strict lifelong diet. This diet aims to decrease the levels of the amino acid phenylalanine (Phe) and ensure adequate intake of Tyrosine (Tyr). This diet helps to prevent severe mental problems that can occur due to high Phe levels. However, it’s important to note that this diet can sometimes lead to deficiencies in selenium, copper, magnesium, and zinc.
Sticking to this special diet can be tricky, especially during adolescent and early adult years, often due to social pressures. Besides the diet, medical researchers are working on new medications to help manage PKU. One of these is oral sapropterin dihydrochloride (KUVAN), an artificial form of a compound called BH4, which may help to lower Phe levels in some patients with PKU. A trial period using this new drug can help to identify which individuals may benefit from it. There’s hope that this drug could also help improve brain function in some individuals with PKU.
Previously it was not possible to treat PKU with enzyme replacement therapy because the PAH enzyme (the enzyme deficient in PKU patients) is unstable. However, a newly FDA-approved therapy substitutes another enzyme to help lower Phe levels. This enzyme treatment, pegvaliase, is given to adult patients who struggle to control their Phe levels. It’s not yet certain whether this treatment can help to relax diet restrictions or provide long-term benefits in preventing or reducing mental impairment.
For women with PKU who can have children, counseling is recommended to discuss the benefits of adhering strictly to their special diet during pregnancy. High Phe levels in an expecting mother can lead to brain damage and heart defects in the baby, regardless of whether the baby also has PKU.
Traditionally, Inborn mistakes of Metabolism, illnesses like PKU, have been managed through dietary and enzyme replacement therapy rather than treating the genetic cause. However, with advancements in gene therapy, there’s hope that treatment directly addressing the genetic disorder might be possible in the future. As of 2018, early trials for gene-based therapy for PKU are in the planning stages.
What else can Phenylketonuria be?
The image below shows that the process of converting the chemical Phe into Tyr, carried out by the enzyme PAH, needs something called BH4. If there’s not enough BH4 around, it can lead to a condition called hyperphenylalaninemia (HPA), even if the PAH is completely normal. This condition can be detected in a baby if they show signs of HPA. For more clarity, additional tests for a group of substances called pterins should be done. Although we won’t go into it in more detail here, it’s actually possible to identify all different types of BH4 deficiencies by looking at the pattern of these pterins.
What to expect with Phenylketonuria
A recent study indicates that even when early treatment for PKU (Phenylketonuria) is provided, some mental abilities might still be affected. These include executive functions – the group of mental processes that help connect past experience with present action and are utilized for managing time, paying attention, switching focus, planning and organizing, remembering details, and controlling inappropriate speech or behavior.
Preventing Phenylketonuria
Hospitals that focus on Inborn mistakes of Metabolism (IEMs), like Phenylketonuria (PKU), often have enough resources to offer comprehensive care. They typically have a team of specialists for handling PKU and provide extensive educational programs for patients.
