Phenylketonuria (commonly known as PKU) is an inherited disorder that increases the levels of a substance called phenylalanine in the blood. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. It is found in all proteins and in some artificial sweeteners. If PKU is not treated, phenylalanine can build up to harmful levels in the body, causing intellectual disability and other serious health problems.

1. peoples friendship university of russia
Phenylketonuria (PKU)
Department of Paediatric Dentistry and Orthodontics
Assistant Loginopulo O.V
Student Name : Silvelius Sitayi Matamu
Group : MC 508

2. Table of contents
1. Introduction ……………………………………………..1-2
2. Epidemiology……………………………………………3
3. Genetics …………………………………………………4
4. clinical signs……………………………………………...5-6
5. Diagnosis…………………………………………………7-8
6. Management and Treatment………………………………9
7. Conclusion……………………………………………….10
8. References ……………………………………………….11

3. 1
Introduction
Phenylketonuria (PKU)
Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine
metabolism caused by deficiency in the enzyme phenylalanine hydroxylase
(chromosome12q) that converts phenylalanine into tyrosine. Phenylalanine
hydroxylase deficiency produces elevated phenylalanine concentrations in plasma,
Cerebrospinal fluid, and urine as a direct result of the inability to convert
phenylalanine to tyrosine. Mutations in the gene for PAH result in either failure to
producea PAH enzyme or productionof an enzyme with decreased catalytic
activity. This leads to an elevation of the blood phenylalanine (phe) level and to
increased transport of phenylalanine into the brain. Different classifications have
been used in the pastto describe PKU severity. In daily practice, the classification
on the severity of PKU is challenging. Before the introduction of neonatal
screening, patients arrived at the clinic due to their symptoms and the severity of
PKU was diagnosed based on the level Phenylalanine measured in the blood. The
condition in those days was classified as follows:
Phenylalanine concentration Classification
50-120 µmol/L Normal
120-600 µmol/L Mild hyperphenylalanaemia
600-900 µmol/L Mild PKU
900-1200 µmol/L Moderate PKU
>1200 µmol/L Classic PKU

4. 2
Commonly, classic PKU is considered to be present when untreated plasma
phenylalanine levels exceed 20mg/dL(1200µmol/L) without treatment. Lesser
degrees of plasma phenylalanine elevation are often referred to
as hyperphenylalaninemia.
If left untreated, PKU results in increased phenylalanine concentrations in blood
and brain, which cause severe intellectual disability, epilepsy and behavioural
problems.A defective gene (genetic mutation) causes PKU, which can be mild,
moderate or severe. In a personwith PKU, this defective gene causes a lack of or
deficiency of the enzyme that's needed to process phenylalanine, an amino acid.
Buildup of phenylalanine is so dangerous , the buildup often occurs when a
personwith PKU eats protein-rich foods, suchas milk, cheese, nuts or meat, and
even grains such as bread and pasta, or eats aspartame, an artificial sweetener. This
buildup of phenylalanine results in damage to nerve cells in the brain.

5. 3
Epidemiology
There is a wide variation in the prevalence of PKU throughout Europe. It is at its
highest in Turkey, where incidence is estimated at around one case in every 4,000
births.7 This compares with less than one case per 100,000 in Finland. Overall, the
European prevalence is estimated at one case per 10,000 births. The table below
cites the prevalence of PKU (neonatal screening) in the five European countries.
Netherlands 1: 18,000
Poland 1: 8,000
Spain 1: 20,000
Sweden 1: 20,000
UK 1: 10,000
The average number of new cases of PKU varies in different human populations.
PKU is found often in Caucasian populations worldwide, with much lower rates in
people of African, Hispanic, and Asian ancestry. As a crossroadsof these cultures,
the Middle East has comparable rates of PKU to much of the Western world. It is
one of the more common genetic diseases, with an estimated incidence of 10 cases
of PKU per 100,000 live births in Bahrain, 8/100,000 in Qatar, and 5/100,000 in
the UAE.In comparison, the rate of PKU in the United States is about 4-6/100,000.

6. 4
Inheritance
Phenylketonuria is an autosomal recessive genetic disease. For personto have
Phenylketonuria he/she must have two faulty copyof PAH genes, which control
the PAH enzyme, in order to develop PKU. Individuals who carry only one faulty
copyof the PAH gene are called “carriers”.
Carriers do not show any signs or symptoms of the disease. For a child to inherit
PKU, both the mother and father must have and pass on the defective gene. This
pattern of inheritance is called autosomal recessive. If both parents are carrying the
faulty copyof PAH gene, the chances for their offspring to have PKU disease is
one in four or 25 %. Therefore PKU is passed to children by two parents who are
carriers of the disorder
The diagram show how PKU inheretancy

7. 5
clinical signs
Babies born with Phenylketonuria appear normal the first few months of life. But
without treatment, they begin to have signs and symptoms of the disease at about 6
months of age. Phenylketonuria mutation causes a change in the protein change
amino acids DNA, RNA, and amino acid.
These include: Jerky movements of the arms and legs, Skin and eyes have a lighter
color. Infants with PKU cannot adequately produce melanin, the pigment that is
responsible for skin color and hair. PKU patients have symptoms such as; Body
odor (smell) similar to Rust caused by phenylacetic acid in the urine and/or
perspiration, Seizures, Skin Rashes, Small head size, Loses interest in the
surrounding environment, Delays in mental and social skills, Intellectual
disabilities and Behavioral problems such as hyperactivity.
If children with PKU are not treated, developmental delay may be obvious at
several months of age. The average IQ of untreated children is usually less than 50.
High levels of phenylalanine interfere with a chemical in the bodythat is
responsible for maintaining pigmentation (melanin). Therefore, affected children
usually have a fair complexion and light hair. Symptoms of autism are not
uncommon in untreated persons.
Neurological symptoms are present in only some patients with PKU and may vary
greatly. Seizures occurin about 25 percent of older children and abnormalities
appear on brain wave tests (EEG) in 80 percent of patients. Jerky muscle
movements (spasticity), abnormally tight muscles (hypertonicity), and/or increased

8. 6
deep tendon reflexes are among the most frequent neurological symptoms. About 5
percent of children with symptoms of PKU become physically disabled. Slow
writhing movements, involuntary muscle movements, and tremors occurin some
cases. Untreated females with this disorder often have spontaneous abortions or
fetal growth delays (intrauterine growth retardation). Children of women with PKU
may have an abnormally small head (microcephaly) and/or congenital heart
disease, and a variety of facial abnormalities. There is a strong relationship
between the severity of these symptoms and high levels of phenylalanine in the
mother. As a result, all women with PKU who have stopped treatment should
return to the diet before conception and continue on the diet throughout any
pregnancy.

9. 7
Diagnosis
Carrier identification tests or screening involves tests for individuals (or couples
who want to have children) with a family history of recessive genetic disorders
such as they may not have a disease but may carry the gene for it. Three common
carrier identification tests include those for cystic fibrosis, Tay-Sachs disease, and
sickle-cell trait.
Prenatal diagnosis involves genetic testing of a fetus using reoutine In Vitro
Fertilization methods. Here the child is suspected to be at the risk of possessing
genes linked to mental retardation or physical deterioration, Down Syndrome being
one of the most common genetic diseases to be screened by this method.
Four main diagnostic tests used in prenatal diagnosis are ultrasound, chorionic
villus sampling (CVS), amniocentesis, and fetal blood sampling (cordocentesis),
the latter three being invasive procedures. Ofall these tests, however, only CVS
testing produces reliable results during the first trimester.
Chorionic villus sampling involves use of a catheter through the cervix or a needle
into the abdomen. The abdominal technique is possiblethroughout pregnancy if
the placenta can be reached. CVS is beneficial because it can be used for DNA and
various other biochemical studies to determine monogenic and other chromosomal
disorders, though tests for congenital malformations and chromosomal disorders
must be done in the second trimester
Ultrasound procedures are used to detect major deformations and are used to
confirm gestation in the uterus and the duration of gestation. These tests normally
are less than a half an hour. Over 90% of several anomalies can be detected in an
ultrasound if done at a gestation period of 19 weeks, allowing organs to have
sufficiently developed
Amniocentesis is another procedure often employed, in which amniotic fluid is
removed. This test can be done at 15-16 weeks of gestation, though lab work may

10. 8
require two weeks time to produceresults of chromosomalabnormalities. There
may be some safety concerns about amniocentesis and its associated risks, and thus
consultations with doctors and genetic counsellors may be appropriate.
Fetal blood sampling is primarily done after the completion of 18 gestation weeks.
With the guidance of an ultrasound, a needle is punctured into the abdomen to
sample some cells of the fetus. Its use ranges from detection of blood disorders to
the karyotyping of fetal lymphocytes.
Newborn screening involves screening a newborn child as a preventative health
measure. Phenylketonuria and congenital hypothyroidism are conditions for which
this screening is frequently used. Benefits of this screening are significant where
treatment is available.
Late-onset Disorders testing includes testing for diseases that may occur in late
life. Adult diseases commonly screened are cancer and heart disease. These
diseases are known to have genetic and environmental causation and genetic
testing plots the susceptibility of the individual for these diseases.
Identity testing or DNA fingerprinting involves profiling the individuals genetic
information from DNA test results of genetic markers in order to locate
characteristics unique to the individual. Most commonly used by forensics in
criminal investigations, this type of testing is increasingly gaining a lot of media
attention and public recognition.

11. 9
Managementand Treatment
Dietary management
The primary goal to treat PKU is to maintain blood Phe concentrations within a
defined target limit as defined by the physician. Dietary Phe restriction is the
cornerstone of PKU treatment and should be initiated immediately in any infant
with a positive screening test. Breast or normal infant formula feeds are reduced in
volume and must be supplemented with a special phenylalanine-free infant protein
substitute. Once weaned the child must avoid protein-rich foods suchas meat, fish,
eggs, cheese and nuts. Phe-free amino acid supplement formulas, bars, capsules,
gels, soups and drinks are available to provide a protein replacement. Amino acid
supplements have to be administered at least three times daily and compliance
tends to diminish once the child begins to take control of his or her own food
intake. The cheese whey protein glycomacropeptide may be a more palatable that
to some degree may replace amino acid supplements.
Drug treatment
The enzymatic cofactorBH4 can be a useful treatment that reduces the blood Phe
levels in some patients. This allows patients to control their phenylalanine levels
and/or to be on less severely restricted diets. A tablet form of BH4, sapropterin
dihydrochloride, is licensed in Europe for oral medical treatment for
hyperphenylalaninaemia (HPA) in patients with PKU or BH4 deficiency. In order
to identify whether a PKU patient responds to sapropterin dihydrochloride, patients
will undergo the so called “oral-responsetest” before treatment initiation. Blau et
al recommend that all patients with PKU should undergo such a responsiveness
test. Around 20 to 56 per cent of PKU patients respond to BH4 with the greatest
responseseen in those with the milder forms of the condition.

12. 10
Conclusion
In conclusion PKU is an autosomal recessive inborn error of phenylalanine
metabolism caused by deficiency in the enzyme phenylalanine hydroxylase
(chromosome12q) that converts phenylalanine into tyrosine. It requires early
diagnosis, as it can be fatal if not managed in early childbirth. Dietary
management is very important for the well being of PKU patients. Screen of PKU
in childbirth should be a mandatory for all children and should be carried out in all
hospital. People that able to do genetics should also be advised to do so.

13. 11
Reference list
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Oct;376(9750):1417-1427.
2. Blau N, Bélanger-Quintana A, Demirkol M, Feillet F, Giovannini M,
MacDonald A, et al. Management of phenylketonuria in Europe: survey results
from 19 countries. Mol. Genet. Metab. 2010 Feb;99(2):109-115.
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Cokun T, Tokatli A, Kalkanolu HS, Dursun A, TokolS, et al. New
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