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Introduction: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder resulting from phenylalanine hydroxylase deficiency, which impacts neurodevelopment. Lifelong low-phenylalanine diets and multidisciplinary care are pivotal for managing PKU. Latin American challenges in PKU care include diverse newborn screening programs, limited specialized healthcare, and resource scarcity. Methods: A systematic literature review was conducted (2010-2023) on PKU management following PRISMA guidelines. Inclusion criteria encompassed English/Spanish articles focusing on PKU management guidelines approved by an organization as well as articles focusing on PKU management in Latin America. After screening 127,276 results, 6 articles were included. Results: Six articles were analyzed, highlighting shared principles like multidisciplinary care, lifelong dietary adherence, personalized plans, and regular monitoring. Guides emphasized regional variations, breastfeeding complexities, and challenges for pregnant women with PKU. Discussion: Multidisciplinary care emerges as critical, incorporating physicians, psychologists, dietitians, nurses, and genetic counselors. Lifelong adherence to low-phenylalanine diets and personalized strategies for different life stages are emphasized. Challenges in Latin America include healthcare gaps, scarce resources, and reliance on international guidance. The importance of breastfeeding, preconception care, and comprehensive support for pregnant women with PKU is underscored. Conclusion: Collaborative efforts are essential to address PKU challenges in Latin America. Advocacy for awareness, specialized training, regional databases, and international collaborations can enhance diagnosis and management, ensuring a better quality of life for PKU individuals in the region. Embracing lessons from existing guides will contribute to improved PKU care and overall well-being.

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Abstract Phenylketonuria (PKU) is an autosomal recessive defect affecting the metabolic pathway of phenylalanine (Phe), causing hyperphenylalaninemia and neurotoxicity. Diagnosis must occur in the neonatal period and treatment should begin as early as possible. Evidence implies that treatment adherence declines as age advances. The aim was to describe the diet of a subgroup of Chilean adults with PKU currently in follow-up. Fifty-three subjects (49% women) followed up between January 2021 to April 2023 were considered. The concentration of Phe (PheC) in dried blood spots measured by fluorometry and 24-hour dietary recalls were analyzed. The median PheC of the sample was 438µmol/L (interquartile range(IQR):351-585µmol/L). A protein intake of 1.35±0.3 gr/Kg/d was observed of which 87% came from the protein substitute without Phe. Participants had a median Phe intake of 459mg/d (IQR:327-976) and 13.1g/d of fiber intake. Most participants, 51% and 92% reported consuming fruits and vegetables, respectively, and 32% consumed Low-Protein foods. Regarding micronutrients, all participants exceeded 90% adequacy according to recommendations. For vitamin-D and vitamin-B12, 100% is provided by the protein substitute. According to our results, it is mandatory to establish transition programs toward adulthood, to constantly maintain good metabolic control, and to adapt diet therapy to their new lifestyle.

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BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive disease resulting from a deficiency of the enzyme phenylalanine hydroxylase (PAH). Hyperphenylalaninemias (HPA) due to PAH deficiency are accompanied by a wide variety of clinical, biochemical, and molecular features. To identify and characterize pathogenic variants in the PAH gene and establish a correlation between genotype and biochemical phenotype in patients with PKU from state of Pará in the North Region of Brazil. METHODS: All 13 exons of the PAH gene from 32 patients (21 PKU and 11 non-PKU HPA) were amplified by PCR and submitted to DNA sequencing (Sanger). Biochemical data were obtained from the patients' medical records. RESULTS: Molecular analysis identified 17 pathogenic variants and 3 nonpathogenic variants. The most frequent pathogenic variants were IVS10-11G>A (7.9%), p. Arg261Gln (7.9%), p. Val388Met (6.3%) and p. Ile65Thr (4.7%). Was observed correlations and inconsistencies between genotype and biochemical phenotype. CONCLUSION: In PKU patients from state of Pará, North Region of Brazil, a heterogeneous mutation spectrum was revealed, in which the most frequent mutations are variants commonly observed in other Brazilian studies and in the region of the Iberian Peninsula.

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OBJECTIVE: To evaluate effects of sapropterin dihydrochloride on blood phenylalanine (Phe) and symptoms of neuropsychiatric impairment in children and adolescents with phenylketonuria (PKU). STUDY DESIGN: PKU subjects 8-17 years of age (n = 86) were randomized to double-blind treatment with sapropterin (n = 43) or placebo (n = 43) for 13 weeks, then all received open-label sapropterin therapy for an additional 13 weeks. Blood Phe and symptoms of inattention, hyperactivity/impulsivity (Attention-Deficit/Hyperactivity Disorder Rating Scale IV [ADHD RS-IV]), executive functioning (Behavior Rating Inventory of Executive Function), depression (Hamilton Rating Scale for Depression), and anxiety (Hamilton Rating Scale for Anxiety) were assessed. RESULTS: Following the 13-week randomization phase, the sapropterin and placebo groups had mean changes in blood Phe of -20.9% and +2.9%, respectively. Corresponding least square mean differences in ADHD RS-IV scores were significantly greater for the sapropterin vs the placebo group: Total (-3.2 points, P = .02), Inattention subscale (-1.8 points, P = .04), and Hyperactivity/Impulsivity subscale (-1.6 points, P = .02). Forest plots favored sapropterin treatment over placebo for all ADHD RS-IV and Behavior Rating Inventory of Executive Function indices. There were no significant differences in reported problems with attention or executive function between the 2 groups at baseline or at week 26 following the 13-week open-label treatment period. Anxiety and depression scores did not differ significantly between cohorts at any time. Sapropterin was well tolerated, with a favorable safety profile. CONCLUSIONS: Sapropterin reduced blood Phe and was associated with significant improvement in parent-reported symptoms of inattention, hyperactivity/impulsivity, and executive functioning in children and adolescents with PKU. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01114737. Registered 27 April 2010, https://clinicaltrials.gov/ct2/show/NCT01114737.

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OBJECTIVE: To investigate the performance of 27 children with phenylketonuria (PKU) in tests of Executive Functions (EF) and Social Cognition (SC), and their associations with metabolic control inferred by phenylalanine (Phe) levels. METHODS: The PKU group was dichotomized according to baseline Phe-levels into; "classical PKU"(n = 14), with Phe-levels above 1200 µmol/L (> 20 mg/dL); and "mild PKU" (n = 13) with Phe-between 360 and 1200 µmol/L (6-20 mg/dL). The neuropsychological assessment focused on the EF and SC subtests of the NEPSY-II battery and intellectual performance. Children were compared to age-matched healthy participants. RESULTS: Participants with PKU presented significantly lower Intellectual Quotient (IQ) compared to controls (p = 0.001). Regarding EF analysis adjusted by age and IQ, significant differences between groups were observed only in the executive attention subtests (p = 0.029). The SC set of variables was significantly different between groups (p = 0.003), as in the affective recognition task (p < 0.001). In the PKU group, the relative variation of Phe-achieved 32.1 ± 21.0%. Relative Phe-variation was correlated only with measures of Working Memory (p < 0.001), Verbal Fluency (p = 0.004), Inhibitory Control (p = 0.035) and Theory of Mind (p = 0.003). CONCLUSIONS: Phonological Verbal Fluency, Working Memory, Inhibitory Control, and Theory of Mind were shown to be most vulnerable when there is non-ideal metabolic control. Variations in the level of Phe-may have a selective negative effect on Executive Functions and Social Cognition, but not on intellectual performance.

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Phenylketonuria (PKU) was the first genetic disease to have an effective therapy, which consists of phenylalanine intake restriction. However, there are patients who do not adhere to treatment and/or are not submitted to neonatal screening. PKU patients present L-carnitine (L-car) deficiency, compound that has demonstrated an antioxidant and anti-inflammatory role in metabolic diseases. This study evaluated the effect caused by exposure time to high Phe levels in PKU patients at early and late diagnosis, through pro- and anti-inflammatory cytokines, as well as the L-car effect in patients under treatment. It was observed that there was a decrease in phenylalanine levels in treated patients compared to patients at diagnosis, and an increase in L-car levels in the patients under treatment. Inverse correlation between Phe versus L-car and nitrate plus nitrite versus L-car in PKU patients was also showed. We found increased proinflammatory cytokines levels: interleukin (IL)-1ß, interferons (IFN)-gamma, IL-2, tumor necrosis factor (TNF)-alpha, IL-8 and IL-6 in the patients at late diagnosis compared to controls, and IL-8 in the patients at early diagnosis and treatment compared to controls. Increased IL-2, TNF-alpha, IL-6 levels in the patients at late diagnosis compared to early diagnosis were shown, and reduced IL-6 levels in the treated patients compared to patients at late diagnosis. Moreover, it verified a negative correlation between IFN-gamma and L-car in treated patients. Otherwise, it was observed that there were increased IL-4 levels in the patients at late diagnosis compared to early diagnosis, and reduction in treated patients compared to late diagnosed patients. In urine, there was an increase in 8-isoprostane levels in the patients at diagnosis compared to controls and a decrease in oxidized guanine species in the treated patients compared to the diagnosed patients. Our results demonstrate for the first time in literature that time exposure to high Phe concentrations generates a proinflammatory status, especially in PKU patients with late diagnosis. A pro-oxidant status was verified in not treated PKU patients. Our results demonstrate the importance of early diagnosis and prompt start of treatment, in addition to the importance of L-car supplementation, which can improve cellular defense against inflammation and oxidative damage in PKU patients.

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The relationship between protein and energy and their appropriate proportions in hyperphenylalaninemia (HPA) or phenylketonuria (PKU) patients in terms of growth have been poorly studied, especially in those diagnosed late. We aimed to describe the protein energy ratio (P:E) and its association with body mass index (BMI) in 638 dietetic and anthropometric assessments from 54 early- or late-diagnosed HPA/PKU patients. Dietetic and anthropometric data were analyzed and classified according to BMI Z-Score and type of diagnosis, early by newborn screening (NBS) or late. Correlation between BMI Z-Score and P:E ratio was established. Percent of dietary protein from Phe-free metabolic formula was analyzed. According to the BMI Z-Score, the majority of assessments were eutrophic (69.4%). The median P:E ratio was >4 in most of the overweight assessments. Remarkably, the underweight group consumed the highest proportion of Phe-free metabolic formula (74.5%). A positive correlation between BMI Z-Score and P:E ratio was found. The highest proportion of underweight was found in the late-diagnosed patients. Our findings might be related to their nutritional history previous to the HPA/PKU treatment. Thus, complex nutritional outcome of the late-diagnosed HPA/PKU patients deserves actions to guarantee the early diagnosis, closer nutritional follow-up and alternative therapeutic approaches.

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Abstract Objective: To investigate the performance of 27 children with phenylketonuria (PKU) in tests of Executive Functions (EF) and Social Cognition (SC), and their associations with metabolic control inferred by phenylalanine (Phe) levels. Methods: The PKU group was dichotomized according to baseline Phe-levels into; "classical PKU"(n = 14), with Phe-levels above 1200 µmol/L (> 20 mg/dL); and "mild PKU" (n = 13) with Phe-between 360 and 1200 µmol/L (6-20 mg/dL). The neuropsychological assessment focused on the EF and SC subtests of the NEPSY-II battery and intellectual performance. Children were compared to age-matched healthy participants. Results: Participants with PKU presented significantly lower Intellectual Quotient (IQ) compared to controls (p = 0.001). Regarding EF analysis adjusted by age and IQ, significant differences between groups were observed only in the executive attention subtests (p = 0.029). The SC set of variables was significantly different between groups (p = 0.003), as in the affective recognition task (p < 0.001). In the PKU group, the relative variation of Phe-achieved 32.1 ± 21.0%. Relative Phe-variation was correlated only with measures of Working Memory (p < 0.001), Verbal Fluency (p = 0.004), Inhibitory Control (p = 0.035) and Theory of Mind (p = 0.003). Conclusions: Phonological Verbal Fluency, Working Memory, Inhibitory Control, and Theory of Mind were shown to be most vulnerable when there is non-ideal metabolic control. Variations in the level of Phe-may have a selective negative effect on Executive Functions and Social Cognition, but not on intellectual performance.

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The present work proposes the use of an agro-industrial residue from the sunflower crop as a feedstock to produce a low-cost adsorbent with a chemically modified surface bearing sulfonic groups. This modified low-cost adsorbent can be used for the removal of phenylalanine, and can also be applied in the process of obtaining a source of protein supplementation for patients with phenylketonuria. The functionalization of the adsorbent with sulfonic groups was adapted and presented advantages in terms of execution time, energy expenditure, number of reagents used and adsorbed amino acids. The produced adsorbent presented a surface area of 317.31 m2 g-1 with a predominance of micro- and mesopores, that influenced an approximate 30-fold reduction in adsorption equilibrium time. The optimization results indicated a higher adsorption capacity (39.64 mg g-1) in pH = 4; temperature of 25 °C and adsorbent dosage of 10 g L-1. The FTIR analyzes and the qualitative analysis of the elements present in the samples by EDS confirmed the introduction of sulfonic groups in the MPS500 coal. This work contributed to the understanding behind the adsorption of L-phenylalanine on charcoal surfaces functionalized with sulfonic groups, showing that they can be more selective for the adsorption of phenylalanine in a competitive system.

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Background: Pterin profiles or molecular analyses of hyperphenylalaninemia (HPA) caused by phenylalanine hydroxylase (PAH) deficiency or tetrahydrobiopterin deficiency (BH4D) are not always available in low- or middle-income countries, including Mexico, limiting information regarding the phenotypic and genotypic characteristics of patients exhibiting BH4D. Objective: To report the genotypes underlying BH4D and the clinical presentation in unrelated Mexican HPA pediatric patients with normal PAH genotypes who attended a single metabolic reference center in Mexico. Methods: Automated Sanger sequencing of the PTS, QDPR, and PCBD1 genes of 14 HPA patients was performed. Predicted effects on protein structure caused by missense variants were assessed by in silico protein modeling. Results and discussion: A high prevalence of BH4D was noted in our HPA cohort (9.8%, N = 14/142). Clinically relevant biallelic genotypes were identified in the PTS (N = 7/14 patients), QDPR (N = 6/14 patients), and PCBD1 (N = 1/14 patients) genes. Four novel QDPR variants [c.714dup or p.(Leu239Thrfs*44), c.106-1G>T or p.(?), c.214G>T or p.(Gly72*), and c.187_189dup or p.(Gln63dup)] were identified. In silico protein modeling of six missense variants of PTS [p.(Thr67Met), p.(Glu81Ala), and p.(Tyr113Cys)], QDPR [p.(Cys161Phe) and p.(Pro172Leu)], and PCBD1 [p.(Glu97Lys)] supports their pathogenicity. Progressive neurological symptoms (mainly intellectual and motor impairment and even death in three patients) were noted in all patients with biallelic QDPR genotypes and in 5/7 patients bearing biallelic PTS genotypes. The single homozygous PCBD1 p.(Glu97Lys) patient remains asymptomatic. Conclusion: A higher proportion of BH4D (9.8 vs. 1%-2% worldwide), attributable to a heterogeneous mutational spectrum and wide clinical presentation, was noted in our Mexican HPA cohort, with the PTS-related HPA disorder being the most frequent. Sequencing-based assays could be a reliable approach for diagnosing BH4D in our population.