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/