What Causes PKU?

PKU, also known as PAH deficiency, is an inborn error of metabolism that occurs when a person inherits two nonworking, or mutated, copies of the phenylalanine hydroxylase (PAH) gene.

The genetics of PKU

Genes are present in every cell in the body. They provide the blueprint for each trait we have, such as eye color and height.

Genes also carry the instructions to make the enzymes our bodies need to break down amino acids such as Phe into building blocks. These building blocks are then used to make new enzymes, cells, tissues, and organs. In genetic diseases, some genes have mutations, or faulty instructions, which make enzymes that do not work well (or at all).

PKU is caused by mutations in the PAH gene

Every individual receives two copies of a gene, one from each parent. For a person to have PKU, both the mother and the father must pass on the mutated phenylalanine hydroxylase (PAH) gene.

Each parent is a “carrier” because he or she carries one copy of the mutated, disease­–causing gene and one copy of the nonmutated gene. People who are carriers of the PKU gene have no known symptoms.

To have PKU, a person must get two mutated genes, one from each parent.

Approximately 1 in 50 to 60 of us has a mutated PAH gene, yet only 1 in 10,000 to 15,000 people in the United States inherits two mutated PAH genes—one from each parent—which is what causes PKU.1,2

What are the different levels of PKU severity?

People with PKU can have different levels of PAH deficiency, resulting in differences in Phe levels and symptoms. Different PKU levels are sometimes classified as classic PKU, moderate or variant PKU, mild PKU, or hyperphenylalaninemia.3

Based on blood Phe levels at diagnosis, there are 4 levels of PKU severity3:

  • Hyperphenylalaninemia, with Phe levels that are slightly above normal range: 120-600 µmol/L (2-10 mg/dL)
  • Mild, with the lowest blood Phe levels: 600-900 µmol/L (10-15 mg/dL)
  • Moderate or variant, with blood Phe levels somewhere in the middle: 900-1200 µmol/L (15-20 mg/dL)
  • Severe or “classic” PKU, with extremely high blood Phe levels: >1200 µmol/L (20 mg/dL)

Because the effects of PKU are based on these varying levels of PAH deficiency, recent guidelines have started referring to PKU as PAH deficiency, which better represents the spectrum of disease severity.4

In PKU, blood Phe levels can be up to 60 times greater than normal blood Phe levels, which average about 1 mg/dL.4

Checking blood Phe levels is an important part of managing PKU. Gaining and maintaining control of blood Phe levels from infancy through adulthood will help protect the health of your brain now and for the rest of your life.

Current treatment guidelines recommend maintaining Phe levels between 120-360 µmol/L (2-6 mg/dL) for life.4



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References: 1. ACOG Committee Opinion No. 449. Maternal phenylketonuria. Obstet Gynecol. 2009;114(6):1432-1433.
2. Guldberg P, Rey F, Zschocke J, et al. A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet. 1998;63(1):71-79. 3. Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376(9750):1417-1427. 4. Vockley J, Andersson HC, Antshel KM, et al; for the American College of Medical Genetics and Genomics Therapeutic Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16(2):188-200.