Casein glycomacropeptide in phenylketonuria: does it bring clinical benefit?

PURPOSE OF REVIEW: Casein glycomacropeptide (CGMP) is a milk-derived bioactive sialyated phosphorylated peptide with distinctive nutritional and nutraceutical properties, produced during the cheese making process. It comprises 20-25% of total protein in whey products. CGMP is low in phenylalanine (Phe) and provides an alternative to Phe-free amino acids as a source of protein equivalent for patients with phenylketonuria (PKU). The amino acid sequence of CGMP is adapted by adding the amino acids histidine, leucine, tyrosine, arginine and tryptophan to enable its suitability in PKU. CGMP has potential antibacterial, antioxidative, prebiotic, remineralizing, digestion /metabolism and immune-modulating properties. The aim of this review is to assess the evidence for the role of CGMP in the management of PKU. RECENT FINDINGS: In PKU, there is no agreement concerning the amino acid composition of CGMP protein substitutes and consequently the nutritional composition varies between products. Although there is evidence in patients or animal models that CGMP has possible beneficial effects on gut microbiota and bone health, the results are inconclusive. Data on kinetic advantage is limited. Most studies report an increase in blood Phe levels with CGMP. Appropriate adaptations and reduction of dietary Phe intake should be made to compensate for the residual Phe content of CGMP, particularly in children. Data from short term studies indicate improved palatability of CGMP when compared to Phe-free amino acids. SUMMARY: In PKU, CGMP with supplementary amino acids, offers a safe low Phe nitrogen source. Current scientific evidence is unconvincing about its bioactive advantage in PKU. Further longitudinal research is necessary.

Outcomes of Pediatric Liver Transplantation in Glycogen Storage Disease Type 1b-A Single-Center Experience.

BACKGROUND: Liver transplantation (LT) normalizes fasting tolerance in glycogen storage disease type (GSD) 1b. However, reported outcomes post-LT with respect to correction of neutropenia, infection risk and growth are varied. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been recently shown to improve neutropenia in GSD1b patients. METHODS: In this single-center retrospective study, we reviewed all children who underwent LT for GSD1b. Neutropenia, dose of granulocyte colony-stimulating factor (G-CSF), unplanned hospital attendance, anthropometrics, graft rejection, survival, and the effects of dapagliflozin were analyzed. Data from protocol biopsies obtained at 1, 5, and 10 years post-LT and immunosuppression levels were collected. RESULTS: Eight children (6 female), all on G-CSF pre-transplant, underwent cadaveric LT for GSD1b at median age 3.6 years (IQR 3.3-5.1) with mean follow-up time of 10.3 years (95% CI 7.5-13.1). Neutrophil count and G-CSF requirement did not improve post-LT. Although a reduction in unplanned hospital attendance due to infection (0.98 [95% CI 0.76-1.26] vs. 0.49 [95% CI 0.41 to 0.57] per person-year, p < 0.01) was observed, gastrointestinal complaints and graft dysfunction accounted for a similar hospitalization burden pre- versus post-LT. Body mass index (BMI) reduced post-LT (Z-score 1.47 [95%CI 0.39-2.23] vs. 0.56 [95% CI -0.74 to 1.45], p = 0.02), with no significant change in height. Although all children and grafts have survived, 75% of recipients developed rejection, despite adequate immunosuppression levels, with two children having been found to have developed significant fibrosis on their 5-year protocol biopsy. Although dapagliflozin allowed cessation of G-CSF, no improvement in neutrophil count was observed. Despite this, a reduction in gastrointestinal and infection-related morbidity was noted following dapagliflozin. CONCLUSION: Although LT normalizes fasting tolerance in GSD1b and reduces hospital attendance due to infection, morbidity from infection and gastrointestinal manifestations persist. Children in our cohort experienced high rates of rejection necessitating titration of immunosuppression to balance risk of infection against organ rejection. Future studies should investigate whether early introduction of SGLT2 inhibitors post-LT impact morbidity in this group.

Casein glycomacropeptide in phenylketonuria: does it bring clinical benefit?

PURPOSE OF REVIEW: Casein glycomacropeptide (CGMP) is a milk-derived bioactive sialyated phosphorylated peptide with distinctive nutritional and nutraceutical properties, produced during the cheese making process. It comprises 20-25% of total protein in whey products. CGMP is low in phenylalanine (Phe) and provides an alternative to Phe-free amino acids as a source of protein equivalent for patients with phenylketonuria (PKU). The amino acid sequence of CGMP is adapted by adding the amino acids histidine, leucine, tyrosine, arginine and tryptophan to enable its suitability in PKU. CGMP has potential antibacterial, antioxidative, prebiotic, remineralizing, digestion /metabolism and immune-modulating properties. The aim of this review is to assess the evidence for the role of CGMP in the management of PKU. RECENT FINDINGS: In PKU, there is no agreement concerning the amino acid composition of CGMP protein substitutes and consequently the nutritional composition varies between products. Although there is evidence in patients or animal models that CGMP has possible beneficial effects on gut microbiota and bone health, the results are inconclusive. Data on kinetic advantage is limited. Most studies report an increase in blood Phe levels with CGMP. Appropriate adaptations and reduction of dietary Phe intake should be made to compensate for the residual Phe content of CGMP, particularly in children. Data from short term studies indicate improved palatability of CGMP when compared to Phe-free amino acids. SUMMARY: In PKU, CGMP with supplementary amino acids, offers a safe low Phe nitrogen source. Current scientific evidence is unconvincing about its bioactive advantage in PKU. Further longitudinal research is necessary.

Altered gut microbiome diversity and function in patients with propionic acidemia.

Propionic acidemia (PA) is an inherited metabolic disorder of propionate metabolism, where the gut microbiota may play a role in pathophysiology and therefore, represent a relevant therapeutic target. Little is known about the gut microbiota composition and activity in patients with PA. Although clinical practice varies between metabolic treatment centers, management of PA requires combined dietary and pharmaceutical treatments, both known to affect the gut microbiota. This study aimed to characterize the gut microbiota and its metabolites in fecal samples of patients with PA compared with healthy controls from the same household. Eight patients (aged 3-14y) and 8 controls (4-31y) were recruited from Center 1 (UK) and 7 patients (11-33y) and 6 controls (15-54y) from Center 2 (Austria). Stool samples were collected 4 times over 3 months, alongside data on dietary intakes and medication usage. Several microbial taxa differed between patients with PA and controls, particularly for Center 1, e.g., Proteobacteria levels were increased, whereas butyrate-producing genera, such as Roseburia and Faecalibacterium, were decreased. Most measured microbial metabolites were lower in patients with PA, and butyrate was particularly depleted in patients from Center 1. Furthermore, microbiota profile of these patients showed the lowest compositional and functional diversity, and lowest stability over 3 months. As the first study to map the gut microbiota of patients with PA, this work represents an important step forward for developing new therapeutic strategies to further improve PA clinical status. New dietary strategies should consider microbial propionate production as well as butyrate production and microbiota stability.

Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day.

INTRODUCTION: In hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens. METHODS: All patients were treated with NTBC (mean 1.08 ± 0.34 mg/kg/day) and a low phenylalanine-tyrosine diet. Thirteen patients received a single dose of NTBC and five patients twice daily. Home bloodspots were collected four times daily for three consecutive days measuring NTBC and SA concentrations. Statistical analyses were performed by using mixed model analyses and generalized linear mixed model analyses to study variation and differences in NTBC concentrations and the correlation with SA, respectively. RESULTS: NTBC concentrations varied significantly during the day especially if NTBC was taken at breakfast only (p = 0.026), although no significant difference in NTBC concentrations between different dosing regimens could be found (p = 0.289). Momentary NTBC concentrations were negatively correlated with SA (p < 0.001). Quantitatively detectable SA was only found in subjects with once daily administration of NTBC and associated with momentary NTBC concentrations <44.3 µmol/l. DISCUSSION: NTBC could be less stable than previously considered, thus dosing NTBC once daily and lower concentrations may be less adequate. Further research including more data is necessary to establish the optimal dosing of NTBC.

The discovery of fluazaindolizine: A new product for the control of plant parasitic nematodes.

Fluazaindolizine is a new highly effective and selective product for the control of plant parasitic nematodes. Specificity for nematodes coupled with absence of activity against the target sites of commercial nematicides suggests that fluazaindolizine has a novel mode of action. The discovery, structure-activity development and biological properties for this new class of nematicides are presented.

The micronutrient status of patients with phenylketonuria on dietary treatment: an ongoing challenge.

BACKGROUND: In phenylketonuria (PKU), phenylalanine-free L-amino acid supplements are the major source of dietary micronutrients. METHODS: Four hundred fifty-two retrospective annual/bi-annual non-fasting blood samples for nutritional markers (plasma zinc, selenium, and serum folate) from 78 subjects aged 1-16 years (median number of blood samples: 6, range 1-14) were analysed over 12 years. Longitudinal blood result data were available for 51 subjects (65%). The dietary intake from supplements was calculated. RESULTS: The median intakes of all of the micronutrients studied were >200% of the reference nutrient intakes (RNI). There was no statistical correlation between dietary intake and nutritional markers outside of the normal reference range (RR) except for selenium, but there was a correlation between a lower plasma zinc, plasma selenium and haemoglobin status and better blood phenylalanine control in 1- to 4-year-old children. On at least one occasion, the individual plasma concentrations of zinc (71%, n = 54/76) and selenium (21%, n = 16/75) were below the RR; however, the concentrations of selenium (41%, n = 31/75) and serum folate (83%, n = 34/41) were also above the RR. Dietary intakes exceeded the upper tolerable intakes for zinc and copper (32%, n = 25) and folate (65%, n = 51). Individual longitudinal data demonstrated little change in micronutrient status over time. CONCLUSIONS: In PKU, biochemical micronutrient deficiencies are common despite micronutrient intakes above the RNI. Further study of the nutritional profiling of L-amino acid supplements in PKU is needed.

A 12-month, longitudinal, intervention study examining a tablet protein substitute preparation in the management of tyrosinemia.

Protein substitutes (PS) without tyrosine (Tyr) and phenylalanine (Phe), are an essential source of synthetic protein in the treatment of tyrosinemia (HT). In the UK, the only available protein substitutes for HT are Tyr/ Phe free amino acid liquid or powders or formulations based on glycomacropeptide (CGMP). A tablet Tyr/ Phe free amino acid supplement (AAT) has now been introduced. The aim of this two-part prospective, longitudinal intervention study was to assess the efficacy, acceptability, and tolerance of AAT in children aged >8 years with HTI. Part 1: was a 28-day acceptability/ tolerance study, part 2, was a 12-month extension study examining efficacy of AAT. Anthropometry and blood Tyr/ Phe were assessed. All subjects were taking NTBC [2-(2-nitro-4-triflourothybenzoyl) cyclohexane-1, 3-dione] with a Tyr restricted diet. Eight subjects with HTI were recruited 4 boys, and 4 girls with a median age of 14.3y (range 10.4-17.3); 3 were Caucasian and 5 of Pakistani origin. The median (range) protein equivalent from PS was 60 g/d (50-60), natural protein 20 g/d (15-30), and NTBC 30 mg/d (25-80). No subjects were taking Phe supplements. Five (63%) subjects completed part 1, with 4 taking all their PS requirements as AAT. Subjects reported AAT were tasteless and had no odour. No adverse gastrointestinal symptoms were recorded, with two reporting improvements in abdominal discomfort. At 12 months, 4 subjects had a non-significant decrease in blood Tyr/ Phe compared to the 12 months pre-treatment. Median blood Tyr (µmol/ L) pre-intervention was 500 (320-590); and at 12 months, 450 (290-530). Median blood Phe (µmol/L) pre-intervention was 40 (30-40); and at 12 months 30 (30-50). Median height z scores remained unchanged, but there was a small decrease in weight z score (pre-study weight - 0.1 (-1.4 to1.1), 12 m - 0.3 (-1.4 to 1.3) and BMI (pre- study BMI 0.2 (-2 to 1.4), and 12 m, -0.1 (-2.5 to 1.5)). Conclusion: AAT were useful for some adolescents with HTI who struggled with the taste and volume of conventional powdered and liquid PS.

Phenylalanine-Free Infant Formula in Patients with Phenylketonuria: A Retrospective Study.

The long-term efficacy and use of phenylalanine-free infant amino acid formula (PFIF) is understudied. This retrospective, longitudinal study evaluated PFIF (PKU Start: Vitaflo International) in children with phenylketonuria, collecting data on metabolic control, growth, dietary intake, and symptoms and the child's experience with PFIF. Twenty-five children (12 males, 48%) with a median age of 3.6 years (2.0-6.2 years) were included. During 24 months follow-up, children maintained normal growth and satisfactory metabolic control. The protein intake from protein substitutes increased from 2.7 at 6 months to 2.8 g/kg/day at 24 months, while natural protein decreased from 0.6 to 0.4 g/kg/day. By 24 months, most children (n = 16, 64%) had stopped PFIF, while nine (36%) continued with a median intake of 450 mL/day (Q1:300 mL, Q3: 560 mL). Children who continued PFIF after 24 months of age had higher energy and fat intakes with higher weight/BMI z-scores compared with those who stopped earlier (p < 0.05). Constipation was reported in 44% of infants but improved with age. Initial difficulty with PFIF acceptance was reported in 20% of infants but also improved with time. Prolonged use of PFIF in pre-school children may contribute to poor feeding patterns and overweight; thus, replacing the majority of the protein equivalent provided by PFIF with a weaning protein substitute by 12 months and discontinuing PFIF before 2 years is recommended.

Patient and carer perceptions of video, telephone and in-person clinics for Phenylketonuria (PKU).

BACKGROUND: In phenylketonuria (PKU), attending multidisciplinary clinic reviews is an important aspect of life-long care. Since the COVID-19 pandemic, video and telephone clinics are used as alternative methods for people with PKU to have contact with their care team. There is limited research concerning patient preference, experience and perceptions of alternative types of clinic review. Individuals from the UK with PKU and their caregivers were invited to complete an online questionnaire, hosted on the National Society for PKU (NSPKU) website and social media platform. RESULTS: Data was available from 203 respondents. Forty one per cent of respondents (n = 49/119) preferred in-person clinics; 41% (n = 49) a hybrid of in-person, video and telephone clinics; 9% (n = 11) video clinics only, 6% (n = 7) telephone only and 3% (n = 3) were unsure. The main respondent obstacles to in-person clinics were costs, travel and time, but this was balanced by the benefits of a physical examination and better patient engagement/motivation. Twenty one per cent (n = 36/169) of respondents were uncomfortable with the number of healthcare professionals (HCPs) in a clinic room. Patients were less likely to consult with a doctor on video (64%, n = 91/143) or phone (50%, n = 59/119) reviews compared to in-person (80%, n = 146/183). Issues with video and telephone reviews included the shorter time length of review, distractions, technical issues and poor patient engagement. CONCLUSIONS: Online video and telephone clinic platforms were effective in overcoming the challenging circumstances in management, monitoring and treatment of patients with PKU during the COVID-19 pandemic. However, in-person clinics remain the preferred respondent option. It is important that HCPs are flexible, enabling people with PKU a choice of clinic options according to their individual clinical need and circumstances.

Longitudinal Dietary Intake Data in Patients with Phenylketonuria from Europe: The Impact of Age and Phenylketonuria Severity.

In phenylketonuria (PKU), natural protein intake is thought to increase with age, particularly during childhood and adolescence. Longitudinal dietary intake data are scarce and lifelong phenylalanine tolerance remains unknown. Nine centres managing PKU in Europe and Turkey participated in a retrospective study. Data were collected from dietetic records between 2012 and 2018 on phenylalanine (Phe), natural protein, and protein substitute intake. A total of 1323 patients (age range: 1-57 y; 51% male) participated. Dietary intake data were available on 1163 (88%) patients. Patient numbers ranged from 59 to 320 in each centre. A total of 625 (47%) had classical PKU (cPKU), n = 357 (27%) had mild PKU (mPKU), n = 325 (25%) had hyperphenylalaninemia (HPA), and n = 16 (1%) were unknown. The mean percentage of blood Phe levels within target ranged from 65 ± 54% to 88 ± 49%. When intake was expressed as g/day, the mean Phe/natural protein and protein equivalent from protein substitute gradually increased during childhood, reaching a peak in adolescence, and then remained consistent during adulthood. When intake was expressed per kg body weight (g/kg/day), there was a decline in Phe/natural protein, protein equivalent from protein substitute, and total protein with increasing age. Overall, the mean daily intake (kg/day) was as follows: Phe, 904 mg ± 761 (22 ± 23 mg/kg/day), natural protein 19 g ± 16 (0.5 g/kg/day ± 0.5), protein equivalent from protein substitute 39 g ± 22 (1.1 g/kg/day ± 0.6), and total protein 59 g ± 21 (1.7 g/kg/day ± 0.6). Natural protein tolerance was similar between males and females. Patients with mPKU tolerated around 50% less Phe/natural protein than HPA, but 50% more than cPKU. Higher intakes of natural protein were observed in Southern Europe, with a higher prevalence of HPA and mPKU compared with patients from Northern European centres. Natural protein intake doubled with sapropterin usage. In sapropterin-responsive patients, 31% no longer used protein substitutes. Close monitoring and optimisation of protein intake prescriptions are needed, along with future guidelines specifically for different age groups and severities.

Blood Phenylalanine Levels in Patients with Phenylketonuria from Europe between 2012 and 2018: Is It a Changing Landscape?

BACKGROUND: In 2011, a European phenylketonuria (PKU) survey reported that the blood phenylalanine (Phe) levels were well controlled in early life but deteriorated with age. Other studies have shown similar results across the globe. Different target blood Phe levels have been used throughout the years, and, in 2017, the European PKU guidelines defined new targets for blood Phe levels. This study aimed to evaluate blood Phe control in patients with PKU across Europe. METHODS: nine centres managing PKU in Europe and Turkey participated. Data were collected retrospectively from medical and dietetic records between 2012 and 2018 on blood Phe levels, PKU severity, and medications. RESULTS: A total of 1323 patients (age range:1-57, 51% male) participated. Patient numbers ranged from 59 to 320 in each centre. The most common phenotype was classical PKU (n = 625, 48%), followed by mild PKU (n = 357, 27%) and hyperphenylalaninemia (HPA) (n = 325, 25%). The mean percentage of blood Phe levels within the target range ranged from 65 ± 54% to 88 ± 49% for all centres. The percentage of Phe levels within the target range declined with increasing age (<2 years: 89%; 2-5 years: 84%; 6-12 years: 73%; 13-18 years: 85%; 19-30 years: 64%; 31-40 years: 59%; and ≥41 years: 40%). The mean blood Phe levels were significantly lower and the percentage within the target range was significantly higher (p < 0.001) in patients with HPA (290 ± 325 µmol/L; 96 ± 24%) and mild PKU (365 ± 224 µmol/L; 77 ± 36%) compared to classical PKU (458 ± 350 µmol/L, 54 ± 46%). There was no difference between males and females in the mean blood Phe levels (p = 0.939), but the percentage of Phe levels within the target range was higher in females among school-age children (6-12 years; 83% in females vs. 78% in males; p = 0.005), adolescents (13-18 years; 62% in females vs. 59% in males; p = 0.034) and adults (31-40 years; 65% in females vs. 41% in males; p < 0.001 and >41 years; 43% in females vs. 28% in males; p < 0.001). Patients treated with sapropterin (n = 222) had statistically significantly lower Phe levels compared to diet-only-treated patients (mean 391 ± 334 µmol/L; percentage within target 84 ± 39% vs. 406 ± 334 µmol/L; 73 ± 41%; p < 0.001), although a blood Phe mean difference of 15 µmol/L may not be clinically relevant. An increased frequency of blood Phe monitoring was associated with better metabolic control (p < 0.05). The mean blood Phe (% Phe levels within target) from blood Phe samples collected weekly was 271 ± 204 µmol/L, (81 ± 33%); for once every 2 weeks, it was 376 ± 262 µmol/L, (78 ± 42%); for once every 4 weeks, it was 426 ± 282 µmol/L, (71 ± 50%); and less than monthly samples, it was 534 ± 468 µmol/L, (70 ± 58%). CONCLUSIONS: Overall, blood Phe control deteriorated with age. A higher frequency of blood sampling was associated with better blood Phe control with less variability. The severity of PKU and the available treatments and resources may impact the blood Phe control achieved by each treatment centre.

Patterns of patient outcomes following specialist pain management in Australasia: a latent class analysis using the electronic Persistent Pain Outcomes Collaboration database.

ABSTRACT: The increasing demand for pain management and limited resources available highlight the need to measure treatment effectiveness. We analysed data collected at 75 specialist persistent pain services located in Australia and New Zealand to calculate the overall treatment outcome for patients receiving care during 2014 to 2020. Sociodemographic and clinical information was provided for 23,915 patients, along with patient-reported measures assessing pain, pain interference, depression, anxiety, stress, pain catastrophizing, and pain self-efficacy. Latent class analysis identified 4 distinct outcomes based on patients' pattern of responses across the assessment tools at treatment end. Group 1 (n = 8369, 35%) reported low/mild severity across all clinical domains at the end of care, while group 4 (n= 7081, 30%) were more likely to report moderate/high severity on all domains. Group 2 (n = 1991, 8%) reported low/mild pain with moderate/high psychological distress at treatment end, and group 3 (n = 6474, 27%) reported moderate/high pain with low/mild psychological distress. Multivariable logistic regression identified those factors associated with the different groups. In particular, factors most predictive of a poor (group 4) vs good outcome (group 1) were unemployment (due to pain or other reasons), requiring an interpreter, widespread pain, pain of longer duration, and attributing the pain to an injury at work. The results may allow identification of those most likely to benefit from the services currently provided and inform development of alternative or enhanced services for those at risk of a poor outcome.

Phenylalanine free infant formula in the dietary management of phenylketonuria.

BACKGROUND: Phenylalanine-free infant formula is an essential source of safe protein in a phenylalanine restricted diet, but its efficacy is rarely studied. We report a multicentre, open, longitudinal, prospective intervention study on a phenylalanine-free infant formula (PKU Start: Vitaflo International Ltd.). RESULTS: This was a 2-part study: part I (28 days short term evaluation) and part II (12 months extension). Data was collected on infant blood phenylalanine concentrations, dietary intake, growth, and gastrointestinal tolerance. Ten infants (n = 8 males, 80%), with a median age of 14 weeks (range 4-36 weeks) were recruited from 3 treatment centres in the UK. Nine of ten infants completed the 28-day follow-up (one caregiver preferred the usual phenylalanine-free formula and discontinued the study formula after day 14) and 7/9 participated in study part II. The phenylalanine-free infant formula contributed a median of 57% (IQR 50-62%) energy and 53% (IQR 33-66%) of total protein intake from baseline to the end of the part II extension study. During the 12-month follow-up, infants maintained normal growth and satisfactory blood phenylalanine control. Any early gastrointestinal symptoms (constipation, colic, vomiting and poor feeding) improved with time. CONCLUSION: The study formula was well tolerated, helped maintain good metabolic control, and normal growth in infants with PKU. The long-term efficacy of phenylalanine-free infant formula should continue to be observed and monitored.

Parent's Perception of the Types of Support Given to Families with an Infant with Phenylketonuria.

BACKGROUND: A diagnosis of phenylketonuria (PKU) in an infant is a devastating and overwhelming event for their parents. Providing appropriate information and support is paramount, especially at the beginning of a child's life. Investigating if parents are receiving the right support is important for continued care. METHODOLOGY: An online survey was distributed to explore parents' perceptions of current support and information provided by their healthcare provider and to rate sources of other support (n = 169 participants). RESULTS: Dietitians received the highest (85%) rate of "very helpful" support. Overall, parents found Facebook to be helpful for support but had mixed reactions when asked if healthcare professionals (HCPs) should provide advice as part of the groups. When rating the most effective learning methods, the top three were 1:1 teaching sessions (n = 109, 70%), picture books (n = 73, 50%), and written handouts (n = 70, 46%). CONCLUSION: Most parents are happy with the support and information they receive from their dietitian but required more support from other HCPs. Facebook groups provide parents with the social support that HCPs and their family may be unable to offer, suggesting a place for social media in future PKU care.

Natural Protein Intake in Children with Phenylketonuria: Prescription vs. Actual Intakes.

In phenylketonuria (PKU), an important component of the UK dietary management system is a 50 mg phenylalanine (Phe)/1 g protein exchange system used to allocate the Phe/natural protein intakes according to individual patient tolerance. Any foods containing protein ≤ 0.5 g/100 g or fruits/vegetables containing Phe ≤ 75 mg/100 g are allowed without measurement or limit. In children with PKU, we aimed to assess the difference between the prescribed natural protein intake and their actual consumed intake, and to calculate the natural protein/Phe intake from foods given without measurement or restriction. Over a 6-month duration, three one-day diet diaries were collected every month by caregivers of children with PKU at the beginning of a follow-up study. Dietary intakes of Phe, as well as natural and total protein intakes, were calculated using Nutritics® (v5.09). Weekly blood Phe spots were collected by caregivers. The target blood Phe level was ≤360 µmol/L for ages up to 12 years and ≤600 µmol/L for ages ≥12 years. Sixteen early treated children (69% females) with PKU were recruited. The median age was 11 years (range: 9-13), and most had classical PKU (n = 14/16). A median of 18 (range 12-18) one-day diaries and 22 blood spots were analysed for each subject over 6 months. The median prescribed natural protein was 6 g/day (range: 3-27), but when calculated, the actual median intake from all foods consumed was 10 g/day (range: 4-37). The median prescribed Phe was 300 mg/day (range: 150-1350), but the actual median intake was 500 mg/day (range: 200-1850). The median difference between the prescribed and actual natural protein daily intakes was +4 g/day (range: -2.5 to +11.5), with a median percentage increase of 40% for natural protein/Phe intake (p < 0.001). The median blood Phe level was 250 µmol/L (range 20-750), with 91% of blood Phe levels within the target range. Only one patient (11 years) had less than 75% of their blood Phe levels within the target range. The UK Phe exchange system provides flexibility in the dietary management of PKU. With this method, the actual natural protein intake was 167% higher than the prescribed amount. Although this led to a variable daily protein intake, the majority of children (n = 15/16) experienced no deterioration in their metabolic control.

Preliminary Data on Free Use of Fruits and Vegetables Containing Phenylalanine 76-100 mg/100 g of Food in 16 Children with Phenylketonuria: 6 Months Follow-Up.

In phenylketonuria (PKU), a previous intervention study assessing the patients ability to tolerate fruits and vegetables containing phenylalanine 76-100 mg/100 g without limit or measurement, found that an extra 50 mg/day phenylalanine, but not 100 mg/day, was tolerated from these fruits and vegetables. In a further 6-month extension study, we examined the effect of the 'free' use of this group of fruits and vegetables on blood phenylalanine control. For 6 months, the patients ate fruits and vegetables containing phenylalanine 76-100 mg/100 g without limit or measurement. Three-day diet diaries and the patients' weights were collected monthly. Blood phenylalanine spots were collected weekly aiming for blood phenylalanine levels <360 µmol/L. Retrospective blood phenylalanine was collected 6 months pre-trial. All 16 patients (69% females) from the intervention study took part in the extension study. Most of the patients (n = 14/16) had classical PKU with a median age of 10.5 years (range: 6-13). There was no statistically significant difference in the median blood phenylalanine pre-study (270, range: 50-760 µmol/L) compared to the 6-month extension study (250, range: 20-750 µmol/L) (p= 0.4867). The patients had a median of 21 and 22 bloodspots, pre- and post-trial, respectively. In the extension study, the patients had an actual mean intake of 11 g/day (4-37) natural protein and 65 g/day (60-80) protein equivalent from a protein substitute. The mean phenylalanine intake was 563 mg/day (200-1850) with only 19 mg/day (0-146) phenylalanine from fruits and vegetables containing phenylalanine 76-100 mg/100 g. The weight z-scores remained unchanged (1.52 vs. 1.60, p = 0.4715). There was no adverse impact on blood phenylalanine control when fruits and vegetables containing phenylalanine 76-100 mg/100 g were eaten without limit or measurement. However, the fruits and vegetable portion sizes eaten were small (60 g/week). Further longitudinal work is necessary to examine the 'free' use of fruits and vegetables containing phenylalanine 76-100 mg/100 g on metabolic control in patients with PKU.

Phenylalanine Tolerance over Time in Phenylketonuria: A Systematic Review and Meta-Analysis.

In phenylketonuria (PKU), natural protein tolerance is defined as the maximum natural protein intake maintaining a blood phenylalanine (Phe) concentration within a target therapeutic range. Tolerance is affected by several factors, and it may differ throughout a person's lifespan. Data on lifelong Phe/natural protein tolerance are limited and mostly reported in studies with low subject numbers. This systematic review aimed to investigate how Phe/natural protein tolerance changes from birth to adulthood in well-controlled patients with PKU on a Phe-restricted diet. Five electronic databases were searched for articles published until July 2020. From a total of 1334 results, 37 articles met the eligibility criteria (n = 2464 patients), and 18 were included in the meta-analysis. The mean Phe (mg/day) and natural protein (g/day) intake gradually increased from birth until 6 y (at the age of 6 months, the mean Phe intake was 267 mg/day, and natural protein intake was 5.4 g/day; at the age of 5 y, the mean Phe intake was 377 mg/day, and the natural protein intake was 8.9 g/day). However, an increase in Phe/natural protein tolerance was more apparent at the beginning of late childhood and was >1.5-fold that of the Phe tolerance in early childhood. During the pubertal growth spurt, the mean natural protein/Phe tolerance was approximately three times higher than in the first year of life, reaching a mean Phe intake of 709 mg/day and a mean natural protein intake of 18 g/day. Post adolescence, a pooled analysis could only be performed for natural protein intake. The mean natural protein tolerance reached its highest (32.4 g/day) point at the age of 17 y and remained consistent (31.6 g/day) in adulthood, but limited data were available. The results of the meta-analysis showed that Phe/natural protein tolerance (expressed as mg or g per day) increases with age, particularly at the beginning of puberty, and reaches its highest level at the end of adolescence. This needs to be interpreted with caution as limited data were available in adult patients. There was also a high degree of heterogeneity between studies due to differences in sample size, the severity of PKU, and target therapeutic levels for blood Phe control.

Impact on Diet Quality and Burden of Care in Sapropterin Dihydrochloride Use in Children with Phenylketonuria: A 6 Month Follow-Up Report.

INTRODUCTION: In phenylketonuria (PKU) changes in dietary patterns and behaviors in sapropterin-responsive populations have not been widely reported. We aimed to assess changes in food quality, mental health and burden of care in a paediatric PKU sapropterin-responsive cohort. METHODS: In an observational, longitudinal study, patient questionnaires on food frequency, neophobia, anxiety and depression, impact on family and burden of care were applied at baseline, 3 and 6-months post successful sapropterin-responsiveness testing (defined as a 30% reduction in blood phenylalanine levels). RESULTS: 17 children (10.8 ± 4.2 years) completed 6-months follow-up. Patients body mass index (BMI) z-scores remained unchanged after sapropterin initiation. Blood phenylalanine was stable. Natural protein increased (p < 0.001) and protein substitute intake decreased (p = 0.002). There were increases in regular cow's milk (p = 0.001), meat/fish, eggs (p = 0.005), bread (p = 0.01) and pasta (p = 0.011) intakes but special low-protein foods intake decreased. Anxiety (p = 0.016) and depression (p = 0.022) decreased in caregivers. The impact-on-family, familial-social impact (p = 0.002) and personal strain (p = 0.001) lessened. After sapropterin, caregivers spent less time on PKU tasks, the majority ate meals outside the home more regularly and fewer caregivers had to deny food choices to their children. CONCLUSION: There were significant positive changes in food patterns, behaviors and burden of care in children with PKU and their families after 6-months on sapropterin treatment.