Classic Phenylketonuria , Metabolic Disorder, Amino acid disorder Screening -Infant

Classic Phenylketonuria , Metabolic Disorder, Amino acid disorder Screening -Infant

Classic Phenylketonuria , Metabolic Disorder, Amino acid disorder Screening

Summary of Recommendation and Evidence

Population

Recommendation

Grade
(What's This?)

Screening of both Genders

The genetic screening for Classic Phenylketonuria is recommended.

B

Classic Phenylketonuria (PKU) is an inborn error of metabolism that is detectable during the first days of life with appropriate blood testing (e.g., during routine neonatal screening). PKU is characterized by absence or deficiency of an enzyme (phenylalanine hydroxylase) that is responsible for processing the essential amino acid phenylalanine. 

OVERVIEW

Deficiency of phenylalanine hydroxylase (PAH), the enzyme responsible for converting phenylalanine to tyrosine, results in accumulation of phenylalanine (Phe) with toxic effects on brain development.

SCREENING

Finding

Elevated phenylalanine, elevated phenylalanine/tyrosine ratio

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=100%; specificity=99.95%

PREVALENCE

The incidence of PKU in the U.S. is approximately 1:23,000 births, although in the African-American population, incidence is about 1:50,000.

INHERITANCE

PKU is inherited in an autosomal recessive manner. It affects both boys and girls equally.

MATERNAL & FAMILY HISTORY

Benign forms of PKU can present with minimal elevations of phenylalanine levels (maximal plasma phenylalanine <360 micromolar), cause no symptoms, and require no therapy. Mild forms of phenylketonuria can present with slightly increased phenylalanine levels (maximal plasma phenylalanine 360-1000 micromolar), are usually easy to control with diet, and respond to therapy with sapropterin. Yet, children born to women with PKU are at risk for "maternal PKU" because high levels of phenylalanine are teratogenic.

Elevated phenylalanine levels can be caused by defects in the synthesis or recycling of tetrahydrobiopterin, an essential co-factor of phenylalanine hydroxylase. Since tetrahydrobiopterin is also a cofactor of other enzymes involved in neurotransmitter synthesis, at-risk patients need to be identified as soon as possible to start appropriate therapy.

PRENATAL TESTING

DNA testing by amniocentesis or CVS

CLINICAL CHARACTERISTICS

With treatment by early introduction and maintenance of special diet, normal IQ and development can be expected. Without treatment, patients with classic PKU have no symptoms at birth, but usually develop them by 6 months of age. 

Initial symptoms may include:

  • A musty or "mousy" odor of the body and urine
  • Developmental delays in sitting, crawling, and standing
  • Microcephaly

 

If patients remain untreated they may develop:

  • Decreased skin and hair pigmentation (due to lack of tyrosine)
  • Eczema
  • Seizures
  • Profound mental retardation

EARLY SIGNS

Different forms of phenylketonuria vary in their severity of signs. Classic phenylketonuria (PKU) is the most severe form. Babies with PKU usually seem healthy at birth. Signs of PKU begin to appear around six months of age.

Signs of classic PKU include:

  • Irritability
  • Seizures (epilepsy)
  • Dry, scaly skin (known as eczema)
  • “Musty” or "mouse-like” body odor
  • Pale hair and skin
  • Developmental delays

Many of these signs may occur when your baby eats foods that his or her body cannot break down. They can be triggered by long periods of time without eating, illnesses, and infections.

CAUSES

When we eat food, enzymes help break it down. Some enzymes break down protein into its building blocks, called amino acids. Other enzymes break down these amino acids. In classic phenylketonuria (PKU), the enzyme phenylalanine hydroxylase (PAH) is not working correctly.

PAH’s job is to break down the amino acid phenylalanine. Babies with PKU either do not make enough or make non-working PAH. When PAH does not work correctly, the body cannot break down phenylalanine and it builds up in the blood. Everyone has some phenylalanine in their blood, but high levels can be toxic.

PKU is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for PKU, one from each parent, in order to have the condition. The parents of a child with an autosomal recessive condition each carry one copy of the non-working gene, but they typically do not show signs and symptoms of the condition. While having a child with PKU is rare, when both parents are carriers, they can have more than one child with the condition.  

TREATMENT

Dietary Treatment

Your baby will need to be on a restricted diet to avoid phenylalanine, a building block of proteins that individuals with phenylketonuria (PKU) cannot break down. Phenylalanine is found in all foods that contain protein and also in artificial sweeteners. The dietary treatment for PKU includes specific medical foods: a phenylalanine-free medical formula that is given regularly throughout the day, as well as foods modified to be low in protein. A registered dietician will help you plan a low-protein diet, that avoids high levels of phenylalanine, and gives your baby the nutrients he or she needs for healthy growth.

Supplements and Medications

Your baby’s doctor may prescribe a low protein formula.  As your baby gets older, their doctor may prescribe a medication that contains BH4. BH4 is a substance naturally produced by the body, but your baby’s body might not make enough of it. Taking BH4 supplements may help break down the phenylalanine that builds up. Your baby’s doctor will need to write a prescription for these supplements. BH4 does not work in everyone with PKU.  A trial period on the drug with evaluation by a physician is necessary.

EXPECTED OUTCOMES

If phenylketonuria (PKU) is detected at birth, early treatment can prevent the signs of the condition mentioned in the Early Signs section. This is why it is so important to screen for PKU at birth.

If babies start treatment several weeks after birth, some signs of PKU can be avoided.

If treatment is started after six months of age, babies are at risk for severe intellectual disabilities.

It is important to treat PKU, even if treatment is started after noticing signs and symptoms, in order to help prevent permanent brain damage.