Phenylketonuria

Definition

• Phenylketonuria (PKU) is an autosomal recessive inborn error of amino acid metabolism.
• Caused by a deficiency of the hepatic enzyme Phenylalanine Hydroxylase (PAH).
• Results in accumulation of phenylalanine (Phe) and deficiency of tyrosine.

Etiology and Pathophysiology

• Enzyme Defect:
  • Classic PKU (>98%): Severe deficiency of PAH enzyme activity.
  • BH4 Deficiency (1-3%): Defects in synthesis or recycling of the cofactor Tetrahydrobiopterin (BH4) (e.g., 6-pyruvoyl-tetrahydropterin synthase deficiency).
• Metabolic Consequences:
  • Phe Accumulation: Neurotoxic; saturates Large Neutral Amino Acid (LNAA) transporters, inhibiting brain uptake of other essential amino acids (Tyr, Trp).
  • Tyrosine Deficiency: Becomes an essential amino acid; impairing synthesis of dopamine, norepinephrine, epinephrine, and melanin.
  • Alternative Pathway: Excess Phe converts to phenylketones (phenylpyruvate, phenylacetate) excreted in urine.
    

Classification (Based on Plasma Phe Levels)

• Classic PKU: Plasma Phe >20 mg/dL (>1,200 µmol/L) on unrestricted diet.
• Mild PKU: Plasma Phe 10–20 mg/dL (600–1,200 µmol/L).
• Mild Hyperphenylalaninemia (HPA): Plasma Phe 2–10 mg/dL (120–600 µmol/L).

Clinical Features

Infants are normal at birth (placental clearance of Phe).

• Untreated Classic PKU:
  • CNS: Profound intellectual disability (IQ <35 in 50-70% if untreated), microcephaly, developmental delay.
  • Neurological: Seizures (25%), spasticity, hyperreflexia, tremors.
  • Behavioral: Hyperactivity, autistic features, aggression, rhythmic rocking.
  • Dermatological: Hypopigmentation (fair skin, blond hair, blue eyes) due to reduced melanin; seborrheic/eczematoid rash.
  • Odor: "Mousey" or "musty" body odor (due to phenylacetic acid).
  • Gastrointestinal: Vomiting in early infancy (often misdiagnosed as pyloric stenosis).

Investigations

• Newborn Screening (Universal):
  • Method: Tandem Mass Spectrometry (TMS).
  • Timing: 24–48 hours of life (after protein feeding to reduce false negatives).
  • Target: Elevated Phe and increased Phe:Tyrosine ratio.
• Confirmatory Testing:
  • Quantitative Plasma Amino Acids: Elevated Phe, low/normal Tyr.
  • BH4 Deficiency Screen: Mandatory for all HPA. Measure urine/blood pterins (neopterin, biopterin) and DHPR activity.
  • Molecular Genetics: PAH gene sequencing (98% cases) or BH4 pathway genes (PTS, QDPR, GCH1).
  • BH4 Loading Test: Oral sapropterin reduces Phe by >30% in responsive variants.

Management

1. Dietary Management (Standard of Care)

• Indication: Start immediately if Phe >6–10 mg/dL (>360–600 µmol/L).
• Principles:
  • Restriction: Restrict natural protein (meat, dairy, eggs).
  • Supplementation: Phe-free medical formula containing Tyrosine, vitamins, and minerals.
  • Duration: "Diet for Life". Discontinuation in adulthood leads to executive dysfunction and emotional lability.
• Targets: Maintain plasma Phe 2–6 mg/dL (120–360 µmol/L) throughout life.

2. Pharmacotherapy

• Sapropterin (Kuvan): Synthetic BH4. Effective in BH4-responsive PKU; allows increased dietary protein tolerance.
• Pegvaliase (Palynzi): Injectable enzyme substitution (PEGylated phenylalanine ammonia-lyase) for adults with uncontrolled levels; converts Phe to harmless metabolites.
• Large Neutral Amino Acids (LNAA): Competitively inhibit Phe transport into the brain.

3. Maternal PKU Syndrome

• Risk: High maternal Phe is teratogenic.
• Fetal Effects: Microcephaly, Intellectual Disability, Congenital Heart Disease, IUGR.
• Protocol: Strict control (Phe 2–6 mg/dL) required pre-conception and throughout pregnancy.

Prognosis

• Early Treated: Normal intelligence and lifespan.
• Late Treated: Permanent cognitive deficit; treatment may improve behavior/seizures but cannot reverse brain damage.