Normalizing Diet in Individuals with Phenylketonuria | NDS – Dove Medical Press
Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism (IEM) caused by pathogenic variants in the phenylalanine hydroxylase (PAH) enzyme. PKU has a global prevalence of approximately 1:23,930 live births and, if untreated, leads to a toxic buildup of phenylalanine that can cause severe intellectual disability.1,2 In many countries, PKU is identified via newborn screening (NBS) and newborns are immediately started on medical nutrition therapy, consisting of a Phe-restricted diet supplemented with a Phe-free medical formula (also referred to as a medical food, amino acid mixture or protein substitute). With early treatment, individuals with PKU can have normal cognitive and physical development.3
While diet therapy is effective, adherence to the Phe-restricted diet is challenging, particularly for adolescents and adults.4,5 The nature of Phe neurotoxicity is very complex and still far from being fully understood. Studies have shown that high brain Phe concentrations may impact synthesis of neurotransmitters and cerebral proteins.6,7 High blood Phe may also influence the metabolism of myelin, increase the parameters of oxidative stress, and decrease the activity of enzymes involved in energy production.8 Research has further shown that even in early and well-treated adults, there may be persistent neurocognitive issues including depression, anxiety, ADHD, phobias, low self-esteem and social isolation/withdrawal, worsening the quality of life of the patients and their families.9,10 Further, many adults discontinue dietary therapy and/or are lost to follow up, highlighting the need for new therapies.11,12
Pegvaliase (PALYNZIQ™, BioMarin, Novato, CA) is a novel enzyme substitution therapy approved in 2018 by the US Food & Drug Administration (FDA) for use in adults with blood Phe >600 µmol/L on current therapy.13 It was subsequently approved by the European Medicines Agency (EMA) in 2019 for adolescents and adults aged 16 and over, also with blood Phe >600 μmol/L.14 Pegvaliase is administered by daily subcutaneous injection and degrades Phe via a PAH-independent pathway.15 In a randomized discontinuation trial, adults with PKU on pegvaliase showed significant decreases in plasma blood Phe while consuming relatively high amounts of intact protein.15 Currently, sapropterin dihydrochloride is the only other approved pharmacologic treatment for PKU, but not all patients are responsive, and a Phe restriction is typically still needed.2 Alternatively, individuals with PKU on pegvaliase are usually able to normalize their protein intake and, ideally, consume an unrestricted diet.16
Evidence and consensus-based recommendations have been described for the use of pegvaliase in clinical practice, including recommendations for the nutrition management of responders.16,17 However, there is limited literature related to the real-world nutrition management of individuals with PKU who have …….