Phenylalanine-restricted Diet Research Articles

Phenylketonuria from the perspectives of patients in Türkiye

BackgroundThe present study aimed to determine the problems, unmet needs and expectations of phenylketonuria (PKU) patients in Türkiye regarding follow-up and treatment in order to provide data for future planning and implementations on PKU.MethodsThe study included patients diagnosed with PKU and/or their parents. They were informed about the study via phone calls and their verbal consents were obtained. Questions in the data collection forms, which were established separately for pediatric, adolescent, and adult age groups, were applied during the interviews and the answers were recorded.ResultsAmong 182 classical PKU patients, 66 (36.3%) were in the pediatric group (0–12 years old), 44 (24.2%) were in the adolescent group (13–19 years old), and 72 (39.5%) were in the adult group (≥ 20 years old). In all patient groups, phenylalanine-restricted diet and medical nutrition products were the main options for treatment. The median of the last measured blood phenylalanine concentration (patient-reported) was 290 µmol/L, 425 µmol/L, and 750 µmol/L in the pediatric, adolescent, and adult groups, respectively. The frequency of blood testing for serum phenylalanine level according to the age groups was appropriate in nearly half of the patients. While the majority of the patients have been visiting the metabolism center they have been diagnosed with PKU for control, considerable proportion of the patients would like to change the center or the doctor they visit for control if they could. It was determined that nearly half of the patients had trouble in accessing the metabolism center. Treatment options’ being limited and expensive were the major problems. The main requests of the patients and patient relatives included easier access to the metabolism centers and more options for treatment and diet.ConclusionsAccess to the services should be easier to improve the patients’ follow-up and treatment. There is need for low-cost, easily applicable, and accessible nutrition products and effective novel pharmacological agents. Focusing on these issues in health policies by providing pedagogic/psychological support, establishing support programs also comprising the families, and increasing the awareness activities were the key outcomes.

Maximal dietary responsiveness after tetrahydrobiopterin (BH4) in 19 phenylalanine hydroxylase deficiency patients: What super-responders can expect

BackgroundInherited phenylalanine hydroxylase deficiency, also known as phenylketonuria (PKU), causes poor growth and neurologic deficits in the untreated state. After ascertainment through newborn screen and dietary phenylalanine (Phe) restriction to achieve plasma Phe in the range of 120–360 μmol/L, these disease manifestations can be prevented. Poor compliance with protein restricted diets supported by medical food is typical in later years, beginning in the late toddler and teenage years. Pharmacologic doses of oral tetrahydrobiopterin (BH4; sapropterin dihydrochloride) is effective in reducing plasma Phe in about 40–50% of PKU patients but effectiveness is highly variable. ObjectiveTo assess the maximal responsiveness to 20 mg/kg/day oral BH4 as it affects plasma Phe and dietary Phe allowance in PKU patients. Materials and methodsThis was a single-center, retrospective observational study, combining case reports of individual patients. We reported an outcome of 85 patients with PKU who were trialed on BH4. Phe levels and dietary records of 19 BH4 “super-responders” were analyzed. ResultsOverall, 63.5% of the patients (54/85) were considered BH4 responders. However, we quantitated the dietary liberalization of 19 of our responsive patients (35%), those with at least a 2-fold increase in dietary Phe and maintenance of plasma Phe in treatment range. In these “super-responders”, the mean plasma Phe at baseline was 371 ± 237 μmol/L and decreased to 284 ± 273 μmol/L after 1 year on BH4. Mean dietary Phe tolerance increased significantly from 595 ± 256 to 2260 ± 1414 mg/day (p ≤0.0001), while maintaining mean plasma Phe levels within treatment range. Four patients no longer required dietary Phe restriction and could discontinue medical food. The majority of patients had at least one BH4-responsive genotype. ConclusionThis cohort demonstrates the maximally achievable dietary liberalization which some PKU patients may expect with BH4 therapy. Health benefits are considered to accrue in patients with increased intact protein.

Phenylketonuria at HMIMV Rabat: About 15 Cases

Phenylketonuria is a disorder of amino acid metabolism causing an intellectually handicapping disease with cognitive and behavioral disorders, caused by elevated serum levels of phenylalanine. The primary cause is phenylalanine hydroxylase deficiency. Diagnosis is based on the detection of elevated phenylalanine and normal or low tyrosine levels. Treatment is lifelong dietary restriction of phenylalanine. The prognosis is excellent under treatment.

Predictors of eventual requirement of phenylalanine-restricted diet in young infants with phenylalanine hydroxylase deficiency initially managed with sapropterin monotherapy

BackgroundPhenylalanine (Phe)-restricted diet is associated with lower quality of life for patients with phenylketonuria (PKU), and a concern for caregivers of recently-diagnosed infants. Sapropterin is an oral drug used as an alternative or adjunct to dietary treatment. We have observed that some of the young infants initially managed successfully with sapropterin monotherapy have required dietary treatment in long-term follow-up. We aimed to determine the baseline factors associated with future initiation of dietary treatment in these patients. MethodsData were obtained retrospectively from the medical records of 80 PKU patients started on sapropterin monotherapy before 3 months of age between 2011 and 2021. ResultsThe patients were followed for a median of 3.9 years (Q1-Q3: 2.5–5.75 years). Sapropterin was tapered down and discontinued in 5 patients (6.3%) as their Phe levels remained below 360 μmol/L without treatment. Sapropterin monotherapy was sufficient in 62 patients (77.5%), while 13 (16.2%) required dietary treatment. Phe and tyrosine (Tyr) levels, and Phe:Tyr ratios differed significantly among the patients maintained on sapropterin monotherapy and those started on dietary treatment, but the Phe:Tyr ratio at diagnosis was the most important independent baseline variable (OR: 1.61, 95% CI: 1.15–2.27, p = 0.006), with Phe:Tyr ratio at diagnosis >5.25 associated with dietary treatment (sensitivity: 90.0%, specificity: 81.8%). Genotypic phenotype value (GPV), unavailable at baseline, was also associated with dietary treatment (median GPV 9.2 vs. 3.8, p = 0.006), but some genotypes were not specific to the final treatment modality. DiscussionWe propose that the Phe:Tyr ratio at diagnosis is an important indicator to predict dietary requirement in young infants initially managed with sapropterin monotherapy.

Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing

Moderate inflammation is essential for standard wound healing. In pathological conditions, such as diabetes, protracted and refractory wounds are associated with excessive inflammation, manifested by persistent proinflammatory macrophage states. However, the mechanisms are still unclear. Herein, we perform a metabolomic profile and find a significant phenylpyruvate accumulation in diabetic foot ulcers. Increased phenylpyruvate impairs wound healing and augments inflammatory responses, whereas reducing phenylpyruvate via dietary phenylalanine restriction relieves uncontrolled inflammation and benefits diabetic wounds. Mechanistically, phenylpyruvate is ingested into macrophages in a scavenger receptor CD36-dependent manner, binds to PPT1, and inhibits depalmitoylase activity, thus increasing palmitoylation of the NLRP3 protein. Increased NLRP3 palmitoylation is found to enhance NLRP3 protein stability, decrease lysosome degradation, and promote NLRP3 inflammasome activation and the release of inflammatory factors, such as interleukin (IL)-1β, finally triggering the proinflammatory macrophage phenotype. Our study suggests a potential strategy of targeting phenylpyruvate to prevent excessive inflammation in diabetic wounds.

Glycomacropeptide (GMP) rescued the oxidative and inflammatory activity of free L-AAs in human Caco-2 cells: New insights that support GMP as a valid and health-promoting product for the dietary management of phenylketonuria (PKU) patients

Phenylketonuria represents the most prevalent inborn error of amino acid metabolism. In early diagnosed patients adequate and continued dietary treatment results in a good neurologic outcome. However, due to the natural protein and phenylalanine-restricted diet, oxidative stress represents a concern in phenylketonuric patients. Clear evidences suggest that the pathophysiology of PKU is also dependent by mitochondrial impairment and oxidative stress. In this context due to the tight connection between oxidative and inflammatory stress and noncommunicable diseases (NCDs) development, it is reasonable to hypothesize that PKU patients may present a higher risk to develop NCDs during their life. Currently available protein substitutes on the market include free amino acids (L-AAs), prolonged-release protein substitute and formula containing glycomacropeptide (GMP). Our results suggest that free L-AAs significanlty worsens the intestinal hydrogen peroxide (H2O2) and lipopolysaccharides (LPS)-induced oxidative and inflammatory status in Caco-2 cells, which are significantly restored towards physiological condition by GMP alone and when present in a 1:1 mixture with free L-AAs, providing new preclinical piece of information which can shed a shadow on the mechanism of action of these products on PKU patients and their future management.

Muscle and Bone Health in Young Chilean Adults with Phenylketonuria and Different Degrees of Compliance with the Phenylalanine Restricted Diet.

Three groups were considered-PKU-1: 10 patients who used a protein substitute (PS) without phenylalanine (Phe); PKU-2: 14 patients who used the PS without Phe until eighteen years old and then practiced mostly a vegan diet; and 24 matched healthy controls. A 24 h recall survey, blood parameters, body composition and bone mineral density through DEXA, rectus femoris thickness by ultrasound, hand grip strength, submaximal exercise test, and walking speed were assessed. PKU-1 patients had lower hand grip strength than their matched controls, but no other differences. Compared to controls, the PKU-2 group had lower fat-free mass (p = 0.01), less spine and femoral bone mineral density (p = 0.04 and p < 0.01, respectively), and peak workload on the incremental test (p = 0.03). When comparing PKU groups, blood Phe levels were significantly lower in the PKU-1 group (p = 0.02). Among PKU patients, abandoning the dietary treatment and maintaining high blood Phe concentrations could be deleterious for muscles and bones. However, we cannot discard other causes of bone and muscle damage in these patients.

Continuous preparation of low-phenylalanine formulations by treatment of edible protein with immobilized phenylalanine ammonia lyase

Dietary restriction of phenylalanine is the predominant treatment for phenylketonuria. However, the currently available medicated formulations depend on an arduous and unsustainable chemical extraction procedure, which inflates the product’s price. Here, we describe a method that uses immobilized phenylalanine ammonia lyase (PAL) and offers a sustainable solution to generate a low-phenylalanine protein supplement for phenylketonuria patients. This enzyme deaminates phenylalanine to trans-cinnamic acid. Here, we optimized the high cell density cultivation of a recombinant Escherichia coli strain harboring Anabaena variabilis PAL (AvPAL) and achieved protein titers greater than 400 mg/l. This AvPAL protein was immobilized on multiwall carbon nanotubes, and the bioconjugate retained > 50 % activity after ten successive cycles with significantly improved thermostability. Batch deamination with the bioconjugate showed an 80 % reduction in the total phenylalanine content of soya protein hydrolysate. In a continuous packed bed column, > 98 % of the phenylalanine content was depleted at a feed flow rate of 0.1 ml/min, resulting in a space-time yield of cinnamate of 6.65 g/l/h. In a 72-h continuous run, the bioconjugate lost only 2 % of its activity with an operational inactivation constant of 3.9 × 10−5 min−1. This simple covalent immobilization method offers the potential to generate low-phenylalanine diet for phenylketonuria patients.

Phenylalanine free infant formula in the dietary management of phenylketonuria

BackgroundPhenylalanine-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.).ResultsThis 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.ConclusionThe 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.

Characterization of Choline Nutriture among Adults and Children with Phenylketonuria.

Choline is an essential nutrient for brain development and function that is attained through high-protein foods, which are limited in the phenylalanine-restricted diet of people with phenylketonuria (PKU). This study compared choline consumption among individuals with PKU to a reference sample from the National Health and Nutrition Examination Survey (NHANES), and identified treatment and diet-related factors that may modulate choline needs. Participants were individuals with PKU (n = 120, 4–61 years) managed with dietary therapy alone (n = 49), sapropterin dihydrochloride for ≥1 year (n = 38), or pegvaliase for ≥1 year with no medical food (n = 33). NHANES participants were not pregnant or nursing and came from the 2015–2018 cycles (n = 10,681, 4–70 years). Dietary intake data were used to estimate total usual intake distributions for choline, and mean probability of adequacy (MPA) was calculated as a summary index of nutrient adequacy for four methyl-donor/co-factor nutrients that impact choline utilization (folate, vitamin B12, vitamin B6, and methionine). Only 10.8% (SE: 2.98) of the total PKU sample (14.7% [SE: 4.03] of children; 6.8% [SE: 2.89] of adults) achieved the adequate intake (AI) for choline, while 12.2% (SE:0.79) of the NHANES sample met the recommended level. Adults receiving pegvaliase were the most likely to exceed the AI for choline (14.82% [SE: 4.48]), while adults who were on diet therapy alone were the least likely (5.59% [SE: 2.95]). Without fortified medical foods, individuals on diet therapy and sapropterin would not be able to achieve the AI, and MPA for other methyl donor/co-factor nutrients would be reduced. More frequent monitoring of choline intake and increased choline fortification of medical foods could benefit this population.

Is the phenylalanine-restricted diet a risk factor for overweight in patients with phenylketonuria? A Systematic Review and Meta-Analysis

Is the phenylalanine-restricted diet a risk factor for overweight in patients with phenylketonuria? A Systematic Review and Meta-Analysis

The Challenges and Dilemmas of Interpreting Protein Labelling of Prepackaged Foods Encountered by the PKU Community.

Phenylketonuria (PKU) can lead to severe intellectual impairment unless a phenylalanine-restricted diet starts early in life. It requires expert user knowledge about the protein content of foods. The ability of adults or caregivers of children with PKU to calculate protein exchanges from food labels on manufactured foods and any difficulties they encounter in interpreting food labels has not been studied systematically. Individuals with PKU or their caregivers residing in the UK were invited to complete a cross-sectional online survey that collected both qualitative and quantitative data about their experience when calculating protein exchanges from the food labelling on prepackaged foods. Data was available from 246 questionnaire respondents (152 caregivers of patients with PKU aged <18 years, 57 patients with PKU aged ≥18 years or their caregivers (n = 28), and 9 teenagers with PKU). Thirty-one per cent (n = 76/246) found it difficult to interpret food protein exchanges from food labels. The respondents listed that the main issues with protein labelling were the non-specification of whether the protein content was for the cooked or uncooked weight (64%, n = 158/246); labels stating foods contained 0 g protein but then included protein sources in the list of ingredients (56%, n = 137/246); the protein content being given after a product was prepared with regular milk rather than the dry weight of the product (55%, n = 135/246); and the non-clarity of whether the protein content was for the weight of prepared or unprepared food (in addition to non-specification of cooked or uncooked weights on food labelling) (54%, n = 133/246). Over 90% (n = 222/246) of respondents had experienced problems with food labelling in the previous six months. Misleading or confusing protein labelling of manufactured foods was common. The food industry and legislators have a duty to provide accurate and clear protein food labelling to protect populations requiring low protein diets.

Perturbation of monoamine metabolism and enhanced fear responses in mice defective in the regeneration of tetrahydrobiopterin.

Increasing evidence suggests the involvement of peripheral amino acid metabolism in the pathophysiology of neuropsychiatric disorders, whereas the molecular mechanisms are largely unknown. Tetrahydrobiopterin (BH4) is a cofactor for enzymes that catalyze phenylalanine metabolism, monoamine synthesis, nitric oxide production, and lipid metabolism. BH4 is synthesized from guanosine triphosphate and regenerated by quinonoid dihydropteridine reductase (QDPR), which catalyzes the reduction of quinonoid dihydrobiopterin. We analyzed Qdpr-/- mice to elucidate the physiological significance of the regeneration of BH4. We found that the Qdpr-/- mice exhibited mild hyperphenylalaninemia and monoamine deficiency in the brain, despite the presence of substantial amounts of BH4 in the liver and brain. Hyperphenylalaninemia was ameliorated by exogenously administered BH4, and dietary phenylalanine restriction was effective for restoring the decreased monoamine contents in the brain of the Qdpr-/- mice, suggesting that monoamine deficiency was caused by the secondary effect of hyperphenylalaninemia. Immunohistochemical analysis showed that QDPR was primarily distributed in oligodendrocytes but hardly detectable in monoaminergic neurons in the brain. Finally, we performed a behavioral assessment using a test battery. The Qdpr-/- mice exhibited enhanced fear responses after electrical foot shock. Taken together, our data suggest that the perturbation of BH4 metabolism should affect brain monoamine levels through alterations in peripheral amino acid metabolism, and might contribute to the development of anxiety-related psychiatric disorders. Cover Image for this issue:https://doi.org/10.1111/jnc.15398.

Dietetic Management of Adults with Phenylketonuria (PKU) in the UK: A Care Consensus Document.

There is an increasing number of adults and elderly patients with phenylketonuria (PKU) who are either early, late treated, or untreated. The principal treatment is a phenylalanine-restricted diet. There is no established UK training for dietitians who work with adults within the specialty of Inherited Metabolic Disorders (IMDs), including PKU. To address this, a group of experienced dietitians specializing in IMDs created a standard operating procedure (SOP) on the dietetic management of adults with PKU to promote equity of care in IMD dietetic services and to support service provision across the UK. The group met virtually over a period of 12 months until they reached 100% consensus on the SOP content. Areas of limited evidence included optimal blood phenylalanine reporting times to patients, protein requirements in older adults, management of weight and obesity, and management of disordered eating and eating disorders. The SOP does not include guidance on maternal PKU management. The SOP can be used as a tool for training dietitians new to the specialty and to raise the standard of education and care for patients with PKU in the UK.

Disorders of Tetrahydrobiopterin Metabolism: Experience from South India

Disorders of tetrahydrobiopterin metabolism represent a rare group of inherited neurotransmitter disorders that manifests mainly in infancy or childhood with developmental delay, neuroregression, epilepsy, movement disorders, and autonomic symptoms. A retrospective review of genetically confirmed cases of disorders of tetrahydrobiopterin metabolism over a period of three years (Jan 2018 to Jan 2021) was performed across two paediatric neurology centres from South India. A total of nine patients(M:F=4:5) fulfilled the eligibility criteria. The genetic variants detected include homozygous mutations in the QDPR(n=6), GCH1(n=2), and PTS(n=1) genes. The median age at onset of symptoms was 6-months(range 3-78 months), while that at diagnosis was 15-months (8-120 months), resulting in a median delay in diagnosis of 9-months. The main clinical manifestations included neuroregression (89%), developmental delay(78%), dystonia(78%) and seizures(55%). Management strategies included a phenylalanine restricted diet, levodopa/carbidopa, 5-Hydroxytryphtophan, and folinic acid. Only, Patient-2 afforded and received BH4 supplementation at a sub-optimal dose later in the disease course. We had a median duration of follow up of 15 months (range 2-48 months). Though the biochemical response has been marked; except for patients with GTPCH deficiency, only mild clinical improvement was noted with regards to developmental milestones, seizures, or dystonia in others. Tetrahydrobiopterin deficiencies represent a rare yet potentially treatable cause for non-phenylketonuria hyperphenylalaninemia with better outcomes when treated early in life. Screening for disorders of biopterin metabolism in patients with hyperphenylalaninemia prevents delayed diagnosis. This study expands the genotype-phenotype spectrum of patients with disorders of tetrahydrobiopterin metabolism from South India.

Tyrosinemia type I: an unusual case presentation

Background: Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive inherited metabolic disorder caused by the fumerylacetoacetate hydrolase enzyme deficiency. It is characterized by liver dysfunction and/ or failure, renal tubular dysfunction. If left untreated it may lead to Fanconi syndrome and neurological crisis (porphyria-like crisis). Nitisinone is the recommended therapy for HT1 in combination with tyrosine and phenylalanine restricted diet. Case Presentation: In this report, we present 3 years and 8-months-old boy who was referred to the Metabolic Clinic after his cousin was diagnosed with HT1. His history was significant for pleural effusion at 8 months of age which contributed to pulmonary tuberculosis. His alpha-fetoprotein was checked (for no apparent reason) at one and a half years of age and was elevated. Upon evaluation at 3 years and 8 months at our facility, his succinylacetone was significantly elevated. Liver function tests and coagulation results were also mildly elevated. Liver ultrasound was routine apart from gallstones. Targeted mutation testing revealed a fumarylacetoacetate hydrolase gene&amp;apos;s homozygous pathogenic variant (c.982C&amp;gt;T; p. Gln328*). Conclusion: In conclusion, we presented a patient with an unusual, late presentation of HT1, to highlight the clinical variability in this rare, treatable metabolic disease.

The increasing importance of LNAA supplementation in phenylketonuria at higher plasma phenylalanine concentrations

BackgroundLarge neutral amino acid (LNAA) treatment has been suggested as alternative to the burdensome severe phenylalanine-restricted diet. While its working mechanisms and optimal composition have recently been further elucidated, the question whether LNAA treatment requires the natural protein-restricted diet, has still remained. ObjectiveFirstly, to determine whether an additional liberalized natural protein-restricted diet could further improve brain amino acid and monoamine concentrations in phenylketonuria mice on LNAA treatment. Secondly, to compare the effect between LNAA treatment (without natural protein) restriction and different levels of a phenylalanine-restricted diet (without LNAA treatment) on brain amino acid and monoamine concentrations in phenylketonuria mice. DesignBTBR Pah-enu2 mice were divided into two experimental groups that received LNAA treatment with either an unrestricted or semi phenylalanine-restricted diet. Control groups included Pah-enu2 mice on the AIN-93 M diet, a severe or semi phenylalanine-restricted diet without LNAA treatment, and wild-type mice receiving the AIN-93 M diet. After ten weeks, brain and plasma samples were collected to measure amino acid profiles and brain monoaminergic neurotransmitter concentrations. ResultsAdding a semi phenylalanine-restricted diet to LNAA treatment resulted in lower plasma phenylalanine but comparable brain amino acid and monoamine concentrations as compared to LNAA treatment (without phenylalanine restriction). LNAA treatment (without phenylalanine restriction) resulted in comparable brain monoamine but higher brain phenylalanine concentrations compared to the severe phenylalanine-restricted diet, and significantly higher brain monoamine but comparable phenylalanine concentrations as compared to the semi phenylalanine-restricted diet. ConclusionsPresent results in PKU mice suggest that LNAA treatment in PKU patients does not need the phenylalanine-restricted diet. In PKU mice, LNAA treatment (without phenylalanine restriction) was comparable to a severe phenylalanine-restricted diet with respect to brain monoamine concentrations, notwithstanding the higher plasma and brain phenylalanine concentrations, and resulted in comparable brain phenylalanine concentrations as on a semi phenylalanine-restricted diet.

Is the Phenylalanine-Restricted Diet a Risk Factor for Overweight or Obesity in Patients with Phenylketonuria (PKU)? A Systematic Review and Meta-Analysis.

Although there is a general assumption that a phenylalanine (Phe)-restricted diet promotes overweight in patients with phenylketonuria (PKU), it is unclear if this presumption is supported by scientific evidence. This systematic review aimed to determine if patients with PKU are at a higher risk of overweight compared to healthy individuals. A literature search was carried out on PubMed, Cochrane Library, and Embase databases. Risk of bias of individual studies was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, and the quality of the evidence for each outcome was assessed using the NutriGrade scoring system. From 829 articles identified, 15 were included in the systematic review and 12 in the meta-analysis. Body mass index (BMI) was similar between patients with PKU and healthy controls, providing no evidence to support the idea that a Phe-restricted diet is a risk factor for the development of overweight. However, a subgroup of patients with classical PKU had a significantly higher BMI than healthy controls. Given the increasing prevalence of overweight in the general population, patients with PKU require lifelong follow-up, receiving personalised nutritional counselling, with methodical nutritional status monitoring from a multidisciplinary team in inherited metabolic disorders.

Symposium Title: Recent Achievement and Future Prospects of Cognitive, Physical, and Nutrition Interventions for Brain and Cognitive Functions in an Aging Population

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.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.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).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.

Does Dietary Treatment Cause Obesity in Phenylketonuria? Comparison of Obesity Ratios of Patients Receiving Dietary Treatment and Tetrahydrobiopterin Treatment

Phenylketonuria is treated either with tetrahydrobiopterin (BH4) or with a phenylalanine-restricted diet. Patients in the diet group may tend to consume carbohydrate-rich foods which have a risk for obesity. In this study, the prevalence of obesity+overweight among phenylketonuria patients either treated with phenylalanine-restricted diet or with BH4 were compared.Patients with phenylketonuria were divided into two groups on dietary treatment and BH4 treatment. Body mass index (BMI), BMI-percentile, and z-score values of patients were calculated and classified as underweight, normal-weight, overweight, and obese according to their nutritional status. The annual mean phenylalanine level of each patient is also evaluated. The study was done retrospectively.A total of 130 patients was included. 77 were receiving diet (female (n,%):37, 48.1%; male (n,%):40, 51.9%) and 53 were receiving BH4 (female (n,%):33, 62.3%; male (n,%):20, 37.7%) respectively. According to BMI-z-score, the sum of the ratio of obesity+overweight was found to be 35.1% in the diet group, 16.9% in the BH4 group. Ratio was significantly higher in diet group (p=0.02). When obesity+overweight ratios were examined in terms of female/male distribution, no significant difference was found. Considering the correlation of obesity+overweight ratios with age in two groups, the median age of the patients with normal weight+underweight in the BH4 group were found as 46-months, and the median age of obese+overweight patients was 137-months (p=0.001). For the same situation, there was no significant difference in the dietary treatment group (p=0.92). Mean annual phenylalanine levels were significantly higher in obese+overweight patients (p=0.047) in the BH4 treatment group but this difference was not significant in the diet group (p=0.051).Patients on the phenylalanine-restricted diet have a risk of obesity or overweight. Therefore, attention should be paid not only to the phenylalanine levels of these patients but also to their weight control and dietary content