Classical PKU is caused by a mutated gene for the enzyme phenylalanine hydroxylase (PAH), which
converts the amino acid phenylalanine to other essential compounds in the body. Other non-PAH
mutations can also cause PKU.
This is an example of non-allelic genetic heterogeneity. The PAH gene is located on chromosome 12
in the bands 12q22-q24.1. PKU results when the recessive form of the phenylalanine hydroxylase
(PAH) producing gene is inherited from both the mother and father
For someone to have PKU, they must be homozygous recessive for the trait
Carriers show no outer symptoms.
More than 400 disease-causing mutations have been found in the PAH gene.
PKU is known to be an autosomal recessive genetic disorder. This means both parents must
have at least one mutated allele of the PAH gene. The child must inherit both mutated alleles,
one from each parent. Therefore, it is possible for a parent with the disease to have a child
without it if the other parent possesses one functional allele of the gene for PAH. Yet, a child
from two parents with PKU will inherit two mutated alleles every time, and therefore causes
the disease .
Symptoms
•Mental Retardation
• Seizures
• Microcephaly (small head size)
• Skin rashes
• Stunted growth
• Hyperactivity
“• Musty” body odor from the excess phenylketone
• Fair skin, hair, and eyes (phenylalanine is linked to melanin production).
Metabolic pathways
The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino
acid tyrosine. If this reaction does not take place, phenylalanine accumulates in the body and deficiency of
tyrosine occurs. Excessive phenylalanine can be metabolized into phenylketones through the minor route, a
transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and
phenyllactate. Elevated levels of phenylalanine in the blood and detection of phenylketones in the urine is
diagnostic, however most patients are diagnosed via newborn screening.
Tetrahydrobiopterin-deficient hyperphenylalaninemia
A rarer form of hyperphenylalaninemia occurs when PAH is normal, but there is a defect in the biosynthesis
or recycling of the cofactor tetrahydrobiopterin (BH4) by the patient.
This cofactor is necessary for proper activity of the enzyme . The coenzyme (called biopterin) can be
supplemented as treatment.
Those who suffer from PKU must be supplemented with tyrosine to account for phenylalanine hydroxylase
deficiency in converting phenylalanine to tyrosine sufficiently.
Dihydrobiopterin reductase activity is to replenish quinonoid-dihydrobiopterin back into its tetrahydrobiopterin
form, which is an important cofactor in many metabolic reactions in amino acid metabolism.
Those with this deficiency may produce sufficient levels of phenylalanine hydroxylase, but since
tetrahydrobiopterin is a cofactor for phenylalanine hydroxylase activity, deficient dihydrobiopterin reductase
renders any phenylalanine hydroxylase enzyme produced unable to use phenylalanine to produce tyrosine.Tetrahydrobiopterin is also a cofactor in the production of L-DOPA from tyrosine and 5-Hydroxy-L-
Tryptophan from tryptophan, which must also be supplemented as treatment in addition to the supplements
for classical PKU.
Levels of dopamine can be used to distinguish between these two types. Tetrahydrobiopterin is required to
convert phenylalanine to tyrosine, but it is also required to convert tyrosine to L-DOPA (via the enzyme
tyrosine hydroxylase), which in turn is converted to dopamine. Low levels of dopamine lead to high levels of
prolactin.
By contrast, in classical PKU, prolactin levels would be relatively normal. Tetrahydrobiopterin deficiency
can be caused by defects in four different genes. These types are known as HPABH4A, HPABH4B,
HPABH4C, and HPABH4D.
Characteristics of PKU
1. Elevated Level of Phe Ala
Phe al is present in tissue, plasma and urine. When phe Ala is not converted into tyrosine due
to deficiency of PAH enzyme, the level of phe ala will increase which will than convert into
phenylpyruvate, phenyllactate and phenylacetate. These ketones bodies are not normally
produced in significant amount in the presence of functional phenylalanine hydroxylase.
Phenylketonuria may lead to
1. Central Nervous System:
Elevated level of phenylalanine and phenylketones bodies can lead to damage of central
nervous system. It leads to mental retardation, Failure to walk and talk, Seizures, hyperactivity,
tremor (Shaking, jerking), microcephaly, growth retardation are characteristic found in PKU.
The patients with untreated PKU typically show symptoms of mental retardation by the age of
one.
How CNS damages occ
ur due to.,
Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the
blood–brain barrier (BBB) via the large neutral amino acid transporter (LNAAT).
3. Hyperphenylalanemia lead to excessive production of ketones bodies which will lowe the pH of
the brain. In result mostly enzymes which will work at physiological pH will stop working in resul
mental retartdation will takes place
2. Hypopigmentation
As tyrosine is the precursor of melanin. If the tyrosine is not produces then melanin production wil
be stoped which lead to hypopigmentation. The patient will have fair skin and blond hairs of head
eyes brows and eye lashes
What happen in this test
The test uses the growth of a strain of bacteria Bacillus subtilis (ATCC 6051) on a specially-
prepared agar plate as a sign for the presence of high levels of phenylalanine, phenylpyruvate,
and/or phenyllactate. The compound B-2-thienylalanine will inhibit the growth of the
bacterium Bacillus subtilis (ATCC 6051) on minimal culture media. If phenylalanine,
phenylpyruvate, and/or phenyllactate is added to the medium, then growth is restored. Such
compounds will be present in excess in the blood or urine of patients with PKU. If a suitably-
prepared sample of blood or urine is applied to the seeded agar plate, the growth of the
bacteria in the test will be a positive indicator for PKU in the patient.
People living with PKU must adhere strictly to a low phenylalanine diet for life, although it
may be relaxed later in life
Sweeteners containing aspartame (which contains phenylalanine) are to be avoided
High protein foods such as meat, milk, and eggs are avoided
PKU patients drink a special formula to compensate for the crucial vitamins and minerals in
high protein foods
Women with PKU who are on a normal diet must resume the low-phenylalanine diet, as the
high levels of phenylalanine in their bodies would hurt a fetus
PKU patients are monitored closely by their doctors to determine exactly how much
phenylalanine the patient needs and can tolerate
In conclusion, PKU patients must be extremely careful about what they eat, but otherwise
live a relatively normal life