Similarities and differences in key diagnosis, treatment, and management approaches for PAH deficiency in the United States and Europe

Abstract

Background Individuals with phenylalanine hydroxylase (PAH) deficiency lack an enzyme needed to metabolize the amino acid, phenylalanine. This leads to an increase of phenylalanine in the blood, which is associated with changes in cognitive and psychological functioning. Skilled clinical management is essential for preventing complications and providing comprehensive care to patients. In the last decade, the American College of Genetics and Genomics (ACMG) and a group of European experts developed separate guidelines to provide recommendations for the management and care of persons with PAH deficiency. The purpose of this paper was to compare and contrast these guidelines in order to understand the different approaches to PAH deficiency care. Methods We examined the procedures used to develop both guidelines, then evaluated key areas in PAH deficiency care which included screening, diagnostic approaches, dietary treatment (initiation and duration), ongoing phenylalanine level/ nutritional monitoring, neurocognitive screening, adherence issues in treatment, and special populations (women and maternal PKU, late or untreated PAH deficiency, and transitioning to adult services). We conducted a scoping review of four key topics in PAH deficiency care to explore recent research studies performed since the publication of the guidelines. Results The ACMG and European expert group identified limited numbers of high quality studies to use as evidence for their recommendations. The ACMG and European guidelines had many similarities in their respective approaches PAH deficiency care and recommendations for the diagnosis, treatment, and management for persons with PAH deficiency. There were also a number of differences between the guidelines regarding the upper range for phenylalanine levels in adolescents and adults, the types of instruments used and frequency of neuropsychiatric examinations, and monitoring of bone health. Treatment adherence can be associated with a number of challenges, such as aversions to medical foods and formulas, as well as factors related to educational, social, and psychosocial issues. From the scoping review, there were many new studies addressing issues in treatment and management including new research on sapropterin adherence and increased dietary protein tolerance and pegvaliase on the reduction in phenylalanine levels and hypersensitivity reactions. Conclusions In the last decade, ACMG and European experts developed comprehensive guidelines for the clinical management of phenylalanine hydroxylase deficiency. The guidelines offered background and recommendations for clinical care of patients with PAH deficiency throughout the lifespan. New research evidence is available and updates to guidelines can keep pace with new developments. Evidence-based guidelines for diagnosis and treatment are important for providing expert care to patients.

A low abundance of genus Bacteroides in gut microbiota is negatively correlated with blood phenylalanine levels in Uygur patients with phenylketonuria

“…Phenylketonuria (PKU; OMIM 261600) is a classical metabolic disorder characterized by high-plasma phenylalanine (Phe) concentration owing to pathogenic variations in the PAH gene. The first line of treatment is a life-long low-Phe diet, a lack of which results in serious neurocognitive deficits, mental health issues, and behavioral concerns (1). However, despite several decades of research, unresolved challenges remain in relation to this genetic metabolic disorder.…”

Protein substitutions as new-generation pharmanutrition approach to managing phenylketonuria

“…In this approach, natural protein sources are limited in the diet based on individual Phe tolerance, and daily protein requirements are supported by amino acid mixtures that do not contain Phe. 7) These patients do not consume primary animal protein sources, such as meat, milk, dairy products, eggs, or vegetable sources (such as oilseeds and legumes), that is, foods with high Phe content. As a natural protein source, foods containing low amounts of protein, such as vegetables and fruits, are preferred, and because of the decrease in blood Phe that results from the diet, while the use of cereals is allowed provided that they are used in limited quantities.…”

A preclinical biosensor for detecting phenylalanine photometrically in plasma and whole blood samples

“…Regarding recommended L-Phe values for follow-up checks, they vary slightly between American and European guidelines. However, it is generally agreed that L-Phe values below 360 mol/L for children less than 12 years of age and women before conception and pregnancy, or below 600 umol/L for adolescents/adults, are considered safe (European guidelines (Lowe, DeLuca, and Arnold 2020)). Furthermore, L-Phe being an essential amino acid for average growth and development, values < 120 mol/L are not recommended for PKU patient in long-term follow-ups.…”