Table of Contents
Overview – Phenylketonuria
Phenylketonuria is a rare autosomal recessive inborn error of metabolism in which phenylalanine accumulates due to a deficiency of phenylalanine hydroxylase. If left untreated, it causes irreversible neurological damage. Early diagnosis through newborn screening and strict dietary management are critical to prevent severe developmental outcomes. Understanding this condition is essential for both paediatrics and genetics in final-year exams and clinical practice.
Definition
- Phenylketonuria (PKU) is a genetic metabolic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase.
- Leads to accumulation of phenylalanine and its toxic by-products in the bloodstream and brain.
Aetiology
- Mode of inheritance: Autosomal recessive.
- Both parents must be carriers for the offspring to be affected.
Pathogenesis
- The phenylalanine hydroxylase enzyme is defective or absent.
- Normally, this enzyme converts phenylalanine → tyrosine.
- Without this pathway:
- Phenylalanine accumulates.
- Alternative pathways produce toxic metabolites that accumulate in the blood and brain.
Clinical Features
- Symptoms typically appear within the first few months of life if untreated.
- Key features include:
- “Mousy” odour to urine (due to phenylacetate)
- Vomiting
- Irritability
- Eczematous rash
- Microcephaly
- Developmental delay
- Severe intellectual disability (if diagnosis is delayed)
Diagnosis
- Heel-prick test (newborn screening):
- Conducted on day 2–5 of life.
- Measures phenylalanine levels in blood.
Management
- Lifelong dietary restriction of phenylalanine (low-protein diet).
- Avoid meat, dairy, nuts, eggs, and artificial sweeteners (e.g. aspartame).
- Monitor blood phenylalanine levels regularly.
- Essential for maintaining normal growth and development.
- Some phenylalanine is still needed for protein synthesis and neurotransmitter production.
Complications
- Maternal PKU syndrome:
- Elevated maternal phenylalanine crosses placenta → interferes with fetal brain development.
- Results in intellectual disability, microcephaly, and congenital heart defects in the offspring.
- Even mothers with well-managed PKU as children must maintain tight metabolic control during pregnancy.
Genetic Consideration: Compound Heterozygosity
- Compound heterozygotes have two different mutations in the same gene.
- Both alleles are defective but not identical.
- In autosomal recessive disorders, compound heterozygotes are typically affected.
- Phenotypic severity may vary depending on the residual activity of each mutant allele.
Summary – Phenylketonuria
Phenylketonuria is a preventable cause of severe neurodevelopmental delay, caused by autosomal recessive mutations in the phenylalanine hydroxylase gene. Early newborn screening and a strict phenylalanine-restricted diet are critical for avoiding complications such as intellectual disability and maternal PKU syndrome. For a broader context, see our Genetics & Cancer Overview page.