Download Inherited metabolic disorders Factfile

PKU-SON-TH1/SM
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Inherited metabolic
disorders
Factfile
HPA and PKU
Dietary restriction is the mainstay of treatment for HPA and
its severe form PKU, write Anne Clark and Eileen Treacy
THE METABOLIC disorder, hyperphenylalaninaemia (HPA) or PKU (in its severe
form) was first described in 1934 by
Folling, and renamed phenylketonuria by
Penrose in 1935 due to the increased
excretion of phenylketones in urine.
HPA is defined as a plasma phenylalanine value of >120µmol/l, severe cases of
HPA (PKU) manifest phenylalanine levels
>1,200µmol/l.
HPA is an inborn error of protein
metabolism. The essential amino acid
phenylalanine cannot be metabolised due
to the absence of the liver enzyme
phenylalanine hydroxylase. Normally
phenylalanine not required for protein
synthesis is converted to tyrosine. In the
absence of phenylalanine hydroxylase,
phenylalanine is not converted to tyrosine.
Tyrosine is necessary for the synthesis of
protein, melanin, thyroxine and catecholamines.
Untreated HPA
The main associated clinical manifestations of untreated HPA are impaired
cognitive development and function
resulting from defective brain myelination
and neurochemical imbalance postnatally
in affected cases and prenatally in the
foetus of an affected pregnant woman not
on treatment.
Symptoms arise due to the accumulation of phenylalanine which inhibits brain
development. In the untreated patient,
this results in intellectual disability, short
attention span, poor short term memory,
problems with visual motor perception
and motor co-ordination, seizures and
behavioural problems.
HPA is the most common aminoacidopathy known and is particularly
common in Ireland with a birth incidence
of 1:4,500.This is in comparison to a worldwide ratio of 1:12,000.
Screening
Newborn screening for HPA was introduced in Ireland in 1966 following the
development of the Guthrie screening
test. A newborn screening blood sample
is taken between 72 and 120 hours following birth. HPA is inherited as an autosomal
recessive disorder, ie. both parents are
carriers. With each pregnancy there is a
25% chance of the child inheriting the
condition. There are now over 400 mutations described at the phenylalanine
hydroxylase gene. There are three common mutations segregating in the Irish
population contributing to the classical
PKU phenotype in Ireland.
The baby with PKU will appear normal
at birth. Parents will be unaware that their
child is unaffected by this condition until
the positive result is relayed by the
National Centre for Inherited Metabolic
Disorders in Dublin. However, symptoms
will arise within the first few months of life
if the condition is undiagnosed.
The HPA diet
HPA is the first example of treatment of
a biochemical genetic disease, in this case
by dietary restriction of the toxic precursor
phenylalanine. The HPA diet has been in
place as the mainstay of treatment of this
condition for over 50 years. Early diagnosis
and prompt treatment with diet is needed
to prevent damage to the developing
brain. Diet is for life
The aims of dietary treatment are to:
● Maintain phenylalanine levels within the
recommended range according to the
treatment guidelines used by the
National Centre
● Replace tyrosine and prevent deficiencies
● Provide adequate protein, energy,
vitamins and minerals for growth and
development.
The basic principle of the diet is to
severely restrict the substance which is
not metabolised, in this case phenylalanine.The missing end product (tyrosine) is
replaced. Normal growth is achieved by
giving synthetically made protein devoid
of phenylalanine and augmented with
tyrosine.
In addition, small amounts of natural
protein are prescribed to allow for normal
growth. Careful dietetic supervision is
essential to ensure an adequate intake of
protein, calories, minerals, vitamins and
trace elements.
Monitoring of height and weight, regular blood tests to determine phenylalanine
and tyrosine levels and nutritional status
are all essential parts of the treatment. Protein rich foods must be avoided as they
are sources of the toxic amino acid phenylalanine.
However, children need a normal to
high intake of other essential amino acids,
as total protein needs to remain similar to
that of normal children.
Protein requirements reduce as the
child gets older and stabilise into adulthood. In order to achieve this, the diet is
divided into three components: synthetic
protein, natural protein and free foods.
Synthetic protein formula
The synthetic protein formula is devoid
of phenylalanine but contains the other 20
amino acids. A number of synthetic
formulas are currently available, manufactured by different companies in Ireland
and the UK. These formulas are expensive
and can have a bitter aftertaste. Some children and adults have difficulty complying
with their prescription.The amount of synthetic protein prescribed depends on
weight.
Synthetic protein should be divided into
three or four drinks each day. Individuals
on this diet have very limited availability
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Factfile
of exchanges. A small amount of phenylalanine is needed for normal growth. This
is provided by a system of exchanges of
natural protein each containing 1g which
is equivalent to 50mg phenylalanine.
Examples of exchanges are: one medium
potato, 30ml milk, one potato waffle.
Free foods
Most patients with phenylketonuria
tolerate only a small number of exchanges
(less than eight a day). The individual with
HPA supplements calories and variety in
the diet by using ‘free foods’ which contain
only negligible amounts of protein.
These consist of naturally occurring
foods such as: fruit and vegetables (except
peas, beans, sweetcorn and potatoes); sugars; jams; sweet drinks; fats and oils; and
specifically manufactured low protein (LP)
products; eg. LP bread, rolls and flour;
LP biscuits and crackers; LP pasta; LP pizza
bases; LP milk; all available on prescription.
Children, as they get older, are encouraged to take responsibility for their diet.
Teenage rebellion can be a problem.
Young women are advised that a
pregnancy must be planned. Prior to conception phenylalanine levels should be
within the physiological range. High
phenylalanine levels can have teratogenic
effects on the foetus.
Catabolism associated with even mild
illness/infection may cause the precursor
phenylalanine to rise despite dietary
compliance. In HPA this should not have
any severe pathological effect in the short
term. Individuals with HPA should not be
prescribed medications containing aspartame as it is a source of phenylalanine.
BH4 studies
Dietary treatment of HPA is demanding
and compliance is frequently problematic
in adolescents and young adults. Tetrahydrobiopterin (BH4) is a natural cofactor
that binds to phenylalanine hydroxylase.
Recent studies have shown that administration of BH4 in patients with mild
classical PKU or HPA can result in a significant reduction of circulating blood
phenylalanine levels and allows the intro-
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duction of more exchanges in the diet.
Tetrahydrobiopterin may act by stabilising
the dysfunctional phenylalanine hydroxylase protein or enhancing its folding.
Clinical trials of this therapy are currently
underway.
Individuals with severe HPA (PKU) carry
two severe mutations and will not
respond to this treatment.
Phenylalanine ammonium lyase (PAL) is
a recombinant enzyme which has been
shown to reduce phenylalanine levels in a
mouse PKU model. Safety studies are in
progress before it can be determined if
this therapy will offer any practical hope in
the future for individuals with severe HPA.
Anne Clark is metabolic dietetic co-ordinator and
Eileen Treacy is clinical director of the National Centre
for Inherited Metabolic Disorders, Children’s
University Hospital, Temple Street, Dublin
References
1. Scriver CR, Kaufman S. Hyperphenylalaninaemia:
Phenylalanine hydroxylase deficiency (Ch. 77) In: The
Metabolic and Molecular Bases of Inherited Metabolic
Diseases, 8th Ed, pp.1,667
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