U01.01.109 Phenylketonuria

Phenylketonuria (PKU) is a metabolic disorder caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) or due to a deficiency in the cofactor tetrahydrobiopterin (BH4) (malignant PKU). This condition results in an inability to metabolize phenylalanine, leading to the accumulation of phenylalanine and its byproducts (phenyl ketones).

Key Points:

Pathophysiology:
- PAH or BH4 deficiency leads to impaired conversion of phenylalanine to tyrosine.
- Tyrosine becomes an essential amino acid.
Clinical Features:
- Accumulation of phenylalanine and phenyl ketones causes intellectual disability, seizures, and growth retardation.
- Affected individuals often have a musty body odor due to phenyl ketones.
- Other findings: fair complexion, eczema.
Inheritance:
- Autosomal recessive disorder.
- Incidence: ~1:10,000 live births.

Clinical Findings and Diagnosis

Feature	Details
Intellectual disability	Due to neurotoxic effects of elevated phenylalanine levels.
Growth retardation	Impaired physical development.
Seizures	Common due to neurotoxicity.
Fair complexion	Reduced melanin synthesis (tyrosine is a precursor to melanin).
Eczema	Chronic skin inflammation.
Musty body odor	Result of accumulated phenyl ketones (Phenylacetate, Phenyllactate, Phenylpyruvate).
Screening	Conducted 2–3 days after birth; results may appear normal at birth due to maternal enzyme activity.

Treatment

Dietary Management

Reduce phenylalanine intake: Eliminate high-protein foods and aspartame (contains phenylalanine).
Supplement tyrosine: Tyrosine becomes essential due to deficient PAH or BH4.

Pharmacologic Treatment

BH4 supplementation: Useful in cases of BH4 cofactor deficiency (malignant PKU).

Maternal PKU

Pathophysiology

Occurs when a mother with PKU does not adhere to dietary restrictions during pregnancy.

Findings in the Infant

Feature	Details
Microcephaly	Small head circumference.
Intellectual disability	Neurotoxic effects on fetal brain development.
Growth retardation	Poor intrauterine development.
Congenital heart defects	Increased risk due to teratogenic effects of phenylalanine.

Key Biochemical Concepts

Phenyl ketones (elevated in PKU):
- Phenylacetate
- Phenyllactate
- Phenylpyruvate
Aromatic amino acid metabolism disorder:
- Results in distinctive musty body odor.

Points to Remember

PKU is an autosomal recessive disorder of phenylalanine metabolism.
Tyrosine becomes essential in PKU due to impaired phenylalanine hydroxylation.
Early detection through neonatal screening is crucial for preventing intellectual disability.
Patients must avoid phenylalanine-containing foods, including the artificial sweetener aspartame.
Maternal PKU requires strict dietary control during pregnancy to avoid fetal complications.

Bibliography

Nelson, D. L., & Cox, M. M. Lehninger Principles of Biochemistry.
UpToDate: “Phenylketonuria (PKU): Pathophysiology and Management.”
National Institute of Health (NIH): Phenylketonuria Information.

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