Download 6.lect PKU NEW

INBORN ERRORS OF AMINO
ACIDS METABOLISM
PHENYLALANINE METABOLISM
THE NORMAL METABOLISM OF PHENYLALANINE
(pathways a and b)
BREAKDOWN
Dietry
sources,
particularly
plant
proteins
PHENYLALANINE
HYDROXYLASE
PHENYLALANINE
(a)
TYROSINE
(b)
BODY
PROTEINS
© 2008 Paul Billiet ODWS
THE ABNORMAL METABOLISM IN PHENYLKETONURIC SUBJECTS
(pathway c)
HYDROXYPHENYLACETIC
ACID
Dietry
sources,
particularly
plant
proteins
(c)
PHENYLALANINE
HYDROXYLASE
PHENYLALANINE*
(a)
(c)
(b)
PHENYLACETIC
ACID*
*Agents, thought to be responsible for mental retardation
© 2008 Paul Billiet ODWS
BODY
PROTEINS
.
.
.
PHENYLKETONURIA (PKU)
PHENYLKETONURIA (PKU)
•
•
•
•
•
What is phenylketonuria (PKU)?
Who does it affect?
What are the origins of PKU?
What are the treatments for PKU?
What are the precautions of PKU?
What is PKU?
“PKU is an inherited metabolic disease in
which the body can’t change one essential
amino acid, phenylalanine, into another
needed amino acid, tyrosine.”
ENZYMATIC ACTIVITY
• In cases of PKU, the enzyme that breaks down
phenylalanine, phenylalanine hydroxylase, or of its
tetrahydrobiopterin cofactor which may be
completely or nearly completely deficient.
• This enzyme normally converts phenylalanine to
another amino acid, tyrosine, which is utilized by the
body.
• When this enzyme, is absent or deficient,
phenylalanine and its breakdown chemicals from
other enzyme routes, accumulate in the blood and
body tissues.
Tyrosine is formed from phenylalanine by
phenylalanine hydroxylase
• The
reaction
requires
molecular oxygen and the
coenzyme tetrahydrobiopterin
(BH4),
which
can
be
synthesized from guano-sine
triphosphate (GTP) by the
body. One atom of molecular
oxygen becomes the hydroxyl
group of tyrosine, and the
other atom is reduced to
water. During the reaction,
BH4 is oxidized to dihydrobiopterin (BH2). BH4 is
regenerated from BH2 by
NADH-requiring
dihydropteridine reductase.
Genetics of PKU
It is inherited from
parents due to a
mutated PAH
(phenylalanine
hydroxylase) gene on
chromosome 12.
WHO DOES PKU EFFECT?
PKU is inherited as
an autosomal
recessive trait.
WHO DOES PKU EFFECT cont’
• Two people who
conceive a child must
both be the carriers of
the defective gene in
order for their child to
have the disorder.
• The “carrier” for PKU
does not have the
symptoms.
Phenylalanine accumulates in all body fluids and converts to
phenylpyruvate.
Defect in myelination of nerves
The brain weight is below normal.
Mental and physical retardations.
The life expectancy is drastically
shortened.
Symptoms of PKU
•
•
•
•
•
Light hair, eyes, and skin
Eczema-like rash
Seizures
Hyperactivity
Unpleasant musty/ mousy body
odor
• Mental retardation
DIAGNOSTIC CRITERIA:
 phenylalanine level in the blood
 FeCl3 test
 DNA probes (prenatal)
HOW CAN PKU BE TREATED cont’
• Usually a few drops of
blood are obtained by a
small prick on the heel,
placed on a card and then
sent for measurement.
• If the screening test is
abnormal, other tests are
needed to confirm or
exclude PKU.
• Newborn screening allows
early identification and
early implementation of
treatment.
LEVELS OF BLOOD PHENYLALANINE
• A normal blood phenylalanine level is about
1mg/dl.
• In cases of PKU, levels may range from 680mg/dl, but are usually greater than
30mg/dl.
Treatment
• A strictly controlled phenylalanine free diet
• up to the age of about 14 years old
• phenylalanine is itself an essential amino acid
small doses must be supplied
• After this age the growth and development of
the brain is not affected by high levels of
phenylalanine in the body
© 2008 Paul Billiet ODWS
WHAT HAPPENS WHEN THERE IS TOO
LITTLE BLOOD PHENYLALANINE?
It is important to remember that some
phenylalanine is needed to maintain normal
body function.
Insufficient phenylalanine intake may cause
mental and physical sluggishness, loss of
appetite, anemia, rashes, and diarrhea.
WHAT TYPE OF DIET IS APPROPRIATE
FOR SOMEONE WITH PKU?
• The goal of PKU treatment is to maintain the blood
levels of pheylalanine between 2 and 10mg/dl.
• Treatment for PKU consists of a diet low in
phenylalanine, which is maintained in infants with
special formulas and in individuals by eliminating
meat and using low protein grain products.
Measured amounts of cereals, starches, fruit, and
vegetables, along with a milk substitute are
recommended instead.
OTHER THINGS TO STAY AWAY FROM
• Individuals with PKU
must be alert for food
sweetened with
aspartame.
• NutraSweet in
particular, should be
avoided because it is a
derivative of
phenylalanine.
• Special diet starting a few days
.
after birth
• People must limit their intake of
protein in their diet for their whole
lives
• Babies must drink a special formula
without phenylalanine.
MATERNAL PKU
It is recommended that women with PKU who are of
child bearing age, closely adhere to the lowphenlyalanine levels before conception and
throughout pregnancy.
MATERNAL PKU SYNDROME
High Phenylalanine level increases the risk of
miscarriage, mental retardation, microcephaly, and
congenital heart disease in the child .
PHENYLKETONURIA
PKU is caused by genetic defects in the hepatic enzyme
phenylalanine hydroxylase. Phenylalanine accumulates
and is further metabolised to the phenylketones.
The natural history of phenylketonuria, PKU is severe and
sustained damage to the developing infantile brain
resulting in profound mental retardation, seizures and
spasticity. However, the foetal brain is protected by
maternal metabolism. Early detection, through neonatal
screening, and the institution of dietary therapy in the first
two or three weeks of life results in near normal
development.
PHENYLKETONURIA
PKU can also be caused by defects in the metabolism of
tetrahydrobiopterin (BH4), an essential cofactor for
phenylalanine hydroxylase. It is vital to identify these
biopterin deficient patients when a new case of
hyperphenylalaninaemia is found because the treatment is
quite different.
The treatment of patients with ‘classical’ PKU is through
dietary restriction of phenylalanine. The success of the
diet is determined by monitoring plasma phenylalanine
concentrations. Patients with BH4 deficient disorders have
a more variable clinical course. They require biopterin
supplements but don’t benefit from a phenylalanine
restricted diet.