Glycomacropeptide (GMP) represents a good alternative protein source in Phenylketonuria (PKU). In a mouse model, it has been suggested to exert a prebiotic role on beneficial gut bacteria. In this study, we performed the 16S rRNA sequencing to evaluate the effect of 6 months of GMP supplementation on the gut microbiota of nine PKU patients, comparing their bacterial composition and clinical parameters before and after the intervention. GMP seems to be safe from both the microbiological and the clinical point of view. Indeed, we did not observe dramatic changes in the gut microbiota but a specific prebiotic effect on the butyrate-producer Agathobacter spp. and, to a lesser extent, of Subdoligranulum. Clinically, GMP intake did not show a significant impact on both metabolic control, as phenylalanine values were kept below the age target and nutritional parameters. On the other hand, an amelioration of calcium phosphate homeostasis was observed, with an increase in plasmatic vitamin D and a decrease in alkaline phosphatase. Our results suggest GMP as a safe alternative in the PKU diet and its possible prebiotic role on specific taxa without causing dramatic changes in the commensal microbiota.

Phenylketonuria (PKU) management aims to control phenylalanine (Phe) intakes. In newborns and infants this implies possible titration of Human milk (HM) with supplementation of Phe-free formula. HM benefits, better if prolonged, are well known in healthy populations, suggesting it may be used in PKU patients. Despite that, the current literature does not define recommendations on how best perform it in such a population. The main purpose of this study was to evaluate nutrition approaches in newborns and infants affected by PKU and to define if differences can influence the duration of breastfeeding. Data from 42 PKU infants were reviewed. Of these, 67% were breastfed with the use of three different approaches. The type of approach used impacted the duration of breastfeeding, which was longer when using a pre-measured amount of Phe-free formula administered prior to HM. This is the first study to suggest a specific method for breastfeeding in PKU. Considering widely known breastfeeding benefits, both for patients and their mothers, our data should encourage adequate awareness on how to choose correct breastfeeding modalities.

Phenylketonuria (PKU) and Hyperphenylalaninemia (HPA) are inborn errors of metabolism (IEM) due to mutations in the PAH gene resulting in increased blood phenylalanine (Phe) concentrations. Depending on the Phe levels, a lifelong dietary intervention may be needed. During the COVID-19 pandemic, finding new strategies to ensure follow-up and metabolic control for such patients became mandatory and telehealth was identified as the most eligible tool to provide care and assistance beyond barriers. The aim of this study was to evaluate how telehealth use may have impacted disease follow-ups. Seven hundred and fifty-five patients affected by PKU/HPA in follow-ups at the Clinical Department of Pediatrics (San Paolo Hospital, ASST Santi Paolo e Carlo, University of Milan, Italy) were included in this study. The data regarding the used telehealth model, type of performed consultations and patients’ perspectives were retrospectively collected and analyzed after a one-year experience of implemented follow-ups. The results demonstrated that telehealth seemed to be a useful tool to improve the adherence to treatment and that it could guarantee continuous assistance and care beyond the surrounding epidemiological status. Patients expressed great satisfaction with the offered services and requested that they were implemented in standards of care on a long-term basis. Our results suggested the implementation of telehealth in the management guidelines for PKU/HPA patients.

Background/Objectives: The first 1000 days of life represent a critical window for growth and neurodevelopment, during which nutrition strongly influences brain development and metabolic programming. In phenylketonuria (PKU), dietary management is essential to prevent neurological impairment and later-life risk of non-communicable diseases (NCDs). This review examines current evidence on PKU from pregnancy through complementary feeding, highlighting the impact of nutritional strategies on neurodevelopmental and metabolic outcomes. Methods: This narrative review, following PRISMA guidelines, used a systematic search of PubMed and Scopus with defined PICO questions. Original research, reviews, and guidelines on PKU nutrition during the first 1000 days were included, emphasizing neurological and metabolic outcomes. Results: Articles addressed prenatal and postnatal factors in PKU. Optimised metabolic control in women with PKU is critical to prevent maternal PKU syndrome, reducing risks of miscarriage, congenital heart defects, microcephaly, and neurocognitive impairment. Pre-conception dietary management, frequent blood Phe monitoring, supplementation with Phe-free protein substitutes (PSs), micronutrients, and emerging pharmacological therapies support maternal and foetal health. Following newborn screening, early dietary treatment in infants with PKU maintains plasma Phe within safe ranges, promoting growth and neurodevelopment. Breastfeeding, combined with Phe-free infant PSs, is feasible, and complementary feeding should be introduced carefully. Frequent monitoring and tailored dietary adjustments, including second-stage PSs, support metabolic control, while data on gut microbiota remain limited. Conclusions: Early multidisciplinary interventions are crucial to optimise metabolic and neurodevelopmental outcomes during this window of opportunity. Further research is needed to address remaining gaps and optimise PKU management across the first 1000 days.

Background/Objectives: Phenylketonuria (PKU) is an inherited metabolic disorder requiring early and lifelong dietary management through a low-phenylalanine (Phe) diet supplemented with Phe-free protein substitutes (PS). Recently developed slow-release PS formulations aim to mimic natural protein absorption, enhancing metabolic stability and tolerability. The PREMP study (effect of Protein RElease on the Microbiota composition and function in Phenylketonuric subjects) assessed the effects of a slow-release, Phe-free PS on gut microbiota composition and metabolic parameters in patients with PKU. Methods: Patients aged ≥6 years with PKU were enrolled from two Italian centers (Milan and Naples). Participants replaced ≥50% of their usual protein equivalent (P.Eq.) intake from Phe-free PS with a slow-release PS for 4 months. Clinical, biochemical, and nutritional assessments were performed at baseline and post-intervention. Gut microbiota composition was analyzed by 16S rRNA gene sequencing, and fecal fatty acids were quantified by gas chromatography–mass spectrometry. Results: Thirteen patients (median age 17 years) completed the intervention, replacing on average 78% of their usual P.Eq. intake with the slow-release formulation. Plasma phenylalanine and tyrosine levels remained stable, while fasting insulin (p = 0.0185) and HOMA-IR (p = 0.0099) significantly decreased, indicating improved insulin sensitivity. Anthropometric and dietary parameters showed no significant changes. Gut microbiota diversity remained stable, with modest increases in microbial richness and beneficial genera such as Bacteroides, Bifidobacterium, and Gemmiger, while Hafnia, Anaerostipes and Romboutsia decreased. Fecal butyrate and other fatty acids showed slight, non-significant increases. Conclusions: The slow-release PS was safe, well-tolerated, and improved insulin sensitivity without affecting amino acid or nutritional status. Microbial changes suggest potential benefits for gut health, warranting confirmation in larger, long-term studies.

Background/Objectives: Casein glycomacropeptide (cGMP) has been modified to enable its suitability as a low phenylalanine (Phe) protein substitute (PS) in phenylketonuria (PKU). No data is available about its global usage. Methods: A 60-item multiple choice and short answer/extended response questionnaire examining the use of modified cGMP in PKU was distributed globally to dietitians and physicians via web-based professional inherited metabolic disorder groups. Results: Respondents (n = 208) from 45 countries across 6 continents completed the questionnaire. Of these, 83.7% (n = 174) were dietitians/nutritionists, 14.9% (n = 31) medical doctors/physicians and 1.4% (n = 3) other health professionals, caring for both paediatric and adult patients (59.1%), paediatrics only (25.0%) or adults only (15.9%). cGMP PS were reported as not available in their centre/hospital by 19.7% (n = 41), mostly in Africa, South America, and southern and western Asia. The main reasons included lack of regulatory approval (65.8%), not promoted by manufacturers (41.5%), and cost (29.3%). An estimated 25% of represented patients globally were using cGMP PS; 78.4% (n = 163) following refusal/poor adherence with Phe-free amino acids and 54.8% (n = 114) for adult patients recommencing dietary treatment. There were concerns about the residual Phe in cGMP negatively impacting blood Phe levels in children <12y (66.3%), adolescents (48.0%), adults (34.6%), and the first trimester of pregnancy (53.1%). Sixty nine percent (n = 145) adjusted dietary Phe prescription according to the cGMP Phe content, particularly in regions with a higher percentage of severe PKU variants. Commonly perceived clinical advantages with cGMP were improved taste/palatability (93.2%, n = 194) and fewer gastrointestinal symptoms (55.8%, n = 116). Perceived clinical disadvantages were residual Phe (72.1%, n = 150), lack of data in children < 3 years (48.1%, n = 100), and the high energy content of some brands (45.2%, n = 94). There were concerns that cGMP PS were too high in sugar (34.1%, n = 71) and dissatisfaction or uncertainty about the adequacy of its Phe (66.3%) and amino acid (34.1%) content. Conclusions: There is global inconsistency in access to cGMP PS suitable for PKU, and in the interpretation of evidence-based research. Some professionals have significant concerns about its nutritional composition particularly residual Phe, limiting its estimated use to approximately 25% of PKU patients globally.