Polytechnic University of the Philippines

Department of Nutrition and Dietetics

Sta. Mesa, Manila

Phenylketonuria (PKU)

Aubrey Aligam
Lyra Jade Amparo
Jersey Mari Arante
Kieth James Balagon
Nica Banayo
Maria Jericka Basañes
Jennica Banzuela
Kc Cassandra Butalon
Stephen Torilllas
BSND 1- 1D

Reynaldo Magpantay Jr., RND

Instructor

August 2019
 I. Introduction

Phenylketonuria, commonly called, PKU was first discovered in Norway by Dr.

Asbjorn Folling. In 1934, a mother came into his clinic to consult about her severely
mentally retarded children, a 6 1/2- year old girl and 4-year old boy. Not wanting to
reject the mother, Dr. Folling agreed to examine the condition of the children. For
several months of urine examination, extraction procedures and chemical analysis,
phenylpyruvic acid, an acid that cannot be found on a normal person’s urine, was
discovered on the urine samples of the children. After this discovery, more research was
done which concluded that: phenylpyruvic acid is only present in the urine of patients
with PKU-related mental retardation; PKU is hereditary (autosomal recessive
inheritance); it is possible to detect carriers; and genetic counseling can be provided.

Over fifty years ago, a simple screening test for PKU was developed by Dr. Robert
Guthrie, which became the prototype for universal newborn screening. In 1970, it
become a routine in every industrialized nation to conduct new born screening for PKU,
and had even extended to third world countries. Phenylketonuria is very rare that the
disease affects only one in fifteen thousand people but it became widely known because
it is a victory for scientific medicine.

In PKU, the gene responsible for producing phenylalanine hydroxilase, the enzyme
that converts one amino acid (phenylalanine) to another (tyrosine) is defective.
Therefore, the body becomes deficient in tyrosine and phenylalanine accumulates in the
blood. This eventually causes imbalance that inhibits protein synthesis in the brain,
which n turn results in severe neurological symptoms or mental retardation.

The severity of PKU varies. Classic PKU is the most severe form of the disorder.
High levels of phenylalanine accumulate in the blood because the enzyme responsible
for converting phenylalanine to tyrosine is absent or severely reduced. This condition
results to severe brain damage. In mild and moderate (or variant) form of PKU, there is
a smaller risk of brain damage because phenylalanine levels are not as high since the
enzyme retains some function. Hyperphenylalaninemia is the most minor type where
phenylalanine has the lowest level above normal.
 Initially, symptoms o PKU is not visible on newborns but without treatment, the
sign of PKU like reversible brain damage and marked intellectual disability, begin to
develop within the first few months of the baby. In children and adults, a stale odor in the
breath, skin, or urine, neurological (seizures and tremors), behavioral, emotional and
social problems are signs and symptoms that can be observed when the PKU was
remained untreated. In mothers with PKU, high blood phenylalanine levels during
pregnancy can lead to fetal birth defects or miscarriage problems.

Protein-rich foods (milk, cheese, nuts or meat), aspartame (an artificial sweetener)
and even grains (bread and pasta) help in the accumulation of phenylalanine in the
blood which results in damage to nerve cells in the brain. This is why, people with
PKU—babies, children and adults—need to follow a diet that limits phenylalanine, for
the rest of their lives.

Objectives of the Study

This paper aims to inform individuals, raise awareness to the public and clarify
misconceptions about the genetic disorder, Phenylketonuria. Specifically, it sought
answers to the following questions:

1. What is Phenylketonuria and its types?

2. What are the signs and symptoms of having
Phenylketonuria?
3. How is Phenylketonuria acquired?
4. What procedures are done to detect Phenylketonuria?
5. What are treatments to prevent severe health problems
caused by Phenylketonuria?

Significance of the Study

 Government and Community

 This study will give information to the government and community. Since the
government have executive department such as the Department of Health, they
could disseminate information and raise awareness about phenylketonuria to
every community. Parents in every community would be aware of what they could
possibly do to lessen the chances of their child from having the disease.
 Professors and Colleges
This study will provide the professors more elaborate information about the
genetic disorder phenylketonuria. Through this, they could give students enough
knowledge about the disease.
 Students
This study will raise awareness to the young ones, most specially the
students. Though phenylketonuria is a very rare disease, this study would still
benefit allied health students as they have the chance to encounter such
condition during their practice.
 Medical Health Professionals
This study can be useful and potent to the medical health professionals
such as pediatrician, obstetrician-gynecologist, neurologist, psychiatrist or
dietician. From this study, they can gain knowledge that could help with further
improvement of the treatment and maintenance of their patient’s diet.
 Future Researchers
This study is significant to future researchers as it will serve as a guide or
reference and will give them a background or an overview of their studies relative
to this research.

Scope and Limitations

This study targets a wide range of people including the community, colleges and
universities, government, medical health professionals and future researchers. Since
this is not a research paper, this focuses only on what the target readers have to know
about phenylketonuria. This includes the history, types, causes, signs, symptoms and
treatment of the disease. The enzyme phenylalanine hydroxylase and amino acids such
as phenylalanine and tyrosine were mentioned to give a more complex reason of how
the disease occurs. Genetic screening and pre-natal diagnosis were briefly discussed.
Other health problems related to the disease were also mentioned though they were not
elaborated because the focus of this term paper is on the disease.

The availability of reference books, journals, articles and online sources set a limit
to the data that was gathered. Being a very rare genetic disorder, studies and articles
about phenylketonuria is not as numerous as those that discuss about other diseases.
 II. Review of Related Literature

According to the Genetic Science Learning Center (2018), "A genetic disorder is a
condition that is caused by an abnormality in an individual's DNA.", flaws found within
the DNA may be in a single-base mutation in a single gene or it may also be additional
chromosomes or lack thereof (General Science Learning Center, 2018). Genetic
disorders regarding cognitive abilities ranges from dyslexia to autism (Tager-Flusberg,
H., 1999), while genetic disorders regarding metabolism ranges galactosemia to maple
sugar urine disease (Lee E., 2017). Both metabolism and cognitive genetic disorders
are found in Phenylketonuria.

A metabolic disorder happens when reactions of a chemical anomaly modify the

natural process of metabolism; most metabolic disorders are autosomal recessive (Lee
E., 2017). PKU is known as an inherited amino acid metabolic disorder. People affected
with PKU cannot process phenylalanine (Phe)--which is found in most food. If the Phe
levels increase, it may cause damages to the brain, which results in severe mental
retardation (Medline, 2019). Since phenylalanine can not be processed, the high levels
of phenylalanine results in a strong, musty odor in urine and on the body and fairer skin
color and blue eyes due to the failure of phenylalanine to convert to melanin, which is
responsible for skin color (Abadie, V., de Baulny H. O., Feillet, F. & de Parscau, L.,
2007).

PKU is a rare metabolic disorder that is also known to simultaneously have

consequences in brain activity; this is due to gene mutations of the phenylalanine
hydroxylase (PAH) enzyme. A mutation in the PAH enzyme restricts the Phe (an amino
acid) to convert to Tyrosine. Thus, the outcome is the rising levels of blood Phe and
then affects the brain consubstantially (Blau, N., de Groot, M. J., Hoeksma, M.,
Reijngoud, D. J. & van Spronsen, F. J., 2010). As brain cells use neurotransmitters to
transfer information to one another, a lack of neurotransmitters result in a brain that may
not function well. In relation to this, interruptions in the neurotransmitter are caused by
high blood Phe levels--Phe is also considered to be highly toxic to the brain (BioMarin
Pharmaceutical Inc., 2019).
 Neurobehavioral problems have significantly decreased due to the early detection
of PKU and a management of Phe controlled diet, yet there are certain disorders, such
as attention, behavior and mood, which may still be observed regardless of the on-going
treatment. For adults, they are advised not to quit their diets in order to prevent such
behavioral problems. Additionally, adults that continue their diets have improved IQ
scores and are more likely to graduate from college (Lang, 2010). Moreover, PKU
affected children who were given immediate care and treatment showed no signs of
autism, whereas some PKU affected children who were lately diagnosed qualified in the
criteria for autism (Baieli, S., Meli, C. & Pavone, L. et al. 2003).

PKU has no known current treatment and is managed solely through restrictions in
the diet; said treatment may lead to certain complications. Furthermore, medical
advancements have been made in improving food and its palatability (Christodoulou, J.
& Hafid, N., 2015). Even mothers, who are diagnosed with PKU, go through a low-
phenylalanine diet. Neonates, who are born to mothers of PKU who no longer follow the
said diet, have a higher risk of developmental delay due to the high exposure of
phenylalanine before birth (Committee on Genetics, 2008).

Gene therapy is a new type of PKU treatment that is still undergoing certain tests
on mice before being presented to the public. This is done by using novel adeno-
associated virus vectors to supplement a non-mutated PAH gene into the liver of a PKU
mice; this is said to restore activities in the liver and lower blood Phe. Yet, the gene
therapy is observed to only have temporary effects and reinjection of the said vector
leads to its damage by antibody-mediated immune reactions (Concolino, D.
&Strisciuglio, P., 2014).

Enzyme therapy is either enzyme replacement or enzyme substitution (Concolino,

D. &Strisciuglio, P., 2014). Enzyme replacement using PAL has more advantages than
its counterpart PAH. PAL is a nonmammalian enzyme as it is appropriated in plants,
fungi, yeasts and also originated from E. coli. A PAL capsule, specifically PAL enteric-
coated capsule, is made from a purified PAL acquired from the R. glutinis yeast
congested in hard gelatin as well as an enteric-coated capsule. This type of oral
ingestion as a PKU treatment significantly lowered blood Phe levels (Erlandsen, H., et
al., 2004).

In order for an amino acid to pass through the blood brain barrier, it requres a
transporter protein (Bhatia, G., 2006). Large neutral amino acids (LNAA) are available in
the market. This treatment involves LNAA blocking Phe from entering the brain. Due to
the blocked passage, Phe may not enter the brain, which will result in lower levels of
Phe found in the brain; introducing LNAA in a Phe-restricted diet will do this. On the
contrary, this is not a permanent solution to the Phe-restricted diet, yet it is a good
supplement for those who are poor in diet control (National PKU Alliance, 2019).
 III. Methodology

A. Identification

Phenylketonuria is known as a rare inherited disorder as it mostly affects only an

approximate of 1 in 15000 people. Though PKU is indeed inherited, it is an autosomal
recessive disease, making it a 1 out of 4 chance when both parents are carriers of the
said disease. In a pediatrician’s lifetime, it will be rare that one will encounter a single
case of PKU. PKU's known 'treatment' is a Phe-restricted diet, however in order for the
said diet to be effective, an infant must be diagnosed with PKU.

Dr. Robert Guthrie was responsible for a screening test that helped detect
Phenylketonuria—this happened 50 years ago. This is a known victory for medicine as
newborns all appeared normal, only later in life will they show certain disorders and by
then, much damage has already occurred and could be considered as irreversible.
Currently, this test is known as newborn screening. This is a mandatory test done to
neonates to detect for any congenital metabolic disorders. Said disorders may cause
severe mental retardation or death if not treated at an early stage. A newborn screening
test is composed of:

 Obtaining a few drops of blood done by pricking the heel of the neonate.
 A hearing test
 Measuring the oxygen level in the blood

Phenylketonuria is detected by performing a heel stick and acquiring blood

samples from the infant. The drops of blood will come in contact with a special
absorbent paper until each circle found on the card consists of a blood sample. After it is
dried, it will be sent to the laboratory for further testing of congenital metabolic disorders.

In terms of diagnosis, an untreated PKU child at 3-6 months will eventually lose
their interest with their environment. At 1 year old, that child will appear as mentally
retarded and their skin is noticeably fairer than their siblings or someone without PKU.
Other symptoms of PKU are:

 Behavior disorders,
 Seizures,
 Slow development or growth,
 Eczema,
 Microcephaly, and
 Offensive or musty urine and skin odor

B. Research Design

This study made use of descriptive method of research to be able to come up with
adequate information regarding the genetic disorder, Phenylketonuria. Descriptive
method was used because it was designed to present facts concerning the nature of
any phenomena. It helps in collecting large amount of data to have a more focused,
detailed and accurate interpretation of findings. Also, it helps in providing answers to the
questions of what and how of this study.

C. Data Gathering

Since the research study is in a qualitative approach, the students used a non-
probability sampling technique, specifically, convenience sampling wherein published
articles or documents are properly gathered through the use of the internet that will
eventually lead the students have an organized and reliable sources for the said topic.
The students preferred using a convenience sampling simply because it is reasonable,
and the collection of datum can be done in a short period or duration of time.

Electronic medias had greatly provide an extension of data that the researchers
will analyze and further explain. Also, the students collected data by the utilization of
document analysis and combined different sets of informations gathered by distinct
sources to make a general awareness along with expanded comprehensions in order to
mainly achieve the aims or objectives of the study that will surely help the readers
apprehend the particular research topic, which is the Phenylketonuria or PKU.
 III. Results and discussion

This part of the term paper presents and discusses the findings, analysis and
interpretation of the data and information gathered pertinent to the comprehension of the
objectives of the study, which was to raise awareness or clarify misconceptions about
the genetic disorder, phenylketonuria or PKU. Specifically, to sough answers or
explanations about the significant informations about PKU, its types, signs and
symptoms, how is it acquired, procedures done to detect it and lastly, its treatment plans
or possible medications to prevent severe health problems caused by Phenylketonuria
or PKU.

Phenylalanine is an amino acid that babies are incapable of breaking and will
eventually precede to a rare condition called Phenylketonuria (PKU). This inherited
disease, which means it is rendered down through the genes of the mother and father;
is caused by mutations in the gene that abet the formation of an enzyme called
phenylalanine hydroxylase. This enzyme alleviates the atomization of phenylalanine and
when this gene does not generate accurately or its levels escalated, the body can’t
disrupt phenylalanine that can antecedent damage to nerve cells in the brain, which
could direct to cognitive and developmental dysfunction.

According to UPMC Children’s Hospital of Pitssburgh, there are four types of

phenylketonuria or PKU. The most habitual disorder of amino acid metabolism and is
the lowest level above normal is known as the hyperphenylalaninemia or HPA.

Next is the mild phenylketonuria, it is an infrequent disposition of phenylketonuria

(PKU variant) which is a congenital fallacy of amino acid metabolism and is denoted by
symptoms of PKU from lenient to middling acuteness or in other words, its blood levels
are slightly upraised.

The third type is known for having slighter critical configurations while having levels
not stunted but also not elevated and is called as moderate, variant or non-PKU
hyperphenylalaninemia. Aside from that, people infected with this type of PKU has a
little probability of brain destruction and may not necessitate treatment with a low-
Phenylalanine diet, but still need to follow a particular diet to avoid cognitive disabilities.

Lastly, a drastic structure of phenylketonuria or PKU is known as classical or

classic PKU, it is an innate error of amino acid metabolism identified in an untreated
patients by an extreme intellectual slippage and neuropsychiatric barriers. Also, there
blood levels of phenylalanine are extortionate and infants with classical PKU seems to
be coherent up to the moment that they are a few months old. Additionally, when left
untreated, children may result to a perpetual mental ailment.

Because PKU is a genetic condition, it can’t be averted but is manageable, the

ultimate key to living with PKU successfully is detecting it early. The avenue to ascertain
if people mount the fallible gene is through genetic testing, one clone of the gene for the
disease to be passed on must be exhibited from both parents. But, some people that
may flaunt the gene but not own PKU is known to be carriers. In often times, PKU is
proceeded to children by two parents who are bearer of the disease but has no idea in
anything about it.

Furthermore, most country in the United States entail a screening test or a simple
blood test as a segment of the newborn screening panel to easily perceive PKU. This
test is mainly done by taking a small drops of blood from the baby prior to when the
baby leaves the hospital. Also, blood and urine tests are in need to assert in diagnosis if
the screening went positive.

Additionally, to determine if a newborn baby has the enzyme required to utilize

phenylalanine in his or her body is done through phenylketonuria or PKU test.

The phenylalanine level builds up in the baby’s blood and again, can cause brain
damage, seizures and cognitive disability. If a baby’s body is impotent to enzyme that
converts phenylalanine into another amino acid, it may known to be as tyrosine.

In Canada and the United States, babies are tested for PKU wholly right after birth
and as mentioned, this disease is very significant to remark untimely. As stated at the
HealthLinkBC website, PKU’s blood sample is conventionally seized from the baby’s
heel or heel stick and the first few days after birth is when it is tested or as early as 24
hours after birth. In some quarter, these tests may be sustained within the first week or
two after birth.

On top of that, newborns are tested consistently for PKU at birth even if they are
born infected and again, signs and symptoms of PKU may not be detectable for a few
months. Besides, the harm caused by PKU can undertake weeks after the baby has
established drinking breast milk or formula.

However, when PKU is not diagnosed at birth and treatment does not begin
ahead of time, babies will eventually flourish signs and symptoms of PKU within few
months. These signs and symptoms mentioned in young babies include:

 Eczema, a type skin rash and

 Stunted growth
 A musty odor in the breath,
 Neurological dilemma that
skin or urine, caused by a lot of
may include seizures
phenylalanine in the body
 Abnormally small head
(microcephaly)

Moreover, uncontrolled PKU can progress to other difficulties as the child grows,
such as:

 Intellectual disability
 Developmental delays
 Problems with memory
 Irritability
and
 Behavioral, emotional and
social problems
 Hyperactivity
 When people with PKU appositely cope their diet normally don’t manifest
symptoms and at one time a particular diet and supplementary treatments got under
way, manifestations will eventually begin to shrink.

A person with PKU must remain on diet and proceed a strict low-Phenylalanine
diet or a diet that bound foods with phenylalanine, both prior to becoming pregnant or
throughout pregnancy for better corporeal and intellectual health. Additionally, foods
with high-protein should also be circumvented, such as milk, cheese, eggs, meats, nuts,
legumes, tofu, and so on. People with PKU are also required to evade the sweetener
aspartame (which is found in medications, vitamins, foods and drinks), because it
liberates phenylalanine when assimilated that will finally source to increase the extent of
phenylalanine in a person’s blood. In often times, people with PKU have to restrict their
consumption of lower-protein foods, like certain fruits and vegetables. However, low-
protein noodles and other special products can be incorporated in PKU diet.

Moreover, swallowed quantity of phenylalanine that is safe to intake varies for an

individual. Therefore, it is significant for a person with PKU to work with a health care
professional to prosper an individualized diet. Also, the amount of phenylalanine
requisite for fine fettle growth and body procedure is a valued goal, but not any further.
On top of that, to help regulate how well the diet is processing is through continual blood
test and doctor visits.

Furthermore, the PKU diet is not that easy and can be very exacting. An
assistance inclined from family and friends or a support group can be beneficial and
sticking or focusing with an established diet fortifies better functioning and ameliorate
overall health.

According to Eunice Kennedy Shriver National Institute of Child Health and Human
Development (NICHD), the U.S. Food and Drug Administration (FDA) has authorized
the drug sapropterin dihydrochloride (Kuvan®) for the treatment of PKU. It is a
manifestation of BH4 (an essential cofactor for countless enzymes in the body, involving
those required in the configuration of nitric oxide (NO), and the key neurotransmitters
dopamine, serotonin and epinephrine) which aid the body to break down phenylalaine
and participates a critical part in both heart and cognitive health. However, one ground a
person may not break down phenylalanine is having a small amount of BH4.

Additonally, Kuvan® only abet people diminish the phenylalanine in their blood
and it will not minimize the phenylalanine to the appropriate amount even if medication
helps, that is why it must be utilized simultaneously with the PKU diet.

The organization advocated that research on the medication resume to ascertain

its long-term security and efficacy if the FDA mandated Kuyan®. The NICHD-assisted
researchers and other scientists while traversing subsidiary treatments for PKU. A
matter distinct to the enzyme that usually breaks down phenylalanine called an enzyme
therapy and a huge neutral amino acid supplementation, which may aid disruption of
phenylalanine from entering the brain are the treatments that are covered. The usage of
gene therapy, which comprises injecting current genes to break down phenylalanine are
also scrutinized by the researchers that would ultimately result in the break down of
phenylalanine and decreased blood phenylalanine levels.

For better understanding of the applicable treatment or prevention plans a person

with PKU must consider or maintain are, proper diet, emotional support, health
education awareness, guidance from a health care professionals or dietitians and safety
being the priority.
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