PKU (Phenylketonuria)
PKUnderstood
Phenylketonuria, or PKU for short, is an inherited, genetic condition in which the body can’t process
phenylalanine (Phe), an amino acid found in many foods.
PKU is caused by a defect in the enzyme in the body that works to process Phe. This enzyme is called
phenylalanine hydroxylase (PAH). In order for the PAH enzyme to work, it needs BH4, a molecule that is
naturally present in your body. When the PAH enzyme can’t do its job, too much Phe builds up in the body.
Phe is found in:
1.
2.
All protein-containing foods (eg, meat, eggs, dairy, nuts)
Many other foods that are not generally thought of as containing protein (eg, most wheat products,
such as pasta and bread, and some fruit, such as oranges and cherries).
If people with PKU followed a normal diet, they would eat more Phe than their bodies can handle.
Too much Phe is toxic to the brain. High Phe levels over an extended period of time can lead to vomiting,
irritability, eczema, seizures, psychological and behavioral issues, and severe mental retardation.
Currently, management of PKU consists of limiting Phe intake. This means following a Phe-restricted diet in
order to limit the amount of Phe in the body. Several other approaches to management are under
investigation.
The Genetics of PKU
PKU is caused by an inherited genetic alteration.27 To understand how PKU is inherited, it is important to
learn a little about genetics.
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Our genes carry the instructions for traits like eye and hair color as well as a multitude of
instructions that our body needs to function properly, including instructions to make PAH and all
other enzymes.
We inherit genes in pairs from our mother and our father. People who have one working PAH gene
and one nonworking gene are called carriers; they make enough PAH to remain healthy and do not
have PKU.
People who inherit one nonworking copy of the PAH gene from the mother and one nonworking
copy of the PAH gene from father end up with PKU.
How PKU is inherited
If both parents are carriers of the nonworking gene (r), then there is a 25% chance that both of them will pass it on
to their child (rr). There is a 50% chance that their child will also be a carrier but not have PKU (Rr), and a 25%
chance that their child will not be a carrier and not have PKU (RR).
Parents might know if they are a carrier of PKU if they have a family history of PKU; but for some parents
the diagnosis of their child is how they find out.
Parents of children with PKU should not feel as though they could have known or done anything to prevent
PKU. We are all carriers of a few nonworking genes and have no way of knowing until, by chance, a
disorder occurs.
The Science of PKU
The chemical dance
All food is broken down and turned into something your body can use. This is done by certain chemicals
called enzymes and cofactors:
•
•
Phenylalanine (Phe), which is found in protein, is broken down by an enzyme called phenylalanine
hydroxylase (PAH) and a cofactor called tetrahydrobiopterin (BH4)
These two molecules work together to transform Phe into another molecule, tyrosine (Tyr), which
the body needs
Without both BH4 and working PAH, this transformation cannot take place.
In people with PKU, the PAH enzyme is broken, and therefore, the body cannot turn Phe into Tyr. The Phe
concentration then builds up inside the body in the bloodstream, eventually passing into the brain.
How a chemist might describe the dance
One PAH molecule combines with one Phe molecule to create what is known as an enzyme-substrate
complex. This complex then comes into contact with a BH4 molecule, removing a part of the BH4 called a
hydroxyl group and attaching it to the Phe. The Phe with the extra hydroxyl group is now a new molecule
called tyrosine, or Tyr, which is released from the enzyme-substrate complex into the bloodstream. The Phe
and the BH4 are used up in this process, but the PAH is not. If either the PAH or the BH4 is unavailable, this
process does not work, and excess Phe is left over, which over time will build to neurotoxic levels.
In summary
In short, people with PKU can’t rid themselves of excess Phe because the PAH enzyme is broken and
cannot break down Phe. This problem with the PAH enzyme allows too much Phe to build up in the body,
which can eventually affect the brain. Because of this, individuals with PKU must control their diet by
consuming only minimal amounts of dietary Phe in order to keep their blood Phe levels relatively low.
The History of PKU
Early research milestones
Since the discovery of PKU as a new disease in 1934, scientific interest in the disease has advanced at an
astonishing pace, taking PKU from obscurity to the forefront of cutting-edge biotechnology research—from
an unidentified syndrome with devastating and permanent consequences to a condition whose management
promises to help people live productive and fulfilling lives. At this pace, it is hard to imagine what discoveries
lie ahead in the first years of the 21st century.
1934: PKU is discovered23
In 1934, a Norwegian doctor named Asbjorn Folling described a group of mentally retarded patients who
had a strange odor. We learned that this smell was caused by phenylacetic acid and that the patients' urine
had large amounts of a phenylketone called phenylpyruvic acid. Hence, the condition was given the name
phenylketon-uria. Not only was Folling the first to understand the disease and its relationship with
phenylalanine, he was also the first to suggest its genetic nature and advise a form of management through
dietary restriction.
1951: PKU management combines dietary restriction and protein replacement24
Less than 20 years after its discovery, PKU was well known in the scientific community as a disease of
protein digestion that could be controlled by a special diet. However, it wasn’t until Horst Bickel, a German
professor, developed a protein supplement that people with PKU had any hope of living a somewhat normal
life. Bickel’s first protein drink was unflavored.
1966: A simple diagnostic test becomes the international standard for newborn screening
In 1958, the Guthrie test, named after its discoverer, Robert Guthrie of Minnesota, was the first affordable
test for screening hyper Phe in newborns. It gained recognition rapidly due to its simplicity, which made its
widespread implementation cost-effective. In 1966, newborn screening with the test became the standard in
hospitals in the United States.
The test, still widely used today, requires only a drop of blood, compared with about 4 teaspoons of blood in
previous tests.
This simple test made it possible to catch virtually every PKU case in infancy, assuring that the disease
could be properly managed from the outset and that mental retardation due to PKU could be avoided. The
pioneering efforts of Guthrie played a pivotal role in helping diagnose the majority of people living with PKU
today.
2007: The first drug therapy for PKU is introduced
KUVAN™ (sapropterin dihydrochloride) Tablets, the first prescription drug therapy approved for the
treatment of PKU, became available to patients in 2007. Produced by BioMarin Pharmaceutical Inc, KUVAN
is indicated to reduce blood Phe levels in patients with hyperphenylalaninemia (HPA) due to BH4-responsive
PKU and is to be used in conjunction with a Phe-restricted diet.
Learn more about KUVAN.
KUVAN™ (sapropterin dihydrochloride) Tablets is approved to reduce blood Phe levels in patients with
hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive phenylketonuria (PKU). KUVAN
is to be used in conjunction with a Phe-restricted diet.
Important Safety Information for KUVAN
High blood Phe levels are toxic to the brain and can lead to lower intelligence and a decrease in the ability to
focus, remember, and organize information. Any change you make to your diet may impact your blood Phe
level. Follow your doctor’s instructions carefully. Your doctor and dietitian will continue to monitor and
change your diet throughout your treatment with KUVAN.
If you have a fever, or if you are sick, your Phe level may go up. Tell your doctor and dietitian as soon as
possible so they can see if they have to adjust your treatment to help keep your blood Phe levels in the
desired range.
KUVAN is a prescription medicine and should not be taken by people who are allergic to any of its
ingredients. Tell your doctor if you have ever had liver problems, are nursing or pregnant or may become
pregnant, have poor nutrition or are anorexic; your doctor will decide if KUVAN is right for you. Tell your
doctor about all the medicines you take.
The most common side effects reported when using KUVAN are headache, diarrhea, abdominal pain, upper
respiratory tract infection (like a cold), throat pain, vomiting, and nausea.
To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100,
or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Q: My newborn has been diagnosed with PKU. Is that serious?
A: PKU, or phenylketonuria (pronounced fen-il-Key-to-New-ree-uh), is a serious but manageable condition.
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Q: Is the condition curable?
A: Currently there is no cure for PKU. Right now, the only way to manage the disease is through a lifelong
restricted diet. With proper diet management, newborns with PKU can look forward to healthy and fulfilling
lives.21
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Q: How did my newborn get PKU?
A: PKU is inherited. Both parents have to carry the PKU gene in order for a child to be born with PKU. You
don’t have to actually have PKU to carry the PKU gene. If you and your partner carry the gene but don’t
have PKU, there is a 25% chance that any future children you have together will have PKU. If one partner
has PKU, and the other is a carrier of the gene, the chance of having a child with PKU increases to 50%; if
both partners have PKU, the likelihood increases to 100%.16
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Q: Are my spouse and I responsible for our newborn’s PKU?
A: Many parents feel they are somehow “to blame” for their child’s PKU. There really is no need to feel this
way. There is nothing that either you or your spouse could have done during the pregnancy to cause this.
You are not responsible for the genes you inherited and possess. It’s important for you to approach PKU
management with a positive attitude, and you will find there is a large community of people prepared to offer
you help in doing so. Your family will join many others successfully living with PKU in the years ahead.
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Q: What exactly is PKU?
Understanding the nature of this disease is key to managing your child's condition.
PKU belongs to a class of diseases referred to as “inherited metabolic diseases,” or “inborn errors of
metabolism.” Most of these diseases are rare (occurring in approximately 1 in 13,500 births) and include
conditions like albinism and congenital hypothyroidism.
Metabolic diseases affect the body’s ability to perform certain chemical processes required for normal
growth and development. For people with PKU this means that a certain enzyme called phenylalanine
hydroxylase (PAH), is broken. This enzyme is required for the breakdown of phenylalanine (Phe), an amino
acid found in foods containing protein.16 Even though they produce some working PAH, most of the PAH
they produce is defective and doesn’t function the way it’s supposed to, and thus isn’t able to properly break
the Phe down.
PAH is a molecule produced in the liver, which sets in motion a chemical reaction that converts Phe into
another amino acid called tyrosine, or Tyr.16 For people who don’t have PKU, the liver produces enough
working PAH to convert Phe into Tyr, and as a result, all the Phe is used up. For a person with PKU, Phe
cannot be turned into Tyr and thus excess Phe builds up, passes into the bloodstream, and circulates
throughout the body, eventually ending up in the brain. While a certain amount of Phe is essential for normal
growth and development, excess Phe in the brain causes damage, particularly in very young children.
The good news is that the brain damage can be prevented.12,16 Currently, this is accomplished by restricting
the amount of Phe ingested. Foods that are very high in Phe, such as meat, eggs, dairy, and nuts are
avoided completely. These foods are replaced by a medical protein formula that has no Phe. Foods with
moderate amounts of Phe can be eaten but in limited quantities. These foods include certain fruits and
starches. Most foods have some Phe in them, meaning people with PKU must always be very careful about
what they eat. Therefore, it is important for someone with PKU to track daily intake of Phe.
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Q: How is PKU managed?
A: The key to PKU management is keeping the amount of Phe in the blood within a safe range. The exact
definition of a safe range is still widely debated, but the National Institutes of Health suggest that blood Phe
concentrations remain between 2 mg/dL and 6 mg/dL (120 µmol/L to 360 µmol/L).12
To achieve the proper blood Phe level, PKU management involves a three-pronged approach: Record,
Restrict, and Replace. A person with PKU (or the parent of a young child with PKU) must record the amount
of Phe consumed; restrict the diet to low-Phe foods; and replace those high-Phe foods with low-Phe
alternatives—most commonly, a regimen of Phe-free medical protein supplement.
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Q: Will my child show any symptoms?
A. When PKU is managed well, there are no overt signs or symptoms,12 with the possible exception of a light
complexion. Despite the fact that PKU is a lifelong disease, people with PKU can expect to lead healthy and
fulfilling lives. By keeping blood Phe levels low, excess Phe will not accumulate in the brain to cause
damage.
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Q: How do I learn to properly manage my child’s PKU?
A. At first, PKU management may sound a little daunting. But relax! You can work with a registered dietician
associated with a metabolic clinic who can help you decide what kind of diet your child will require. That
person can give you tips for establishing a management routine.
As you begin your PKU research, you will find that a wealth of resources is available, including support
groups and internet-based bulletin boards for communication with other parents.
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Q: What if I don’t regulate my child’s diet closely?
A: If you don’t carefully monitor your child’s diet, your child runs the risk of having elevated blood Phe levels.
Maintaining low blood Phe levels is particularly important in young children, while the brain is undergoing its
most dramatic development and is most vulnerable to the neurotoxic effects of excessive Phe.22
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Q: Tell me about the Phe-free formula.
A: The PKU diet replaces meat, dairy, and eggs with a special medical formula that does not contain Phe.
This formula is prescribed by a doctor at a metabolic clinic. This formula is actually the centerpiece of the
PKU diet. For people with PKU, most of the calories they consume come from this formula, which may take
the form of a powder mixed with drinks or as a premixed drink. The remaining calories, and all of the Phe
that a person with PKU needs, come mostly from relatively low-Phe foods such as grains, fruits, and
vegetables. Since most food contains some Phe, people with PKU must be cautious about what—and how
much—they eat.
Remember, it’s not that your child can’t consume protein, but rather your child can’t have too much of a
certain amino acid, Phe, that’s found in proteins.
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Q: How long will my child be on the restricted diet?
A: In 2000, the National Institutes of Health recommended that a person with PKU requiring dietary
restriction never be taken off the special diet. This is often referred to as “diet for life.”12
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Q: What can happen if my child goes off the diet?
A: This is difficult to answer due to the way the disease can vary, both among individual people with PKU
and at different stages of life. It is important to talk to your doctor about any changes to your child’s diet. If
the child goes off the diet very early in life (infancy/toddler to elementary school years), he or she may suffer
irreparable brain damage and IQ loss. If a child goes off the diet later in life, the symptoms may be more
subtle, but they will still be present. Scientific evidence suggests that people with PKU who go off the diet at
any age may suffer emotional and intellectual problems.12
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Q: Is my child more at risk for attention deficit hyperactivity disorder (ADHD)?
A: PKU varies a lot, depending on the individual. The relationship between ADHD and PKU is not completely
understood but has been studied.
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Q: How will a metabolic clinic be involved?
A: When your child first tested positive for PKU, the results were sent to a lab at your local metabolic clinic to
confirm a diagnosis. The staff there is now committed to helping you and your child with the management of
PKU, including periodic blood testing, formula prescriptions, and dietary consultations based on feedback
from you and the blood tests. As part of managing your child’s condition, you will be required to stay in close
contact with the clinic.
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Q: How frequent are the Phe blood tests?
A: Your doctor will determine the frequency of Phe blood tests. In the beginning, your child may be tested
rather frequently while the clinic determines the appropriate diet. Testing can occur once or twice a week
until your child’s Phe levels stabilize at an appropriate level. Thereafter, testing may be required once a
month until the child reaches adolescence. During adolescence through young adulthood, testing may be
conducted twice a year. In adulthood, yearly testing will likely continue for life.
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Q: What’s the difference between classic PKU and moderate PKU?
A: PKU is divided into two types: classic PKU and moderate PKU. These two types refer to different levels of
blood Phe. A person with moderate PKU has lower blood Phe levels than a person with classic PKU. Both
classic and moderate PKU patients can suffer significant neurological damage, if untreated, although this
damage is more significant in classic PKU.12
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Living with PKU
The goal of PKU management is to keep the amount of Phe in the blood at a safe level in order to protect
the brain from high levels of Phe. Exactly what blood Phe level to aim for is still widely disputed, but the
National Institutes of Health (NIH) recommends that blood Phe concentrations remain between 2 and 6
mg/dL (120–360 µmol/L) for newborns to age 12. In light of findings that Phe levels are related to cognitive
function in adolescents and adults, it is recommended that Phe levels be maintained between 2–15 mg/dL
after 12 years of age. Considering the fact that brain development is ongoing during adolescence the NIH
strongly encourages Phe levels of 2–10 mg/dL (120-600 µmol/L) for PKU patients during this age period.12 A
healthcare professional should determine your target range.
PKU and Your Diet
Diet for life
A big challenge in life with PKU is the Phe-restricted diet. When you go to a restaurant and all you can get is
a salad—“but no, not the bleu cheese; oh I can’t have ranch either…what’s in the house? You know, just
give it to me plain”—you may feel limited, not just in dietary options, but in social settings as well. But there
is enough scientific evidence to suggest that “diet for life” is important.
What do the experts say about diet for life and the goal for blood Phe levels?
In 2000, a National Institutes of Health (NIH) panel of experts decided that lifelong care is required for the
treatment of PKU.12 This solid statement settled the debate about how long people with PKU should remain
on the diet. This was the statement that has come to be known as “diet for life.”
There was a time when people believed that it was only important to stay on the diet until about age 6 or 8,
when the brain is growing the most. Even though it is still not fully understood why high Phe levels can
cause brain damage, more evidence is suggesting that maintaining relatively low Phe levels is important in
adulthood as well as childhood.
What should we aim for?
Just as it is important to keep the PKU “diet for life,” the NIH experts also agree that there is a certain goal
for Phe levels in people with PKU. The experts said, “Maintenance of Phe levels between 2 and 6 mg per dL
for newborns through 12 years of age appears to be medically necessary for ensuring optimal outcome.”12
The range that they suggest (2–6 mg/dL) is a common target that people with PKU should aim for. Because
we are all different and our bodies may have different needs, the experts left a little “wiggle room” for doctors
and dietitians to determine individuals’ Phe tolerance.
The important thing to remember is that people with PKU should stay on the diet for life and aim to keep
their blood Phe in the target range provided to them by their doctor or dietitian.
What will enable me to attain my target Phe goal?
A combination of these items has been the basis for PKU management for years:
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Phe-free formula
Phe-free protein replacement bars
Low-Phe natural foods
Low-Phe medical foods
In the future, there may also be pharmaceutical therapy that would reduce blood Phe and potentially allow a
person with PKU to eat more foods from a normal diet while keeping blood Phe levels low. New research
continues in this area.
Managing PKU With the 3 Rs
To help maintain consistently low blood Phe levels, management involves a three-pronged approach:
Record, Restrict, and Replace. People with PKU must record the amount of Phe consumed, restrict their diet
to the right amount of low-Phe foods, and replace those high-Phe foods with low-Phe alternatives,
specifically a regimen of Phe-free medical protein supplement. While this type of management is not a cure,
it has been effective in helping to prevent many of the symptoms of PKU. Your doctor should be consulted to
help you understand PKU management, including Record, Restrict, and Replace.
Record
You should work to keep track of how much Phe you consume every day. A registered dietitian should be
consulted and can give you a daily number of exchanges (one exchange = 15 mg of Phe) appropriate for
you. This number is your Phe tolerance. Everything you eat in a day should count toward the number of
allowable exchanges. A good practice is to record daily intake on a Phe calendar.
Restrict
You’ll soon realize that there are many foods that have too much Phe to be included in your diet. These
include meat, eggs, and dairy, and because of their high Phe content, they must be avoided entirely. There
are a variety of substitute foods, and on this Website you will find frequently updated recipe ideas. Come
back often to check new ideas.
Replace
Because protein is an essential part of any diet, you must consume some protein. Therefore, the
centerpiece of a PKU diet is a special low-Phe or Phe-free protein formula, which is available by
prescription. This Phe-free formula comes in two forms—powder and mixed drinks—and a variety of flavors.
Some formulas also have extra vitamins in them.
Keeping a healthy diet and being careful not to have too much Phe can be a balancing act. Below is an
example of how to Record, Restrict, and Replace for a 14-year-old PKU patient who is allowed about 400
mg of Phe per day.
Why Diet Is Important
It is well known that high Phe levels during early childhood can cause mental retardation. What is not as well
understood is how high Phe levels affect adults who have managed PKU their whole lives. Recent research
has shown that high Phe levels can affect adults, and that diet may not always be enough. Even adults who
have managed their diet fairly well sometimes show mild symptoms, such as:
Psychiatric disorders1,2,4
People with PKU are more likely to have psychiatric disorders like depression, phobias, anxiety, and
hypochondria than people without PKU.
Case studies have shown that adults with high Phe can become dangerously hyperactive and, in extreme
cases, even agoraphobic. Again, no one understands this relationship fully.
Attention deficit hyperactivity disorder (ADHD) symptoms4,5
Studies on this issue suggest that elevated Phe levels are associated with ADHD symptoms. What’s more,
the severity of these symptoms seems to depend on Phe levels. The higher the levels, the more severe the
symptoms.
Cognitive problems9
A study comparing the performance of people with PKU and people with diabetes found that people with
PKU scored lower on a special timed test. It wasn’t that the people with PKU got so many wrong answers,
but instead it had to do with how many questions they were able to answer in the allotted time. In other
words, they were simply slower at taking the test. The people with PKU kept their Phe levels within the
targeted range, and their performance was more closely related to what their Phe level was when they
took the test, instead of what it had been in the past.
Brain abnormalities10,11
There are certain kinds of brain abnormalities that are noticeable in early-treated adults (adults who have
been on the diet their whole lives). These abnormalities are more noticeable when the individual has
unusually high Phe levels.
When some adults have unusually high Phe levels, despite the fact that they have maintained good control
during childhood, their brains look different from those of people without PKU. The difference is in the
amount of cerebral white matter in the brains of these people. Less white matter means slower
communication between brain areas. A telephone modem versus a DSL.
Pregnancy and PKU
The effect on the unborn child
Pregnant mothers with PKU need to be extra careful about their Phe intake to lessen the risks of birth
defects to their unborn child28-30. Because a number of weeks can pass prior to the discovery of the
pregnancy, it is especially important for a woman who is pregnant, is planning to become pregnant, or is of
childbearing age to follow the Phe-restricted diet and the target Phe level that was prescribed for her by her
healthcare provider. A pregnant woman should also consult her doctor and the staff at her clinic for special
instructions.
Even though the child of a mother with PKU might not be born with PKU, the unborn child is still at risk of
brain damage and other serious problems from exposure to the mother’s high Phe levels.
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•
One research study showed that women with PKU who kept their Phe levels in control during
pregnancy had children with higher IQ levels than the children of women with uncontrolled PKU.28
Also, the occurrence of congenital heart disease in the children of women who closely followed
their Phe-restricted diet very early in the pregnancy dropped to 1%-2% compared to 14%-17% in
those women who did not control the Phe in their diets.29
Other problems in the children of women with uncontrolled Phe levels include facial deformities,
microcephaly (abnormally small head size), developmental delays, and growth retardation prior to
birth.30
Phe levels in the placenta can be 1.5-2 times higher than blood Phe levels.
At School with PKU
Back to school essentials
Summer is almost over and soon your child will be returning to school. Since you will not be around all the
time to help manage the PKU diet, PKU.com wants to help you explain PKU to the new teachers,
babysitters, and others who may care for your child. So here are some “back-to-school supplies” you will
want to download right now to share with your child’s caretakers. We are sure you will find these as helpful
and essential as pencils, erasers, and notebooks.
The caretaker’s guide to PKU
A brochure explaining everything a teacher, babysitter, or other kind of caretaker needs to know, before
watching over your child, about PKU and the Phe-restricted diet. Click here to view and download.
Phe trackers: PKU.com Eat-Sheets
PKU.com Eat-Sheets can help you track your or your child’s Phe intake or help you leave a list of approved
foods for a babysitter. The Eat-Sheets are also ideal for keeping a record just before a dietitian visit. The
Eat-Sheets can record 1, 2, or 3 days with room to write in calories, protein, and food quantity in addition to
Phe.
1-day Eat-sheet
2-day Eat-Sheet
3-day Eat-Sheet
1-day Eat-Sheet for infants
Caregiver’s Eat-Sheet
Leaving your child with a babysitter today? Compile a list of foods that your child can eat for a given day. Fill
this sheet out and hand it to a babysitter to ensure that your child will be eating right while you are away.
1-day Caregiver’s Eat-Sheet
PKU in the News
Stay informed
There’s a lot to know about PKU, especially as we gain a better understanding of this condition. Check here
often for information on recent breakthroughs and other news as it becomes available.
2007—KUVAN™ (sapropterin dihydrochloride) Tablets approved for the treatment of PKU
The US Food and Drug Administration (FDA) approved KUVAN, the first prescription drug therapy for the
treatment of PKU. Produced by BioMarin Pharmaceutical Inc, KUVAN is proven to reduce blood Phe levels
in patients with hyperphenylalaninemia (HPA) due to BH4-responsive PKU and is to be used in conjunction
with a Phe-restricted diet.
“The approval of KUVAN represents an important milestone for PKU patients and their families,” said JeanJacques Bienaime, Chief Executive Officer of BioMarin.
“In clinical trials, KUVAN has been shown to help control blood Phe levels in PKU patients, and I am thrilled
that this new therapy is now available to the PKU community,” stated Dr Barbara Burton, Professor of
Pediatrics, Northwestern University Feinberg School of Medicine; Director, PKU Clinic at Children’s
Memorial Hospital; and Clinical Investigator in the KUVAN Phase 2 and Phase 3 trials. “With KUVAN now
approved, physicians and patients have, for the first time, a drug therapy option to manage the disease.”
Learn more about KUVAN.
2005—BioMarin begins clinical trials for testing BH4 in the treatment of PKU
BioMarin Pharmaceutical Inc began testing the effect of a pharmaceutical formulation of BH4 on lowering
Phe levels in people with PKU. BH4 is the enzyme cofactor that works together with phenylalanine
hydroxylase (PAH) to break down Phe. Some researchers think that the BH4, taken orally, works with the
residual amounts of active PAH to speed up the Phe breakdown, actively lowering Phe levels in patients.
2000—NIH recommends "diet for life"12
As recently as 2000, there was no national agreement in the United States on how long someone with PKU
should be on the diet. In the past, many people had believed that it was only important to be on the diet
during certain years when the brain was growing the most.
In light of a 2000 National Institutes of Health statement, it is now agreed upon that a person with PKU
should never go off the diet.
KUVAN™ (sapropterin dihydrochloride) Tablets is approved to reduce blood Phe levels in patients with
hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive phenylketonuria (PKU). KUVAN
is to be used with a Phe-restricted diet.
Important Safety Information for KUVAN
High blood Phe levels are toxic to the brain and can lead to lower intelligence and decrease in the ability to
focus, remember, and organize information. Any change you make to your diet may impact your blood Phe
level. Follow your doctor’s instructions carefully. Your doctor and dietitian will continue to monitor and
change your diet throughout your treatment with KUVAN.
If you have a fever, or if you are sick, your Phe level may go up. Tell your doctor and dietitian as soon as
possible so they can see if they have to adjust your treatment to help keep your blood Phe levels in the
desired range.
KUVAN is a prescription medicine and should not be taken by people who are allergic to any of its
ingredients. Tell your doctor if you have ever had liver problems, are nursing or pregnant or may become
pregnant, have poor nutrition or are anorexic; your doctor will decide if KUVAN is right for you. Tell your
doctor about all the medicines you take.
The most common side effects reported when using KUVAN are headache, diarrhea, abdominal pain, upper
respiratory tract infection (like a cold), throat pain, vomiting, and nausea.
To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100,
or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.