Review of pediatric phenylketonuria: potential and limits of dietary and nutritional management and adjunctive therapies
Background: Balancing phenylalanine control and growth
Research into drug and gene therapies for pediatric phenylketonuria (PKU) is expanding, but a review reports that no drug therapy can yet universally replace dietary and nutritional management. Published in Nutrients, the paper is a nonsystematic review of dietary treatment, protein substitutes, challenges in maintaining treatment, and emerging therapies in children. It is not a new clinical trial or a direct comparison of treatments.
PKU is an autosomal recessive genetic disorder in which impaired phenylalanine hydroxylase (PAH) function disrupts the conversion of phenylalanine (Phe) to tyrosine. Untreated elevated blood Phe carries a risk of severe intellectual disability and seizures. Early detection and metabolic control are therefore the starting points of treatment.
Dietary management limits Phe accumulation while supplying the nutrients needed for growth. Because Phe is an essential amino acid, it is not eliminated completely; intake is adjusted to each person’s tolerance. Protein intake limited by restrictions on ordinary foods is supplemented with products such as Phe-free, amino acid-based substitutes. According to the review, most children and adolescents who adhered to their diets and received regular monitoring generally had adequate micronutrient status. However, insufficient intake of substitutes can raise the risk of nutritional deficiencies, so food restrictions and nutritional supplementation must be considered together.
Key findings: Different conditions for using substitutes and medicines
Casein glycomacropeptide (CGMP)-based substitutes derived from whey were considered as alternatives to amino acid-based products. They require amino acid supplementation to provide a complete protein source and also contain some Phe. In children, the effect of residual Phe on metabolic control must be considered; studies also did not consistently find superior taste or satiety.
Sapropterin, a synthetic form of the cofactor tetrahydrobiopterin (BH4), may help control Phe and ease dietary restrictions in patients who respond to BH4. Responsiveness must be confirmed before selecting this treatment. Studies of sepiapterin, a BH4 precursor, reported lower plasma Phe in carriers of both BH4-responsive and nonresponsive variants. This finding differs from that for sapropterin, but it does not mean that sepiapterin works for every patient or allows dietary treatment to be stopped.
Pegvaliase is an enzyme replacement therapy delivered by injection, using phenylalanine ammonia lyase (PAL) conjugated to polyethylene glycol. Clinical trials in adults reported lower Phe, while the treatment also carries risks of anaphylaxis and hypersensitivity reactions. The adolescent phase 3 PEGASUS trial described in the review involved 55 participants aged 12–17. Preliminary efficacy results were announced by the sponsor, but a peer-reviewed paper reporting the full results was not available when the review was written. Adult clinical evidence should therefore be distinguished from the preliminary adolescent announcement.
Implications and outlook: Gene-based approaches require assessment of durability and safety
Gene addition, which uses an adeno-associated virus (AAV) vector to deliver a functional PAH gene, and gene editing, which changes the DNA itself, are distinct approaches. Observations of lower Phe or restored PAH function in animals do not establish a permanent therapeutic effect in humans. The review also described a clinical trial of AAV gene addition, but did not present results from that trial.
In children in particular, liver cell proliferation may reduce the durability of expression from genes delivered by AAV. Immune responses to AAV can also limit repeat dosing. In some gene correction studies using homology-directed repair after DNA double-strand breaks, PAH function was only partly restored and effects varied substantially. These limitations should not be generalized to every form of gene editing.
For current care, the review presented an approach that addresses the ease of consuming substitutes, the cost and accessibility of low-protein foods, and the burden on caregivers together. Some nutritional studies had small samples and differed in their products and treatment approaches, making it difficult to conclude that a particular substitute is superior for all children. While the long-term potential of gene-based approaches is evaluated, nutritional support and regular monitoring remain central to treatment.
Source: Full text of the Nutrients review, DOI: 10.3390/nu18091347.
Phenylketonuria (PKU) is an autosomal recessive disorder characterised by an inborn error of phenylalanine (Phe) metabolism. Such errors are attributed to pathogenic gene variants causing phenylalanine hydroxylase (PAH) deficiency, impairing the hydroxylation of phenylalanine to tyrosine in the Phe metabolic pathway. This defect leads to plasma Phe concentrations above the normal range. If untreated, hyperphenylalaninemia can adversely affect brain function, leading to severe intellectual disability and seizures. Since 1969, the newborn dried blood spot test has remained the main method of early screening and diagnosis for PKU. The primary therapeutic management is a lifelong phenylalanine-restricted diet with the aim of decreasing plasma Phe levels. The recommended diet consists of avoiding high-protein foods such as meat, fish, eggs and nuts, and can be supplemented with high-protein medical formulas which are low in phenylalanine. Pharmacological interventions such as sapropterin, sepiapterin and pegvaliase can also be used as treatment adjuncts in patients with PKU. Currently, small-molecule inhibitors reducing renal phenylalanine reabsorption are being explored as a potential therapeutic intervention. Furthermore, novel gene-editing techniques are under evaluation as potential curative strategies, with preclinical studies showing promising results in correcting pathogenic phenylalanine hydroxylase variants. This non-systematic review synthesises current literature on the management of PKU, with a focus on dietary interventions and recommendations.
This review outlines an approach to pediatric PKU care that assesses blood Phe control alongside the nutrition needed for growth. For example, if Phe control becomes difficult in a child who does not consume enough protein substitute, clinicians can assess not only the degree of food restriction but also the product’s taste and how it is consumed, the family’s circumstances for purchasing food, and caregiver burden. Medicines may be considered as options for easing the dietary burden, depending on responsiveness and the population for which they are appropriate. Developers of medical foods should assess nutritional composition and sustained real-world consumption as well as low Phe content. However, this review is not a comparative trial for determining an individual patient’s prescription, and preclinical results for gene therapy do not support stopping current dietary management or monitoring.