Management of early treated adolescents and young adults with phenylketonuria: Development of international consensus recommendations using a modified Delphi approach.

BACKGROUND: Early treated patients with phenylketonuria (PKU) often become lost to follow-up from adolescence onwards due to the historical focus of PKU care on the pediatric population and lack of programs facilitating the transition to adulthood. As a result, evidence on the management of adolescents and young adults with PKU is limited. METHODS: Two meetings were held with a multidisciplinary international panel of 25 experts in PKU and comorbidities frequently experienced by patients with PKU. Based on the outcomes of the first meeting, a set of statements were developed. During the second meeting, these statements were voted on for consensus generation (≥70% agreement), using a modified Delphi approach. RESULTS: A total of 37 consensus recommendations were developed across five areas that were deemed important in the management of adolescents and young adults with PKU: (1) general physical health, (2) mental health and neurocognitive functioning, (3) blood Phe target range, (4) PKU-specific challenges, and (5) transition to adult care. The consensus recommendations reflect the personal opinions and experiences from the participating experts supported with evidence when available. Overall, clinicians managing adolescents and young adults with PKU should be aware of the wide variety of PKU-associated comorbidities, initiating screening at an early age. In addition, management of adolescents/young adults should be a joint effort between the patient, clinical center, and parents/caregivers supporting adolescents with gradually gaining independent control of their disease during the transition to adulthood. CONCLUSIONS: A multidisciplinary international group of experts used a modified Delphi approach to develop a set of consensus recommendations with the aim of providing guidance and offering tools to clinics to aid with supporting adolescents and young adults with PKU.

A multinational study of acute and long-term outcomes of Type 1 galactosemia patients who carry the S135L (c.404C > T) variant of GALT.

Patients with galactosemia who carry the S135L (c.404C > T) variant of galactose-1-P uridylyltransferase (GALT), documented to encode low-level residual GALT activity, have been under-represented in most prior studies of outcomes in Type 1 galactosemia. What is known about the acute and long-term outcomes of these patients, therefore, is based on very limited data. Here, we present a study comparing acute and long-term outcomes of 12 patients homozygous for S135L, 25 patients compound heterozygous for S135L, and 105 patients homozygous for two GALT-null (G) alleles. This is the largest cohort of S135L patients characterized to date. Acute disease following milk exposure in the newborn period was common among patients in all 3 comparison groups in our study, as were long-term complications in the domains of speech, cognition, and motor outcomes. In contrast, while at least 80% of both GALT-null and S135L compound heterozygous girls and women showed evidence of an adverse ovarian outcome, prevalence was only 25% among S135L homozygotes. Further, all young women in this study with even one copy of S135L achieved spontaneous menarche; this is true for only about 33% of women with classic galactosemia. Overall, we observed that while most long-term outcomes trended milder among groups of patients with even one copy of S135L, many individual patients, either homozygous or compound heterozygous for S135L, nonetheless experienced long-term outcomes that were not mild. This was true despite detection by newborn screening and both early and life-long dietary restriction of galactose. This information should empower more evidence-based counseling for galactosemia patients with S135L.

In Vivo Metabolic Responses to Different Formulations of Amino Acid Mixtures for the Treatment of Phenylketonuria (PKU).

Phenylketonuria (PKU) is a rare autosomal recessive inborn error of metabolism where the mainstay of treatment is a Phe restricted diet consisting of a combination of limited amounts of natural protein with supplementation of Phe-free or low-Phe protein substitutes and special low protein foods. Suboptimal outcomes may be related to the different absorption kinetics of free AAs, which have lower biological efficacy than natural proteins. Physiomimic TechnologyTM is a technology engineered to prolong AA (AA-PT) release allowing physiological absorption and masking the odor and taste of free AAs. The aim of these studies was to assess the impact of AA-PT formulation on selected functional and metabolic parameters both in acute and long-term experimental studies. Adult rats in fasting conditions were randomized in different groups and treated by oral gavage. Acute AA-PT administration resulted in significantly lower BUN at 90 min versus baseline. Both BUN and glycemia were modulated in the same direction as intact casein protein. Long-term treatment with AA-PT significantly reduces the protein expression of the muscle degradation marker Bnip3L (-46%) while significantly increasing the proliferation of market myostatin (+58%). Animals dosed for 15 days with AA-PT had significantly stronger grip strength (+30%) versus baseline. In conclusion, the results suggest that the AA-PT formulation may have beneficial effects on both AA oxidation and catabolism with a direct impact on muscle as well as on other metabolic pathways.

Unveiling the Metabolic Effects of Glycomacropeptide.

For many years, the main nitrogen source for patients with phenylketonuria (PKU) was phenylalanine-free amino acid supplements. Recently, casein glycomacropeptide (GMP) supplements have been prescribed due to its functional and sensorial properties. Nevertheless, many doubts still persist about the metabolic effects of GMP compared to free amino acids (fAA) and intact proteins such as casein (CAS). We endeavour to compare, in rats, the metabolic effects of different nitrogen sources. Twenty-four male Wistar rats were fed equal energy density diets plus CAS (control, n = 8), fAA (n = 8) or GMP (n = 8) for 8 weeks. Food, liquid intake and body weight were measured weekly. Blood biochemical parameters and markers of glycidic metabolism were assessed. Glucagon-like peptide-1 (GLP-1) was analysed by ELISA and immunohistochemistry. Food intake was higher in rats fed CAS compared to fAA or GMP throughout the treatment period. Fluid intake was similar between rats fed fAA and GMP. Body weight was systematically lower in rats fed fAA and GMP compared to those fed CAS, and still, from week 4 onwards, there were differences between fAA and GMP. None of the treatments appeared to induce consistent changes in glycaemia, while insulin levels were significantly higher in GMP. Likewise, the production of GLP-1 was higher in rats fed GMP when compared to fAA. Decreased urea, total protein and triglycerides were seen both in fAA and GMP related to CAS. GMP also reduced albumin and triglycerides in comparison to CAS and fAA, respectively. The chronic consumption of the diets triggers different metabolic responses which may provide clues to further study potential underlying mechanisms.

Optimising amino acid absorption: essential to improve nitrogen balance and metabolic control in phenylketonuria.

It has been nearly 70 years since the discovery that strict adherence to a diet low in phenylalanine prevents severe neurological sequelae in patients with phenylalanine hydroxylase deficiency (phenylketonuria; PKU). Today, dietary treatment with restricted phenylalanine intake supplemented with non-phenylalanine amino acids to support growth and maintain a healthy body composition remains the mainstay of therapy. However, a better understanding is needed of the factors that influence N balance in the context of amino acid supplementation. The aim of the present paper is to summarise considerations for improving N balance in patients with PKU, with a focus on gaining greater understanding of amino acid absorption, disposition and utilisation. In addition, the impact of phenylalanine-free amino acids on 24 h blood phenylalanine/tyrosine circadian rhythm is evaluated. We compare the effects of administering intact protein v. free amino acid on protein metabolism and discuss the possibility of improving outcomes by administering amino acid mixtures so that their absorption profile mimics that of intact protein. Protein substitutes with the ability to delay absorption of phenylalanine and tyrosine, mimicking physiological absorption kinetics, are expected to improve the rate of assimilation into protein and minimise fluctuations in quantitative plasma amino acid levels. They may also help maintain normal glycaemia and satiety sensation. This is likely to play an important role in improving the management of patients with PKU.

Polishing of municipal secondary effluent using native microalgae consortia.

This work evaluates the use of native microalgae consortia for a dual role: polishing treatment of municipal wastewater effluents and microalgae biomass feedstock potential for biodiesel or biofertilizer production. An initial screening was undertaken to test N and P removal from secondary effluents and biomass production by 12 consortia. A subsequent treatment was performed by selected consortia (01 and 12) under three operational conditions: stirring (S), S + 12 h of daily aeration (S + A) and S + A enriched with CO2 (S + AC). All treatments resulted in compliance with environmental regulations (e.g. Directive 91/271/EEC) and high removal efficiency of nutrients: 64-79% and 80-94% of total N and PO43--P respectively. During the experiments it was shown that pH alkalinization due to microalgae growth benefits the chemical removal of ammonia and phosphorus. Moreover, advantages of pH increase could be accomplished by intermittent CO2 addition which in this research (treatment S + AC) promoted higher yield and lipid concentration. The resulting dry biomass analysis showed a low lipid content (0.5-4.3%) not ideal for biodiesel production. Moreover, the high rate of ash (29.3-53.0%) suggests that biomass could be readily recycled as a biofertilizer due to mineral supply and organic constituents formed by C, N and P (e.g. carbohydrate, protein, and lipids).

Weight Management in Phenylketonuria: What Should Be Monitored.

BACKGROUND: Severe intellectual disability and growth impairment have been overcome by the success of early and continuous treatment of patients with phenylketonuria (PKU). However, there are some reports of obesity, particularly in women, suggesting that this may be an important comorbidity in PKU. It is becoming evident that in addition to acceptable blood phenylalanine control, metabolic dieticians should regard weight management as part of routine clinical practice. SUMMARY: It is important for practitioners to differentiate the 3 levels for overweight interpretation: anthropometry, body composition and frequency and severity of associated metabolic comorbidities. The main objectives of this review are to suggest proposals for the minimal standard and gold standard for the assessment of weight management in PKU. While the former aims to underline the importance of nutritional status evaluation in every specialized clinic, the second objective is important in establishing an understanding of the breadth of overweight and obesity in PKU in Europe. KEY MESSAGES: In PKU, the importance of adopting a European nutritional management strategy on weight management is highlighted in order to optimize long-term health outcomes in patients with PKU.

Biochemical and Anthropometric Outcomes in Paediatric Patients with Heterozygous Familial Hypercholesterolemia after COVID-19 Pandemic Lockdowns: An Exploratory Analysis.

The COVID-19 pandemic lockdowns affected the lifestyles of children and adolescents, leading to an increase in childhood obesity. Paediatric patients with familial hypercholesterolemia (FH) may be more susceptible to lockdown effects due to their increased cardiovascular risk. However, data are lacking. We investigated the effect of lockdowns on the metabolic profile of paediatric patients with FH. Blood lipids and anthropometry measured in September 2021-April 2022 were retrospectively compared with pre-pandemic values. Thirty participants were included (1-16 years; 57% female). From baseline to post-pandemic, median [P25, P75] blood LDL-C concentration was 125 [112, 150] mg/dL vs. 125 [100, 147] mg/dL (p = 0.894); HDL-C was 58 [52, 65] mg/dL vs. 56 [51, 61] mg/dL (p = 0.107); triglycerides were 64 [44, 86] mg/dL vs. 59 [42, 86] mg/dL (p = 0.178). The BMI z-score did not change significantly (0.19 [-0.58, 0.89] vs. 0.30 [-0.48, 1.10], p = 0.524). The lack of deterioration in metabolic profiles during lockdowns is positive, as some deterioration was expected. We speculate that patients and caregivers were successfully educated about healthy lifestyle and dietary habits. Our results should be interpreted with caution since the study sample was small and heterogeneous. Multicentre research is needed to better understand the impact of lockdowns on this population.

Case report: Primary CDK4/6 inhibitor and endocrine therapy in locally advanced breast cancer and its effect on gut and intratumoral microbiota.

Locally advanced breast cancer poses significant challenges to the multidisciplinary team, in particular with hormone receptor (HR) positive, HER2-negative tumors that classically yield lower pathological complete responses with chemotherapy. The increasingly significant use of CDK 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) in different breast cancer settings has led to clinical trials focusing on this strategy as a primary treatment, with promising results. The impact of the microbiota on cancer, and vice-versa, is an emerging topic in oncology. The authors report a clinical case of a postmenopausal female patient with an invasive breast carcinoma of the right breast, Luminal B-like, staged as cT4cN3M0 (IIIB). Since the lesion was considered primarily inoperable, the patient started letrozole and ribociclib. Following 6 months of systemic therapy, the clinical response was significant, and surgery with curative intent was performed. The final staging was ypT3ypN2aM0, R1, and the patient started adjuvant letrozole and radiotherapy. This case provides important insights on primary CDK4/6i plus ET in locally advanced unresectable HR+/HER2- breast cancer and its potential implications in disease management further ahead. The patient's gut microbiota was analyzed throughout the disease course and therapeutic approach, evidencing a shift in gut microbial dominance from Firmicutes to Bacteroidetes and a loss of microbial diversity following 6 months of systemic therapy. The analysis of the intratumoral microbiota from the surgical specimen revealed high microbial dissimilarity between the residual tumor and respective margins.

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.

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.

Effect of light stress on lutein production with associated phosphorus removal from a secondary effluent by the autoflocculating microalgae consortium BR-UANL-01.

Microalgae have become promising microorganisms for generating high-value commercial products and removing pollutants in aquatic systems. This research evaluated the impact of sunlight intensity on intracellular pigment generation and phosphorus removal from secondary effluents by autoflocculating microalgae consortium BR-UANL-01 in photobioreactor culture. Microalgae were grown in a secondary effluent from a wastewater treatment plant, using a combination of low and high light conditions (photon irradiance; 44 µmol m-2 s-1 and ≈ 1270 µmol m-2 s-1, respectively) and 16:8 h light:dark and 24:0 h light:dark (subdivided into 18:6 LED:sunlight) photoperiods. The autoflocculant rate by consortium BR-UANL-01 was not affected by light intensity and achieved 98% in both treatments. Microalgae produced significantly more lutein, (2.91 mg g-1) under low light conditions. Phosphate removal by microalgae resulted above 85% from the secondary effluent, due to the fact that phosphorus is directly associated with metabolic and replication processes and the highest antioxidant activity was obtained in ABTS•+ assay by the biomass under low light condition (51.71% µmol ET g-1). In conclusion, the results showed that the autoflocculating microalgae consortium BR-UANL-01 is capable of synthesizing intracellular lutein, which presents antioxidant activity, using secondary effluents as a growth medium, without losing its autoflocculating activity and assimilating phosphorus.

Total Protein Intake in Patients with PKU: Adequacy Evaluation According to the European PKU Guidelines from 2017.

In PKU, the protein requirements are contentious. In 2018, we evaluated the protein intake in patients with PKU. Ninety-nine early treated patients aged 19.3 ± 8.2 years (54% males) were studied. A total of 24 had hyperphenylalaninemia (HPA), 48 mild and 27 classical PKU. All had an annual nutritional status evaluation. A total of 83% were on diet therapy only, and 17% were on diet with tetrahydrobiopterin therapy. Anthropometry, metabolic control and nutritional intake [total protein (TP, g/kg), natural protein (NP, g/kg), protein equivalent from protein substitutes (PE, g/kg)] were collected. TP adequacy (TPA) was calculated as a % of WHO (2007) safe levels of protein intake. Results were compared with the European PKU Guidelines (EPG). The median % contribution NP of TP intake was 53% [31-100]. Most patients (78%) had a TP intake above the EPG recommendations. The median TPA was 171% [146-203], with 79% [51-165] from NP and 84% [0-109] from PE. A TPA of 100-140% was observed in 16 (16%) patients. Only n = 6 (6%) patients had a TPA < 100%. These results emphasize the heterogeneity of PKU. More research is needed to understand the necessity of a single protein recommendation for all, as a 'one-size-fits-all' solution might not be appropriate.

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.

Muscle Quality and Risk of Metabolic Syndrome in Adult Patients with Inherited Metabolic Diseases.

Adult patients with several Inherited Metabolic Diseases (IMD) follow diets controlled in proteins, rich in carbohydrates, and free amino acids formulae, which cause hyperinsulinism and ectopic fat. Previous studies showed IMD adult patients have a higher prevalence of metabolic syndrome and their complications [1]. Recently, ultrasound [US) has been validated for malnutrition, assessing muscle quality subjectively [2]. Higher echo intensity (EI) is associated with poorer muscle quality and functional results in aging [3] and other clinical settings, but it has never been evaluated in IMD. US measurements were conducted on 19 IMD patients and 6 healthy controls at Hospital Universitario de Badajoz (HUB) to assess EI, anthropometry, bioimpedance, and biochemistry. The HUB ethics committee approved the protocol and informed consent. Statistics were made with Jamovi. The mean age was 29.9 (range 18-47) in IMD patients vs. 33.7 (26-47) in controls. The distribution of IMD is shown in Figure 2. The mean EI in IMD was 56.9 (60.9 in PKU) vs. 54.4 in controls, NOT being the differences statistically significant (t- Student p =0.633; in PKU, p =0.246). The box plot is shown in Figure 3. IMD patients had excess body fat in a variable degree depending on the method (Figure 4): anthropometry, BIA, preperitoneal fat or myosteatosis. 40% had insulin resistance by HOMA, 20% prediabetes by HbA1c, 58.8% had low HDL-cholesterol levels, and 29.4% had hypertriglyceridemia. Insulin resistance status is shown in Figure 5. Obesity by anthropometry was significantly correlated with subcutaneous abdominal and preperitoneal fat by ultrasound and fat mass by BIA. Fat mass by BIA was correlated to preperitoneal fat, and fat-free mass by BIA with HOMA and degree of metabolic control of IMD. Muscle quality, by an objective tool, such as echo intensity, is worse in patients with IMD than in controls, reflecting poorer muscle metabolic condition and a higher risk of metabolic syndrome. It is not statistically significant, probably due to the small sample size. The prevalence of obesity and other metabolic syndrome components is higher in IMD patients than in the general population of the same age. Body composition analysis by BIA and nutritional ultrasound can help to identify patients at risk of metabolic syndrome before biochemical markers show.

Expert Consensus on the Long-Term Effectiveness of Medical Nutrition Therapy and Its Impact on the Outcomes of Adults with Phenylketonuria.

Many adults with phenylketonuria (PKU) rely on medical nutrition therapy (MNT; low phenylalanine (Phe) diet with protein substitutes/medical foods) to maintain blood Phe concentrations within recommended ranges and prevent PKU-associated comorbidities. Despite disease detection through newborn screening and introduction of MNT as early as birth, adherence to MNT often deteriorates from childhood onwards, complicating the assessment of its effectiveness in the long term. Via a modified Delphi process, consensus (≥70% agreement) was sought on 19 statements among an international, multidisciplinary 13-member expert panel. After three iterative voting rounds, the panel achieved consensus on 17 statements related to the limitations of the long-term effectiveness of MNT (7), the burden of long-term reliance on MNT (4), and its potential long-term detrimental health effects (6). According to the expert panel, the effectiveness of MNT is limited in the long term, is associated with a high treatment burden, and demonstrates that adults with PKU are often unable to achieve metabolic control through dietary management alone, creating an unmet need in the adult PKU population.