Phenylketonuria

Phenylketonuria (PKU) is an autosomal recessive disorder due to deficiency of phenylalanine hydroxylase (PAH, 12q23.2), the enzyme that converts phenylalanine (Phe) to tyrosine. Accumulating Phe is neurotoxic and competes with other large neutral amino acids for transport across the blood brain barrier, damaging myelin and neurotransmitter synthesis. Incidence is about 1 in 10,000 to 15,000, higher in Turkey and Ireland and lower in Africans.

Forms are graded by untreated Phe: classic PKU (above 1,200 micromol/L), moderate PKU (900 to 1,200), mild PKU (600 to 900), mild hyperphenylalaninaemia (120 to 600), and BH4-deficient hyperphenylalaninaemia from defects of tetrahydrobiopterin synthesis or recycling (1 to 2%).

• Untreated: normal at birth, then developmental delay from 3 to 6 months, severe intellectual disability (IQ below 50), seizures, microcephaly, behavioural problems (hyperactivity, autistic features, aggression), eczema, hypopigmentation (fair skin, blue eyes, light hair), a musty or mousy odour (phenylacetic acid), tremor and spasticity
• Treated but poorly controlled: reduced executive function, ADHD, anxiety, depression, lower IQ
• Maternal PKU: fetal exposure to high maternal Phe (above 360 micromol/L) causes microcephaly, intellectual disability, congenital heart defects, intrauterine growth restriction and miscarriage

• Newborn screening by tandem mass spectrometry on a dried blood spot at 24 to 72 hours (Phe above 120 micromol/L or Phe:tyrosine ratio above 2), confirmed by quantitative plasma amino acids.
• BH4 disorders are separated by dihydropteridine reductase activity in dried blood, urinary and blood pterins, and a BH4 loading test (20 mg/kg orally).
• PAH gene analysis (over 1,000 variants) predicts phenotype and BH4 responsiveness.

• Phe restricted diet started as early as possible, ideally within the first 10 days of life.
• Natural protein is restricted to tolerance (usually 250 to 500 mg/day of Phe in infants; tolerance in children and adults ranges 200 to 1,000 mg/day). Supplement with Phe free amino acid formula (total protein equivalent 0.8 to 1.2 g/kg/day) enriched with tyrosine, vitamins and minerals, plus special low protein foods.
• Target blood Phe 120 to 360 micromol/L up to age 12 years and throughout pregnancy, and 120 to 600 micromol/L above age 12. Monitor Phe weekly in infancy and monthly in later childhood
• Sapropterin dihydrochloride (BH4, a PAH cofactor) 5 to 20 mg/kg/day orally with food in the morning: a trial for 1 to 4 weeks; responders show at least a 30% fall in Phe; effective in mild to moderate PKU and allows relaxation of the diet
• Pegvaliase (phenylalanine ammonia lyase) subcutaneously, titrated from 2.5 mg weekly to a maintenance of 20 to 60 mg daily, for adults with Phe persistently above 600 micromol/L; anaphylaxis risk (prescribe auto injectable adrenaline, supervise early doses) and arthralgia; 50 to 60% can eventually eat a normal diet
• Large neutral amino acid supplementation (adults who are not pregnant) and glycomacropeptide based foods
• Pregnancy: Phe 120 to 360 micromol/L before conception and throughout, with the diet started at least 3 months before conception
• Adult follow up is lifelong: neuropsychological assessment, nutritional review (vitamin B12, selenium, omega-3 fatty acids, iron, vitamin D, zinc) and bone density
• BH4 deficiencies: BH4 replacement and neurotransmitter precursors (levodopa with carbidopa, 5-hydroxytryptophan) and folinic acid
• Gene and mRNA therapies are under trial
• Genetic counselling: 25% recurrence risk; carrier testing and prenatal diagnosis are available