Phenylketonuria (PKU): Pathogenesis and clinical findings

Phenylketonuria (PKU): Pathogenesis and clinical findings
Authors: Hamna Tariq Reviewers: Chandan Kaur Bal Nicola Adderley Rebecca Sparkes* * MD at time of publication
PAH – phenylalanine hydroxylase BH4 – tetrahydrobiopterin
Phe – phenylalanine
Tyr – tyrosine
LAT-1 – L-amino acid transporter 1 LNAA – large neutral amino acids NT – neurotransmitter
Biallelic mutations in PAH gene on chromosome 12q23.2
Loss of activity/deficiency of PAH
Inability to convert Phe to Tyr
Buildup of Phe and its metabolites
↑ transport of Phe via LAT-1 at the blood brain barrier
Phe outcompetes LNAA for binding sites on LAT-1
↓ LNAA transport
↓ cerebral protein synthesis and ↓ NT synthesis
White matter lesions, oxidative damage, hypomelination & demyelination
Sources of Phe
Dietary protein
Breakdown into amino acids
↓ Tyr and derivatives
↓ melanin
Fair skin and hair
Endogenous recycling of amino acid stores
Phe oxidized to phenylacetate
Musty odor to urine, sweat and breath
• Autosomal recessive inborn error of metabolism; clinical severity depends on residual PKU activity
• This slide denotes clinical features of classical PKU in untreated patients. Symptoms develop within a few months of birth only if untreated.
• PAH, using a BH4 cofactor, converts Phe to tyrosine, which is necessary to produce epinephrine, norepinephrine, dopamine and melanin. (Rare inherited disorders of BH4 synthesis/recycling cause elevated Phe and neurologic symptoms.)
• PKU is screened for at birth in most developed nations.
• In early-diagnosed, continuously treated patients, ID,
microcephaly and neurologic features are not expected, but there is still an increased incidence of behavioral, emotional and social problems
↑ brain [Phe]
Behavioral, emotional & social problems (ADHD, mood disorders, aggression, ↓ self-esteem, ↓ social competency, ↓ autonomy)
Intellectual disability
(↓ language, memory & learning skills, executive function, IQ, school performance)
Neurological findings (tremor, shaking, seizures, poor coordination)
Sign/Symptom/Lab Finding
Published November 19, 2018 on