Phenylketonuria

PKU is caused by a mutation in each copy of the gene for phenylalanine hydroxylase (PAH) on chromosome 12. Both parents are carriers of a mutant gene, which in a single copy has no clinical consequences. Several hundred different mutations in the PAH locus have been described, with 6 accounting for most of the disease-causing alleles in Europeans and Asians.[3]Scriver CR, Kaufman S. The hyperphenylalaninemias: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly SW, et al, eds; Childs B, Kinzler KW, Vogelstein B, assoc eds. The metabolic and molecular bases of inherited disease. 8th ed. New York, NY: McGraw-Hill; 2001:1667-1724.

Mutations in the gene for phenylalanine hydroxylase (PAH) result in either failure to produce a PAH enzyme or production of an enzyme with decreased catalytic activity. This leads to an elevation of the blood phenylalanine (phe) level and to increased transport of phe into the brain. Phe toxicity is thought to be a direct cause of neurotoxicity in PKU. Neurotransmitter deficiency and decreased protein synthesis in the brain may be other mechanisms of neurotoxicity, related to decreased tyrosine and competition at the blood brain barrier.[4]Burton BK, Adams DJ, Grange DK, et al. Tetrahydrobiopterin therapy for phenylketonuria in infants and young children. J Pediatr. 2011 Mar;158(3):410-5. http://www.ncbi.nlm.nih.gov/pubmed/20884009?tool=bestpractice.com Chronic elevations of blood phe in infancy and early childhood, beyond a certain threshold, result in abnormal myelination, small brain size, seizures, and diminished IQ. The magnitude of these adverse effects is related to the extent and duration of blood phe elevation, which is a function of the severity of the enzymatic defect and the extent of metabolic control in a treated patient. Inhibition of the enzyme tyrosinase by elevated phe levels leads to decreased melanin synthesis in an untreated patient, resulting in hypopigmentation. An acute rise in blood phe in a treated patient with PKU later in life may result in measurable cognitive and behavioral abnormalities as well as MRI abnormalities that may be reversible with control of the blood phe level. If the elevated blood phe persists for a longer duration, irreversible chronic toxicity may occur and manifest with neuropsychiatric symptoms such as anxiety, depression, phobias, attentional disorders, and defects in executive functioning. 

NIH consensus development statement[1]National Institutes of Health Consensus Development Panel. National Institutes of Health consensus development conference statement: phenylketonuria - screening and management. 2000 [internet publication]. http://consensus.nih.gov/2000/2000Phenylketonuria113html.htm

Divided PKU into:

• Classical PKU: associated with high levels of blood phenylalanine (phe), typically >20 mg/dL, and a complete absence or profound deficiency of phenylalanine hydroxylase activity

• Non-PKU hyperphenylalaninemia: defined as a lower elevation of blood phe.

Informal classification in common practice

Although there is uniform agreement on the definition of classical PKU, many terms are used in clinical practice to describe patients with lesser elevations of blood phe.

Classical PKU: blood phe on unrestricted diet >20 mg/dL

• NonPKU hyperphenylalaninemia:

  • Mild-to-moderate or nonclassical PKU: blood phe on unrestricted diet above the threshold for triggering intervention but <20 mg/dL.

  • Benign hyperphenylalaninemia: blood phe on unrestricted diet above normal but below the threshold for triggering intervention. Typically the threshold is 6 mg/dL.

Patients who have hyperphenylalaninemia resulting from rare defects in tetrahydrobiopterin synthesis or recycling are excluded from this definition.