Other Metabolic Diseases: Clinical,
Genetic and Newborn Screening Aspects
Phenylketonuria (PKU) is a genetic
condition associated with abnormally
high levels of phenylalanine in
the body. Elevated phenylalanine
leads to increased levels of phenylketones
in the blood which are excreted
in the urine, thus the name phenylketonuria.
In order to understand PKU, it is
necessary to understand some basic
concepts of metabolism, which is
the process by which compounds from
our diet are chemically changed
and used by our body to carry out
the basic functions of life.
processes occur along multiple steps
called pathways. Each step in the
pathway is catalyzed by a specific
enzyme. Enzymes are special proteins
which act as catalysts to induce
chemical changes in other substances
in our body. These enzymes are manufactured
by our bodies in response to instructions
contained in our genes.
Phenylalanine is one
of the amino acids, which are important
nutrients that we get from our diets.
Amino acids are used by the body
to make protein which is essential
for most physiological processes.
Amino acids also serve as precursors
to be converted by enzymes into
other important compounds for the
brain and other organs.
The metabolic pathway
we are dealing with in PKU is the
conversion of phenylalanine into
another amino acid, tyrosine. The
importance of this pathway is that
it removes excess phenylalanine
and it enables the production of
sufficient tyrosine. Tyrosine is
important for the production of
neurotransmitters that function
in the brain. The enzyme phenylalanine
hydroxylase (PAH) is responsible
for enabling the phenylalanine to
tyrosine conversion to take place.
Individuals with PKU
have a genetic defect in the ability
to produce PAH, therefore the phenylalanine
they get from their diet keeps accumulating
rather than being converted to tyrosine.
The two major consequences are:
(1) toxic levels of phenylalanine
in the body and (2) high ratio of
phenylalanine to tyrosine associated
with impairment of the production
High levels of phenylalanine,
as seen in untreated PKU, cause
brain damage and associated mental
retardation. Early implementation
of a low phenylalanine diet prevents
the mental retardation associated
with this condition.
The deficiency of PAH in a person
with PKU is the result of a mutation
or error in the gene that instructs
our cells to make PAH. We all inherit
two copies of the PAH gene, one
from our mother and one from our
father. To have PKU, both of these
copies must have a mutation. Therefore,
both parents must have at least
one copy of the defective gene.
People with one normal PAH gene
and one defective PAH gene are carriers.
Because having one normal PAH gene
is enough for the body to produce
sufficient PAH, carriers do not
common is PKU?
PKU is a relatively common genetic
condition. It occurs in about 1
in 10,000 to 1 in 15,000 newborns.
The incidence varies according to
geographic location and ethnic group.
a couple has a child with PKU, what
is the chance of PKU occurring in
their future children?
The chance of PKU in each future
pregnancy (assuming the same mother
and father) is 25% or 1 out of 4.
is PKU diagnosed?
All newborns in the United States
are screened for PKU. This is accomplished
by obtaining "blood spots"
on a special newborn screening card,
which is then sent to a screening
laboratory. The screening laboratory
is usually operated by the state
in which the baby is born. If the
screen shows a high phenylalanine
level, a confirmatory test is ordered
to determine if the baby has PKU
or if the original screen was a
"false positive." Babies
who are diagnosed with PKU should
always be referred to a metabolic
specialist. The parents and primary
care physician should be made aware
of the available specialists and
clinics in the state in which they
live, so that they can make an informed
decision about where to go for treatment.
is the treatment for PKU and when
should it be implemented?
The treatment for PKU is a low phenylalanine
diet. This should be implemented
as soon as possible in the neonatal
period. Special formula with a low
phenylalanine content is prescribed
for infants and children with PKU.
Adjustments are made in the phenylalanine
content of the formula based on
frequent monitoring of phenylalanine
levels in the blood. Foods which
are low in phenylalanine are added
to the diet as the infant grows.
Adherence to a low-phenylalanine
diet should be life-long.
is the goal of treatment and how
is response to treatment monitored?
The overall goal is for the patient
to attain normal growth and normal
cognitive development. This is accomplished
by a low phenylalanine diet which
maintains blood phenylalanine at
safe levels. Most clinics in the
U.S. try to keep plasma phenylalanine
levels between 2 mg% and 6mg%. In
a recent NIH consensus conference,
the treatment range of 2 - 6mg%
was recommended especially until
12 years of age. After 12 years
of age, the suggested treatment
range is 2 to 15 mg%. However, maintaining
the levels in the lower part of
this range is advisable. It was
also recommended that during infancy
blood phenylalanine levels be monitored
weekly. Between 1 and 12 years of
age, twice monthly monitoring is
recommended and monthly after 12
years of age. Frequent dietary adjustments
are needed, especially in infancy
and childhood, when rapid growth
of the brain and body occurs. The
diet should be prescribed and supervised
by a dietician with experience in PKU management (see chapter on dietary
management by Heidi Schumacher,
is the outcome of treated PKU?
Mental retardation due to PKU has
become largely a thing of the past.
This is because newborn screening
has enabled early diagnosis and
the implementation of dietary treatment
during the neonatal period. National
collaborative studies have shown
normal IQs in treated patients.
Although IQ is normal, studies indicate
that some individuals with PKU may
have subtle difficulties with behavior,
attention and cognitive function.
Some reports suggest an increased
rate of attention deficit. The reason
for this is unclear although it
has been hypothesized that, even
in treated patients, when the plasma
phenylalanine levels are above 6
mg%, the resulting disturbance in
neurotransmitter metabolism may
have an adverse effect on the function
of the prefrontal cortex region
of the brain. The prefrontal cortex
is thought to be involved in sustaining
attention and for exercising inhibitory
control of distractions. These functions
are important for focusing and concentration
on new tasks. More research is needed
to evaluate the above and other
hypotheses regarding the possible
subtle problems in some treated
patients with PKU.
is the treatment for PKU patients
who are pregnant?
It is critical that females with
PKU have acceptable phenylalanine
levels before becoming pregnant
(optimally at least three months before
conception) and that the levels
be within the treatment range throughout
the pregnancy. The levels should
be strictly within the 2 to 6 mg%
range. Untreated maternal PKU is
associated with a very high risk
of mental retardation and other
birth defects (such as congenital
heart disease and small head size)
to the baby. Adherence to dietary
treatment throughout pregnancy markedly
reduces the risk of these problems.
II. Newborn Screening
for PKU and other Metabolic Diseases
is newborn screening and what is
Newborn screening is the process
by which specific disorders are
screened for in all newborns in
the population of a particular place,
usually a state. For example the
state of Louisiana screens all newborns
for congenital hypothyroidism, hemoglobin
disorders, and two metabolic diseases,
phenylketonuria and biotinidase
deficiency. The purpose of screening
for these conditions is to enhance
the health and well-being of affected
infants through early diagnosis
and provision of timely therapy.
performs the screening test?
In most locations, screening is
performed by collecting "blood
spots" on appropriate filter
papers which are sent to newborn
screening laboratories usually operated
by the state in which the baby is
has newborn screening affected the
clinical outcome of PKU?
Before newborn screening was available,
the vast majority of patients with
PKU suffered mental retardation.
Screening for PKU started over 30
years ago and has enabled early
dietary treatment and normal IQs
in the vast majority of patients.
is biotinidase deficiency and how
does screening affect outcome?
Biotinidase is an enzyme that when
deficient is associated with skin
rashes, hair loss, hearing loss,
small head size and developmental
delay. Screening for biotinidase
deficiency enables the treatment
to be implemented in the neonatal
period and prevents these symptoms. Biotinidase newborn
screening is performed in Louisiana.
Galactose is the main source of
sugar (carbohydrate) found in breast
milk and formulas made from cow's
milk. Classical galactosemia is
caused by deficiency of an enzyme
involved in the metabolism of galactose.
Affected infants have liver and
kidney disease as well as cataracts
and developmental problems. This
disorder is part of the newborn
screening panel in most states.
The treatment is withdrawal of galactose
from the diet.
developments are on the horizon
for newborn screening of metabolic
The most recent and significant
technical development is the implementation
of tandem mass spectroscopy (TMS)
in some states. Using TMS it is
now possible to screen for over
20 additional metabolic diseases
in a single blood spot. In states
where this technology is not yet
available, blood spots can be sent
to outside newborn screening laboratories
for supplemental screening. A partial
list of disorders screened by this
new technology include:
Urea Cycle Disorders
- such as citrullinemia, arginosuccinic
aciduria, and argininemia
Organic Acidemias -
such as methymalonic acidemia,
propionic acidemia, glutaric
Amino Acid Disorders
- such as maple syrup urine
disease and tyrosinemia
Fatty Acid Disorders
- such as medium chain acyl
CoA dehydrogenase deficiency
Like for PKU, it is expected
that early diagnosis and treatment
of these conditions will lead to
improved outcomes. Patients with
metabolic diseases should be referred
to a facility which specializes
in the management of these conditions.
Two such centers in Louisiana include
the Children's Hospital/ LSU Metabolic
and PKU clinic and the Tulane Hayward
Dr. Mike Marble
LSU Dept. of Pediatrics
200 Henry Clay Ave.
New Orleans, La 70118
Tel: 504- 896- 9254
E- mail: firstname.lastname@example.org
to learn more:
Phenylketonuria: Screening and Management,
Report of the NIH Consensus Development
Conference on PKU odp.od.nih.gov/consensus/cons/113/113_intro.htm
National PKU News
National Coalition for
PKU and Allied Disorders
supplemental and comprehensive Newborn
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