Phenylketonuria and Other Metabolic Diseases: Clinical, Genetic and Newborn Screening Aspects
Dr. Michael Marble
I. Phenylketonuria (PKU)
What is PKU?
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.
Metabolic 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 of neurotransmitters.
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.
What causes PKU?
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 have PKU.
How 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.
If 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.
How 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.
What 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 should be life-long.
What 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 up 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, R.D).
What 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.
What 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 3 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
What is newborn
screening and what is its purpose?
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.
Who 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 born.
How 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.
What 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 the prevention of the above symptoms. Biotinidase
newborn screening is performed in Louisiana.
What is galactosemia?
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.
What developments
are on the horizon for newborn screening of metabolic
diseases?
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 acidemia
Amino Acid Disorders - such as maple syrup urine disease and tyrosinemia
Fatty Acid Disorders - such as medium chain acyl CoA dehydrogenase deficiency (MCAD)
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 Genetic Center.
Contact Information:
Tel: 504- 896- 9254
E- mail: mmarbl1@lsuhsc.edu
How 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
www.pkunews.org
National Coalition for PKU and Allied
Disorders
www.pku-allieddisorders.org
Regarding supplemental
and comprehensive Newborn Screening:
Neogen
www.neogenscreening.com
Baylor
www.baylorhealth.com/newbornscreening/