School of Medicine

Department of Genetics

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:

How to learn more: 
Phenylketonuria: Screening and Management, Report of the NIH Consensus Development Conference on PKU

National PKU News

National Coalition for PKU and Allied Disorders

Regarding supplemental and comprehensive Newborn Screening: