Phenylketonuria
First Two Paragraphs from the Phenylketonuria entry on Wikipedia, the free encyclopedia
Phenylketonuria (PKU) is an autosomal recessive
genetic disorder characterized by a
deficiency in the enzyme phenylalanine hydroxylase (PAH).
This enzyme is necessary to metabolize the amino acid phenylalanine
to the amino acid tyrosine.
When PAH is deficient, phenylalanine accumulates and is converted into
phenylpyruvate (also known as phenylketone), which is detected in the urine. PAH
is found on chromosome number 12.
Left untreated, this condition can cause problems with brain
development, leading to progressive mental retardation and seizures.
However, PKU is one of the few genetic diseases that can be controlled
by diet. A diet low in phenylalanine and high in tyrosine can be a very
effective treatment. There is no cure. Damage done is irreversible so
early detection is crucial.
Background and Diagrams of the Problem
Phenylalanine is one of the eight "essential amino acids." These are
amino acids that we cannot make, but must ingest in our diet. We need
them to build proteins.
Normally, after protein synthesis uses what phenylalanine is needed
at the moment, the excess can be converted to tyrosine, another amino
acid, with the enzyme PAH (phenylalanine hydroxylase).
PAH
phenylalanine ----------------> tyrosine
But if PAH is defective (by mutation) then, phenylanine builds up.
This extra phenylalanine is metabolized to phenylketone.
so,
PAH
phenylalanine ----------------> tyrosine
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V
phenylketone
It is phenylketone (and related products) that interfere with neural
development that causes mental retardation.
The Pattern of Inheritance is Explained by Biochemistry!
PKU is inherited in a Mendelian recessive pattern. This means you need
two PKU genes to have the condition. We can understand this by
realizing that to have a normal (non-PKU) gene is to have a gene that
codes for
a necessary enzyme (PAH). If you have this gene, then you have the
information to
make this enzyme, and you can make the enzyme and not have PKU. If,
however, neither your mother nor your father gave you a functional copy
of the gene, you can't make the enzyme and you suffer from this disease.
Knowing the Biochemistry Suggests the Treatment
A diet low (as in close to zero) in phenylalanine and supplemented with
tyrosine
effectively replaces the enzyme, not in function, but in effects.
Why is PKU around in the first place?
It is believed that PKU exists because of mutations to the PAH gene on
chromosome 12. Certainly, before treatment, PKU individuals did not
interbreed. In fact, in traditional societies in the past, malformed
babies and people with serious conditions like PKU were put to death.
This would be expected to lead to the extinction of the
gene. Instead, it is found worldwide in human populations. It is
thought that there is constant mutation on this locus and the "bad"
copies of the gene enter the population but only cause problems when
there are two present because this means there is no code for a
functioning enzyme.
Why PKU is an excellent example
The whole story of PKU, its inheritance pattern, the way it develops
the phenotype, its importance to human populations, the probable origin
of the disease and its treatment, is a case study in genes and disease.
It highlights how our understanding of fundamental biochemistry and
genetics is crucial to our understanding of the world. Realize that
throughout the ages, disease in general, including PKU, have been
considered to be either an indication of possession by evil spirits or
punishment by the local god or gods. At this point, disease can be
considered from a naturalistic view and the results are much more
satisfying -- especially in terms of treatment!
And we owe the beginning of our understanding to that Austrian Monk
Mendel and his patient exploration of pea plants.