U01.01.117 Phenylketonuria

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Learning Objectives

  • Explain the biochemical basis of Phenylketonuria (PKU) and the role of BH4.
  • Recognize the clinical presentation of untreated PKU, including the musty body odor and skin changes.
  • Identify the management strategies, including dietary restrictions and supplementation.
  • Understand the risks of maternal PKU on fetal development.

1. Pathophysiology and Genetics

PKU is an autosomal recessive disorder of aromatic amino acid metabolism. It is most commonly caused by a deficiency in Phenylalanine Hydroxylase (PAH). A less common but more severe form is caused by a deficiency in Tetrahydrobiopterin (BH4), which is the essential cofactor for PAH.

Because Phenylalanine cannot be converted to Tyrosine:

  • Tyrosine becomes essential: It must now be supplied by the diet.
  • Phenylalanine Accumulates: Excess phenylalanine is shunted into alternative pathways, creating Phenyl ketones (phenylacetate, phenyllactate, and phenylpyruvate).
  • Screening: Occurs 2–3 days after birth. It is normal at birth because the maternal enzymes handle the fetus’s phenylalanine levels in utero.

2. Clinical Findings

Classic symptoms are now rare in developed countries due to mandatory neonatal screening and early intervention.

  • CNS Effects: Intellectual disability, microcephaly, and seizures.
  • Skin/Pigmentation: Hypopigmented skin and eczema (due to decreased melanin synthesis from tyrosine).
  • Odor: A characteristic musty body odor caused by the phenyl ketones.

Activity

Memory Hook: PKU: Pale skin, Phenyl ketones (musty odor), and Pregnancy risks (maternal PKU).

3. Management and Maternal PKU

Treatment focuses on strict lifelong control of Phenylalanine intake.

Management Strategy Details
Dietary Modification \downarrow Phenylalanine and $Latex\uparrow$ Tyrosine. Avoid Aspartame (contains phenylalanine).
Supplementation BH4 (Sapropterin) may be used in patients with partial enzyme activity or BH4 deficiency.

Clinical Notes & Corrections:

  • Maternal PKU: High phenylalanine levels in a pregnant woman act as a teratogen. This “Phenylalanine embryopathy” causes microcephaly, intellectual disability, and congenital heart defects in the fetus, even if the fetus does not have PKU.
  • Safe Proteins: While Phenylalanine must be limited, Tyrosine must be supplemented via specific medical foods or high-tyrosine sources like soy, chicken, and milk (under strict supervision).

Activity