Pubertal origin of growth retardation in inborn errors of protein metabolism: A longitudinal cohort study.

OBJECTIVES: Inherited amino-acid metabolism disorders (IAAMDs) require lifelong protein-restricted diet. We aimed to investigate: 1/ whether IAAMDs was associated with growth, pubertal, bone mineral apparent density (BMAD) or body composition impairments; 2/ associations linking height, amino-acid mixture (AAM), plasma amino-acids and IGF1 concentrations. DESIGN: Retrospective longitudinal study of 213 patients with neonatal-onset urea cycle disorders (UCD,n = 77), organic aciduria (OA,n = 89), maple syrup urine disease (MSUD,n = 34), or tyrosinaemia type 1 (n = 13). METHODS: We collected growth parameters, pubertal status, BMAD, body composition, protein-intake, and IGF1 throughout growth. RESULTS: Overall final height (n = 69) was below target height (TH): -0.9(1.4) vs. -0.1(0.9) SD, p < 0.001. Final height was ≤ TH-2SD in 12 (21%) patients. Height ≤ - 2SD was more frequent during puberty than during early-infancy and pre-puberty: 23.5% vs. 6.9%, p = 0.002; and vs. 10.7%, p < 0.001. Pubertal delay was frequent (26.7%). Height (SD) was positively associated with isoleucine concentration: ß, 0.008; 95%CI, 0.003 to 0.012; p = 0.001. In the pubertal subgroup, height (SD) was lower in patients with vs. without AAM supplementation: -1.22 (1.40) vs. -0.63 (1.46) (p = 0.02). In OA, height and median (IQR) isoleucine and valine concentrations(µmol/L) during puberty were lower in patients with vs. without AAM supplementation: -1.75 (1.30) vs. -0.33 (1.55) SD, p < 0.001; and 40 (23) vs. 60 (25) (p = 0.02) and 138 (92) vs. 191 (63) (p = 0.01), respectively. No correlation was found with IGF1. Lean-mass index was lower than fat-mass index: -2.03 (1.15) vs. -0.44 (0.89), p < 0.001. CONCLUSIONS: In IAAMDs, growth retardation worsened during puberty which was delayed in all disease subgroups. Height seems linked to the disease, AAM composition and lower isoleucine concentration, independently of the GH-IGF1 pathway. We recommend close monitoring of diet during puberty.

Amino acid supplementation during the adaptation period did not affect the standardized ileal digestibility of amino acids in corn and soybean meal fed to pigs.

OBJECTIVE: The objective was to determine the influence of amino acid (AA) supplementation during the adaptation period on the ileal digestibility of crude protein and AA in corn and soybean meal (SBM) fed to pigs. METHODS: Six barrows with an initial body weight of 30.9±2.6 kg fitted with a T-cannula at the distal ileum were assigned to a 6×6 Latin square design with 6 dietary treatments and 6 periods. Two experimental diets contained corn or SBM as the sole AA source and an N-free diet was additionally prepared. For AA supplementation groups, an AA mixture consisted of Gly, Lys, Met, Thr, Trp, Ile, Val, His, and Phe was added to the corn diet and the N-free diet at the expense of cornstarch, and an AA mixture of Lys, Met, and Thr was added to the SBM diet. All diets contained 0.5% of chromic oxide. The 6 experimental diets were fed to the pigs for four and half days, and the 3 diets containing an AA mixture were switched to the respective diets without AA mixture during the following two and half days. Ileal digesta were collected on days 6 and 7. RESULTS: The addition of an AA mixture during the adaptation period increased apparent ileal digestibility of Arg and Trp in corn (p<0.05) but did not affect that in SBM. The addition of an AA mixture during the adaptation period increased apparent ileal digestibility of Pro and Gly regardless of feed ingredient (p<0.05) but did not affect that of other AA. All AA except Pro in corn and SBM were unaffected by the addition of the AA mixture during the adaptation period. CONCLUSION: The addition of amino acids to a low-protein diet during the adaptation period does not affect the standardized ileal digestibility of indispensable amino acids in pigs.

Protein Substitute Requirements of Patients with Phenylketonuria on BH4 Treatment: A Systematic Review and Meta-Analysis.

The traditional treatment for phenylketonuria (PKU) is a phenylalanine (Phe)-restricted diet, supplemented with a Phe-free/low-Phe protein substitute. Pharmaceutical treatment with synthetic tetrahydrobiopterin (BH4), an enzyme cofactor, allows a patient subgroup to relax their diet. However, dietary protocols guiding the adjustments of protein equivalent intake from protein substitute with BH4 treatment are lacking. We systematically reviewed protein substitute usage with long-term BH4 therapy. Electronic databases were searched for articles published between January 2000 and March 2020. Eighteen studies (306 PKU patients) were eligible. Meta-analyses demonstrated a significant increase in Phe and natural protein intakes and a significant decrease in protein equivalent intake from protein substitute with cofactor therapy. Protein substitute could be discontinued in 51% of responsive patients, but was still required in 49%, despite improvement in Phe tolerance. Normal growth was maintained, but micronutrient deficiency was observed with BH4 treatment. A systematic protocol to increase natural protein intake while reducing protein substitute dose should be followed to ensure protein and micronutrient requirements are met and sustained. We propose recommendations to guide healthcare professionals when adjusting dietary prescriptions of PKU patients on BH4. Studies investigating new therapeutic options in PKU should systematically collect data on protein substitute and natural protein intakes, as well as other nutritional factors.

Everyday Life, Dietary Practices, and Health Conditions of Adult PKU Patients: A Multicenter, Cross-Sectional Study.

BACKGROUND: Only few data on dietary management of adult phenylketonuria (PKU) patients are published. OBJECTIVES: This study aimed to assess living situation, dietary practices, and health conditions of early-treated adult PKU patients. METHODS: A total of 183 early-treated PKU patients ≥18 years from 8 German metabolic centers received access to an online survey, containing 91 questions on sociodemographic data, dietary habits, and health conditions. RESULTS: 144/183 patients (66% females) completed the questionnaire. Compared with German population, the proportion of single-person households was higher (22 vs. 47%), the rate of childbirth was lower (1.34 vs. 0.4%), but educational and professional status did not differ. 82% of the patients adhered to a low-protein diet, 45% consumed modified low-protein food almost daily, and 84% took amino acid mixtures regularly. 48% of the patients never interrupted diet, and 14% stopped diet permanently. 69% of the patients reported to feel better with diet, and 91% considered their quality of life at least as good. The prevalence of depressive symptoms was high (29%) and correlated significantly to phenylalanine blood concentrations (p = 0.046). However, depressive symptoms were only mild in the majority of patients. CONCLUSION: This group of early-treated adult German PKU patients is socially well integrated, reveals a surprisingly high adherence to diet and amino acid intake, and considers the restrictions of diet to their daily life as low.

Acute supplementation with an amino acid mixture suppressed the exercise-induced cortisol response in recreationally active healthy volunteers: a randomized, double-blinded, placebo-controlled crossover study.

BACKGROUND: Few studies have demonstrated the suppressive effects of amino acids (AAs) on the level of cortisol during exercise in humans. We hypothesized that an AA mixture containing arginine, which promotes lipid metabolism, valine, which effectively decreases the level of glucocorticoid, and serine, a substrate in the production of phosphatidylserine that is reported to blunt increases in cortisol, would suppress the exercise-induced cortisol response by combining the positive effects of the AAs synergistically. METHODS: A randomized, double-blinded, placebo-controlled crossover trial was conducted. Twenty healthy recreationally active males ingested either an AA mixture containing 1.8 g of arginine, 1.1 g of valine, and 0.1 g of serine or a placebo. Thirty minutes after ingestion, subjects performed an exercise trial on a cycle ergometer for 80 min at 50% maximal oxygen consumption. Plasma cortisol and other blood parameters immediately before and after the exercise were evaluated. RESULTS: Plasma cortisol concentrations after exercise were significantly higher than those before exercise in the placebo condition (9.51 ± 0.85 vs 14.39 ± 2.15, p < 0.05), while there was no significant difference in the AA condition (9.71 ± 0.93 vs 9.99 ± 1.23, p = 0.846). In addition, the increase in plasma cortisol before and after exercise was significantly lower in the AA condition than in the placebo condition (0.28 [- 2.75, 3.31] vs 4.87 [0.89, 8.86], p < 0.05). For the level of adrenocorticotropin, there was a significant difference between before and after exercise only in the placebo condition (24.21 ± 2.91 vs 53.17 ± 6.97, p < 0.01) but not in the AA condition (27.33 ± 3.60 vs 46.92 ± 10.41, p = 0.057). Blood glucose, plasma lactate, plasma ammonia, serum creatine phosphokinase, serum total ketone body, and serum free fatty acid were also significantly changed by the exercise load in both conditions, but no significant differences were observed between the two conditions. CONCLUSIONS: The present study demonstrated that the AA mixture suppressed the cortisol response during exercise without affecting exercise-related biological parameters such as glucose or lipid metabolism. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000023587 . Registered 19 August 2016.

An open-label, single-center pilot study to test the effects of an amino acid mixture in older patients admitted to internal medicine wards.

OBJECTIVE: Older patients are frequently subjected to prolonged hospitalization and extended bed rest, with a negative effect on physical activity and caloric intake. This results in a consistent loss of muscle mass and function, which is associated with functional decline and high mortality. The aim of this study was to investigate the effect of 1 wk of oral amino acid (AA) supplementation in older patients subjected to low mobility during hospitalization. METHODS: Hospitalized older patients (69-87) were included in the control group (n = 50) or were administered 25 g of AA mixture (n = 44) twice daily throughout 7 d of low mobility. We collected data related to length of stay as primary outcome measure. In-hospital mortality, 90-d postdischarge mortality, 90-d postdischarge rehospitalization, and falls also were considered. Moreover, variations of anthropometric measures, body composition and muscle architecture/strength, circulating interleukins, and oxidative stress markers between the beginning and the end of the supplementation period were analyzed as secondary outcomes. RESULTS: Similar values were reported between the two groups regarding age (76.6 ± 6.8 versus 79 ± 7.2 y old), body weight (61.5 ± 14.3 versus 62.1 ± 16.1 kg), and body mass index (28.7 ± 4.15 versus 28.1 ± 3.62 kg/m2). Although no difference in terms of in-hospital, 90-d postdischarge, or overall mortality rate was observed between the two groups, a reduction in length of stay, 90-d postdischarge hospitalization, and falls was observed in the AA supplementation group rather than in controls. Furthermore, the AA mixture limited muscle architecture/strength impairment and circulating oxidative stress, which occurred during hospitalization-related bed rest. The latter data was associated with increased circulating levels of anti-inflammatory cytokines interleukin-4 and -10. CONCLUSIONS: These results suggest that the AA mixture limits several alterations associated with low mobility in older hospitalized patients, such as length of stay, 90-d postdischarge hospitalization, and falls, preventing the loss of muscle function, as well as the increase of circulating interleukins and oxidative stress markers.

Combined Effect of Arginine, Valine, and Serine on Exercise-Induced Fatigue in Healthy Volunteers: A Randomized, Double-Blinded, Placebo-Controlled Crossover Study.

Although several kinds of amino acids (AAs) are known to affect physiological actions during exercise, little is known about the combined effects of a mixture of several AAs on fatigue during exercise. The aim of the present study was to investigate the effect of an AA mixture supplement containing arginine, valine, and serine on exercise-induced fatigue in healthy volunteers. These AAs were selected because they were expected to reduce fatigue during exercise by acting the positive effects synergistically. A randomized, double-blinded, placebo-controlled crossover trial was conducted. Thirty-nine males ingested an AA mixture containing 3600 mg of arginine, 2200 mg of valine, and 200 mg of serine or a placebo each day for 14 days. On the 14th day, the participants completed an exercise trial on a cycle ergometer at 50% of VO2max for 120 min. After the two-week washout period, the participants repeated the same trial with the other test sample. The participant's feeling of fatigue based on a visual analog scale (VAS) and a rating of perceived exertion (RPE), as well as blood and physical parameters were evaluated. The feeling of fatigue based on VAS and RPE were significantly improved in AA compared to those in placebo. In the blood analysis, the increase in serum total ketone bodies during exercise and plasma tryptophan/branched-chain amino acids were significantly lower in AA than those in placebo. The present study demonstrated that supplementation with an AA mixture containing arginine, valine, and serine reduced the feeling of fatigue during exercise. The AA mixture also changed several blood parameters, which may contribute to the anti-fatigue effect.

The challenge of long-term tetrahydrobiopterin (BH4) therapy in phenylketonuria: Effects on metabolic control, nutritional habits and nutrient supply.

BACKGROUND AND AIMS: BH4-sensitive phenylketonuria (PKU) patients relax their phenylalanine (Phe) restricted diet due to increased Phe tolerance, while keeping dried blood Phe concentrations with in the therapeutic range. We aimed to investigate metabolic control, eating habits and nutrient supply under long-term BH4-therapy. PATIENTS AND METHODS: Retrospective analysis of mean dried blood Phe concentrations and their variability, food and nutrient intake in BH4-sensitive patients (n = 8, 3f, age 6.0-16.6 y) under classical dietary treatment for one year and during the three years after initiation of BH4. RESULTS: Phe concentrations of BH4-sensitve PKU patients remained within therapeutic range throughout the observation period, independent of therapeutic regime. Under BH4, Phe tolerance increased significantly (493.2 ± 161.8 mg/d under classical diet vs 2021.93 ± 897.4 mg/d two years under BH4; P = 0.004). Variability of Phe concentrations remained unchanged (mean SD; P = 1.000). Patients adjust their food choice and significantly increased their intake of cereals, potatoes, dairy products and meat (P = 0.019, P = 0.016, P = 0.016 and P = 0.016, respectively). Under diet changes after implementation of BH4 a drop in micronutrient intake (vitamin D, folic acid, iron, calcium, iodine) could be revealed (P = 0.005, P < 0.001, P = 0.004, P = 0.001, P = 0.003, respectively). CONCLUSIONS: BH4-sensitive PKU patients can achieve good metabolic control under an adjuvant BH4- or a BH4 monotherapy. The liberalized diet under BH4 seems to jeopardize the quality of patients' nutrition, and these patients require close follow-up and special nutrition education to minimize the risk for imbalanced diet and nutrient deficiencies.