In Phenylketonuria, also called PKU, can be broken down. “Phenylketone” is a product of the amino acid phenylalanine, and “uria” means a substance present in urine. So people
with phenylketonuria who are untreated, have phenylketones in their urine,
Now, amino acids are the basic building blocks that make up proteins.
Phenylalanine is one of the essential amino acids, meaning our bodies can't make but must be acquired through food that contains protein.
Since the body can’t store amino acids, any excess amino acids are converted into glucose or ketones and used for energy. Phenylalanine is converted to tyrosine by phenylalanine hydroxylase enzyme. Tyrosine is then used to synthesize various molecules.
It is turned into dopamine, which is a neurotransmitter that neurons use to communicate, norepinephrine and epinephrine, which are also neurotransmitters and hormones used by
the sympathetic nervous system, and the pigment melanin, which gives color to the skin, hair, and eyes.
Alternatively, when phenylalanine levels in the blood are high, it gets converted by the enzyme phenylalanine transaminase into phenylketones such as phenylpyruvate, phenyllactate, and phenylacetate.
The most common cause of hyperphenylalaninemia is deficiency of the enzyme phenylalanine hydroxylase, which catalyzes the conversion of phenylalanine to tyrosine. When phenylalanine metabolism is blocked because of a lack of phenylalanine hydroxylase enzyme, minor shunt pathways come into play, yielding several intermediates that are excreted in large amounts in the urine and in the sweat. These impart a strong musty or mousy odor to affected infants.
In phenylketonuria, the elevated blood phenylalanine levels can change the way the brain functions.This is because phenylalanine uses the same transporters to get across
the blood brain barrier as other amino acids including- tyrosine and tryptophan.
Tyrosine, is needed to synthesize dopamine and norepinephrine, and tryptophan is needed to synthesize neurotransmitter serotonin.
As phenylalanine levels rise, it occupies all the transporters, making it hard for tyrosine and tryptophan to get across the blood brain barrier.
As a result, dopamine, norepinephrine, and serotonin levels in the brain begin to fall, and that leads to problems in brain development and intellectual disability.
Affected infants are normal at birth but within a few weeks develop a rising plasma phenylalanine level, which impairs brain development. Usually by 6 months of life severe mental retardation becomes evident. About one third of these children are never able to walk, and two thirds cannot talk. Seizures, other neurologic abnormalities, decreased pigmentation of hair and skin, and eczema often accompany the mental retardation in untreated children
To prevent intellectual disability, diagnosis and initiation of dietary treatment of classic phenylketonuria must occur before the child is 2 weeks of age. For this reason, newborns in North America, Australia, and Europe are screened by determinations of blood phenylalanine levels. Abnormal values are confirmed using quantitative analysis of plasma amino acids. And then genetic testing can be done to determine the exact type.
The human phenylalanine hydroxylase gene is located on chromosome 12 and over 600 mutations have been described.Treatment consists of a special diet low in phenylalanine and supplemented with tyrosine, since tyrosine becomes an essential amino acid in phenylalanine hydroxylase deficiency. Dietary restriction should be continued and monitored indefinitely.
The natural protein restriction is typically severe in order

to limit phenylalanine and requires the intake of an amino acids mixture called a medical food that supplies protein that is free of phenylalanine.
All high protein foods such as meat, fish, eggs and dairy are eliminated from the diet.Measured amounts of fruits, vegetables and some grains may be allowed depending on phenylalanine tolerance.

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