Case study

Phenylketonuria (PKU)

Submitted by:

Bilazon, Jibrille Mikaila

Franco, Carol Len

Lat, Hannah Nicole

Manaig, Zyna Nicole

Submitted to:
Mr. Franklin Espinosa

November 2023
 I. Background/ description of the disease

History of the disease

A genetic error in the metabolism of phenylalanine is known as phenylketonuria (PKU).

Phenylketonuria (PKU) has been the standard case for hereditary metabolic diseases. It also made it
possible to provide the first biochemical theory explaining mental impairment. Furthermore, 65 years
have passed since Asbjörn Fölling, a Norwegian physician, identified the reason for two young
children's severe mental retardation during 1934 in Oslo, Norway. It was during the 1920s when the
two young children developed symptoms from an unexplained illness. Despite being normal, the two
young children had been exhibiting symptoms of severe mental retardation but no physician could
diagnose them because the condition was yet unidentified. It took ten years for physician and
biochemist Asbjörn Fölling to unravel the mystery of the children's illness. Asbjörn Fölling tested the
urine of the two mentally retarded children using ferric chloride to check for "ketone bodies," but the
results showed green rather than the predicted purple color. He recognized phenylpyruvic acid as the
unknown chromogen with accuracy. This material was previously undiscovered in the natural world.
Følling came to the conclusion that it originated from phenylalanine in food and gave the illness the
name oligophrenia phenylpyruvica which is also known as Phenylketonuria (PKU).

A. Epidemiology

Global

PKU prevalence varies greatly between ethnic groups and geographical areas. PKU affects
around 0.45 million people globally, with an estimated prevalence of 1 in 23,930 live births.
Moreover, the affected persons are typically higher in European and Middle Eastern countries and
lowest in Asian countries, with the exception of China. In addition, Asian nations including Thailand
(1:227,273), Japan (1:125,000), the Philippines (1:116,006), and Singapore (1:83,333) have the lowest
PKU prevalence records.

Local

PKU has been observed to occur in between 1:13,500 and 1:19,000. 9

PKU/hyperphenylalaninemia (HPA) patients were identified in the Philippines between September
1996 and June 2008 via screening 966,096 infants.

B. Etiology/pathogenesis

Origin of the disease

PKU is a metabolic condition that is inherited genetically wherein the body is unable to
metabolise the amino acid phenylalanine due to a lack of the enzyme phenylalanine hydroxylase
(PAH). Phenylalanine is often broken down by PAH into tyrosine, another amino acid. Phenylalanine
accumulates in the blood of PKU patients and then travels to the brain, where it is toxic and damages
tissue. Lack of this enzyme causes abnormal posture, mental retardation, organ damage, and may
seriously endanger pregnancy in cases where the mother has PKU.

Moreover, Phenylalanine is an amino acid. Amino acid molecules are the building blocks of
proteins. The neurotransmitters norepinephrine and dopamine, which are necessary for the healthy
operation of the brain and nervous system, are produced in part by phenylalanine. Many foods (e.g
meat and eggs) that a person eats that mix protein and the artificial sweetener aspartame contain
 phenylalanine. In addition, the lack of phenylalanine hydroxylase results in phenylketonuria
(PKU), an inborn error of phenylalanine (Phe) metabolism. Phe is an essential amino acid that can
only be supplied from proteolysis or the diet. It is essential for the production of proteins, Tyr, and its
byproducts, including melanin, norepinephrine, and dopamine.

Furthermore, the deficiency or lack of phenylalanine hydroxylase leads to the accumulation of

Phe and its metabolites in tissues and bodily fluids of PKU patients. Though the underlying cause of
this disease is unclear, the brain is host to the majority of the indications and symptoms. Within this
framework, metabolic abnormalities including oxidative stress, dysfunctional mitochondria, and
reduced synthesis of proteins and neurotransmitters have been observed in animal models as well as
human patients.

Genetic etiology

PKU, also known as phenylketonuria, is inherited from an individual's parents. Due to the
recessive pattern of inheritance for the illness, a child must inherit a mutant copy of the PAH gene
from both parents in order for them to acquire PKU. The child of PKU-afflicted parents will also have
PKU. There are, however, some situations in which a parent carries an altered PAH gene but does not
have PKU. In these cases, the parent is a carrier. Nevertheless, the child will not get PKU if the
defective gene is carried by just one parent.

The phenylalanine hydroxylase, or PAH, enzyme is produced by the mutations of both alleles,
which makes the condition a genetic disorder. This enzyme is found in chromosomes 12. The amino
acid phenylalanine must be converted by this enzyme into other compounds that the body needs. The
accumulation of the disease results from the body's inability to break down phenylalanine when this
gene, sometimes referred to as the PAH gene, is faulty.

Phenylketonuria (PKU) comes in various forms, depending on how severe the diagnosis is. In
severe cases, symptoms worsen if treatment is not received. PKU types include:

(a) Classic PKU (the most severe kind).

Classic PKU refers to the most severe form of the condition. There is either very little or none
of the enzyme required to break down phenylalanine. High quantities of phenylalanine are produced
as a result, which may seriously harm the brain.

(b) Mild or moderate PKU.

Phenylalanine levels are lower in mild or moderate forms due to the enzyme's continued
action, which lowers the likelihood of serious brain damage.

(c) Maternal PKU.

Maternal PKU is a variant of PKU that can occur in women with PKU who get pregnant.
Blood phenylalanine levels can rise during pregnancy and endanger the growing infant if women do
not adhere to the particular PKU diet.
 III. Signs and symptoms of the disease (PKU)
If treatment is started as soon as possible, PKU typically has no symptoms. Furthermore,
PKU may cause neurological and brain damage in the absence of treatment, which might result in
learning or mental impairments. Additional signs of untreated PKU are indicated in the table below:

1. A musty or 2.Neurological 3.Skin rashes, 4.Lighter than 5.Microcephaly,

mousy smell in the issues with the such as eczema. family members' unusually small
urine, skin, or breath nervous system skin, hair, and eye head size.
that results from the that could result in colors due to
body having too seizures. phenylalanine's
much phenylalanine. inability to convert
into melanin, the
pigment that
determines skin
tone and hair color.

6. Hyperactivity. 7 .Cognitive 8. Delayed 9. Social, 10. Mental illness

incapacity. development. emotional, and conditions.
behavioral issues.

Table I. Signs and Symptoms

IV. Pathophysiology
V. Laboratory Diagnosis (PKU)
In Laboratory Diagnosis of Phenylketonuria (PKU). The measurement of tyrosine and
phenylalanine levels in plasma must be carried out by an accredited laboratory. To rule out any
anomalies in the synthesis or recycling of biopterin, the laboratory should also analyze blood and
urine for neopterins and biopterins.

Laboratory diagnosis for Phenylketonuria (PKU)

Newborn Screening
This test is designed to check for phenylketonuria (PKU) in newborns, a condition that, if
untreated, can lead to brain damage and significant intellectual disability. There are two
categories of screening conducted for newborns:

a.) Guthriei test. This blood test is conducted for phenylketonuria (PKU) in newborns. The
Guthrie test, alternatively referred to as the Guthrie bacterial inhibition assay, is a medical
examination conducted on newborns to identify phenylketonuria, a congenital disorder related
to amino acid metabolism.

b.) Ferric chloride test. This test checks for phenylpyruvic acid in urine, indicating
Phenylketonuria (PKU). PKU is an inherited condition that affects the body's ability to
process phenylalanine, an amino acid. When not metabolized correctly, phenylalanine builds
up in the blood, leading to issues like intellectual disabilities and seizures. Early detection
through this test is crucial for timely intervention and management of PKU.

Serum phenylalanine screening.

This is a blood test aimed at identifying indications of phenylketonuria (PKU). The
examination identifies elevated levels of the amino acid phenylalanine.
Genetic testing.
- Genetic testing entails the analysis of your DNA, the molecular database containing
instructions for your body's functions. It can unveil alterations (mutations) in your genes that
might lead to illness or disease.

VI. Treatment Management (PKU)

PKU has no cure, although treatment can help avoid intellectual impairments and other health
issues. PKU patients should be treated at a medical center that specializes in the illness.

● A lifetime diet with very limited intake of foods with phenylalanine

● Taking a PKU formula(a special nutritional supplement)- for life to make sure that you get
enough essential protein (without phenylalanine) and nutrients that are essential for growth
and general health
● Medications, for certain people with PKU

A safe amount of phenylalanine varies from person to person with PKU and can change over
time. In general, the goal is to consume no more phenylalanine than is required for healthy growth and
bodily functioning. A safe dosage can be determined by your doctor by:

● Food records and growth charts should be reviewed on a regular basis.

● Blood phenylalanine are monitored on a regular basis, notably during childhood growth spurts
and pregnancy.
● Other tests for growth, development, and health.

Foods and Products to avoid:

● Milk
● Eggs
● Cheese
● Nuts
● Soy Products(soy beans, tofu, tempeh, and milk)
● Beans and Peas
● Poultry, beef, pork, and any other meat
● Fish
● Potatoes, Grains and vegetable will be likely limited

Other foods and beverages that should be avoided by both children and adults include
numerous diet sodas and other drinks containing aspartame (NutraSweet, Equal). Aspartame is a
phenylalanine-based artificial sweetener.

Formula for People with PKU

People with PKU must obtain critical nutrients through a particular nutritional supplement
due to their restricted diet. The phenylalanine-free formula offers vital protein (amino acids) and other
nutrients in a PKU-safe form.

● Formula for babies and toddlers

 - Because phenylalanine is present in both conventional infant formula and breastmilk,
newborns with PKU must consume phenylalanine-free infant formula. A nutritionist
can precisely calculate how much breastmilk or ordinary formula should be added to
the phenylalanine-free formula. The dietician can also advise parents how to choose
solid foods for their children while avoiding exceeding their daily phenylalanine
allotment.
● Formula for older children and adults
- Adults and older children should continue to drink or eat a phenylalanine-free
nutritional supplement(protein equivalent formula) as advised by a doctor or
nutritionist. Instead of being consumed or consumed all at once, your daily dose of
formula for older children and adults differs from that for infants, although it also
contains needed protein without phenylalanine, The formula is followed indefinitely.

PKU Medication
The medication sapropterin (kuvan) has been approved by the Food and Medication
Administration(FDA) for the treatment of PKU. The medication can be taken in conjunction with a
PKU diet. Some PKU patients who are receiving medication may not work for everyone who has
PKU.

The FDA also approved Pegvaliase-pqpz(Palynziq), a new enzyme treatment, for adults with
PKU when current medication does not adequately lower phenylalanine levels. However, due to
frequent and sometimes severe side effects, this treatment is only provided as part of a limited
program under the supervision of licensed health care practitioners.

References
Benign Hyperphenylalaninemia (H-PHE) - Florida Newborn Screening. (2022, April 14). Florida

Newborn Screening.

https://floridanewbornscreening.com/condition/benign-hyperphenylalaninemia-h-phe/#:~:text
 =Benign%20hyperphenylalaninemia%20(H%2DPHE)%20is%20a%20mild%20form%20of,d

o%20not%20show%20any%20symptoms.

Centerwall, S. A., & Centerwall, W. R. (2000, January 1). The Discovery of Phenylketonuria: The

Story of a Young Couple, Two Retarded Children, and a Scientist. Pediatrics; American

Academy of Pediatrics. https://doi.org/10.1542/peds.105.1.89

Elhawary, N. A., AlJahdali, I. A., Abumansour, I. S., Elhawary, E. N., Gaboon, N. E. A., Dandini, M.,

Madkhali, A., Alosaimi, W., Alzahrani, A., Aljohani, F., Melibary, E. M., & Kensara, O. A.

(2022, July 19). Genetic aetiology and clinical challenges of phenylketonuria. Human

Genomics; BioMed Central. https://doi.org/10.1186/s40246-022-00398-9

Faap, E. T. R. M. (n.d.). Phenylketonuria (PKU) workUp: approach considerations, laboratory

studies, magnetic resonance imaging.

https://emedicine.medscape.com/article/947781-workup?form=login&anfErr=true&anfErrHi

nt=true&client=205502&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUubWVkc2NhcGUuY2

9tL2FydGljbGUvOTQ3NzgxLXdvcmt1cCNjMT9mb3JtPWZwZiZzY29kZT1tc3Amc3Q9Zn

BmJnNvY2lhbFNpdGU9Z29vZ2xl#c1?form=fpf&scode=msp&st=fpf&socialSite=google&ic

d=login_error_gg_mismatch_fpf&su=lPJeCrvFF6vM4s3AflgTIgt%2FUsi7fbrx0Vd8lqz5vKz

O2LLVp5fQ%2FR1CB9LKLVFH

Ferric Chloride test for phenylketonuria | Sprint Diagnostics. (n.d.).

https://www.sprintdiagnostics.in/hyderabad/test/ferric-chloride-test-for-phenylketonur

ia

Genetic testing - Mayo Clinic. (2020, April 14).

https://www.mayoclinic.org/tests-procedures/genetic-testing/about/pac-20384827

Guthrie_test. (n.d.). https://www.bionity.com/en/encyclopedia/Guthrie_test.html

Malcolm, E. (2020, July 23). What is genetic testing for phenylketonuria and its pros and

cons? Phenylketonuria News.

 https://phenylketonurianews.com/2020/07/23/what-is-genetic-testing-for-phenylketon

uria/

National Center for Biotechnology Information. (n.d.). https://www.ncbi.nlm.nih.gov/

National Library of Medicine. (n.d.). Newborn screening.

https://medlineplus.gov/newbornscreening.html

Phenylketonuria (PKU) - Diagnosis and treatment - Mayo Clinic. (2022, May 13).

https://www.mayoclinic.org/diseases-conditions/phenylketonuria/diagnosis-treatment/drc-203

76308

Phenylketonuria (PKU) - Health Encyclopedia - University of Rochester Medical Center.

(n.d.-c).

https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&conte

ntid=pku

Phenylketonuria (PKU) - Symptoms and causes - Mayo Clinic. (2022, May 13). Mayo Clinic.

https://www.mayoclinic.org/diseases-conditions/phenylketonuria/symptoms-causes/sy

c-20376302#:~:text=For%20a%20child%20to%20inherit,but%20not%20have%20the

%20disease.

Phenylketonuria (PKU) - Symptoms and causes - Mayo Clinic. (2022b, May 13). Mayo

Clinic.https://www.mayoclinic.org/diseases-conditions/phenylketonuria/symptoms-ca

uses/syc-20376302

Professional, C. C. M. (n.d.). Phenylketonuria (PKU). Cleveland Clinic.

https://my.clevelandclinic.org/health/diseases/17816-phenylketonuria

The Guthrie Test for Early diagnosis of Phenylketonuria | Embryo Project Encyclopedia.

(2017, March 30).

https://embryo.asu.edu/pages/guthrie-test-early-diagnosis-phenylketonuria#:~:text=To

%20conduct%20a%20ferric%20chloride,that%20the%20patient%20had%20PKU
Vela-Amieva, M. (2011). History of

phenylketonuria.

https://www.medigraphic.com/cgi-bin/new/resumenI.cgi?IDARTICULO=31105#:~:text=Phe

nylketonuria%20(PKU)%20is%20an%20innborn,biochemical%20explanation%20of%20men

tal%20retardation

What causes phenylketonuria (PKU)? (2016, December 1). https://www.nichd.nih.gov/.

https://www.nichd.nih.gov/health/topics/pku/conditioninfo/causes#:~:text=PKU%20is

%20inherited%20from%20a,will%20have%20PKU%20as%20well.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413859/