Phenylketonuria (PKU) Workup

Updated: Nov 23, 2020
  • Author: Eric T Rush, MD, FAAP; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Approach Considerations

Older textbooks and protocols occasionally called for phenylalanine-loading studies to help determine if a child with phenylketonuria (PKU) still required phenylalanine restriction after 1 or more years; however, as the treatment range for phenylalanine levels has decreased, these studies generally have been abandoned.

A qualified laboratory should measure plasma phenylalanine and tyrosine. A qualified laboratory should perform blood and urine analysis of biopterin and neopterins in order to rule out defects of biopterin synthesis or recycling. DNA mutation analysis is adjunctive and may be helpful in some cases, although is not required for diagnosis.

Prenatal diagnosis is available but rarely used because the disorder is so treatable. Prenatal diagnosis can be accomplished by DNA mutation analysis following chorionic villous sampling or amniocentesis.


Laboratory Studies

Perform screening on blood samples during the first week of life. Wide variability in phenylalanine concentrations in a 24-hour period in children with PKU may necessitate repeat screening. Screening for PKU involves the following:

  • Determination of phenylalanine levels, the standard amino acid analysis done by means of ion exchange chromatography or tandem mass spectrometry
  • The Guthrie test as a bacterial inhibition assay; formerly used, now being replaced by tandem mass spectrometry

Further measures may be indicated, depending on the results of screening:

  • Abnormal newborn screening results require immediate follow-up in accordance with local regulations.
  • Less-prominent elevations of phenylalanine or ambiguous results may require repeat screening.
  • More significant elevations still require definitive testing and referral to a metabolic treatment facility experienced with PKU.
  • Late diagnoses are usually made during amino acid analysis of individuals who are developmentally abnormal.

Results of urine tests (ie, ferric chloride test) may be negative in the first month of life and are rarely used in current practice. It is important to measure erythrocyte dihydropteridine reductase and urine neopterin and biopterin.

Follow nutritional adequacy on a regular basis because deficiencies of iron, vitamins, selenium, protein, essential fatty acids, and other nutrients have been reported in patient with treated PKU.


Magnetic Resonance Imaging

Cranial magnetic resonance imaging studies may be indicated in older individuals who have poor dietary control and are experiencing deficits in motor or cognitive function, or when there are behavioral, cognitive, or psychiatric concerns. White matter changes are common and may have some reversibility with improved diet and reduced phenylalanine levels. These areas appear to be related to both higher phenylalanine levels in the blood and brain and to poorer cognitive outcome. In terms of volume loss, the most severely affected brain structures are the cerebrum, the corpus callosum, the hippocampus, and the pons. [4]

Preliminary indications suggest that brain phenylalanine levels can be measured by means of cranial magnetic resonance spectroscopy (MRS) and that these levels may be more predictive of outcome than blood phenylalanine levels are; however, this work is done in only a few centers, and there is some controversy surrounds whether such state-of-the-art technology is useful.