Diet therapy and metabolic control among Chilean adults with a neonatal diagnosis of Phenylketonuria

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.

Genetic profiles of phenylalanine hydroxylase gene mutations in neonates with phenylketonuria in Xinjiang / 中国新生儿科杂志

Objective:To study the genetic profiles of phenylalanine hydroxylase (PAH) gene mutations in neonates with phenylketonuria (PKU) in Xinjiang.Methods:From January 2015 to December 2021,neonates born and genetically diagnosed with PKU in our region were retrospectively included. The genetic profiles of different ethnic groups were analyzed and compared with PKU patients from central, northwest and northern regions of China.Results:A total of 131 neonates with PKU were enrolled, including 82 Han, 25 Hui and 20 Uyghur patients, 4 cases of other ethnic groups. 46, 20 and 14 types of pathogenic variants were detected in each ethnic group with detection rates of 95.1% (156/164), 66.0% (33/50), and 60.0% (24/40), respectively. The variants were mainly missense mutations and located in exons 2, 3, 6,7 and 11. The most common loci in Hui patients were c.158G>A (18.2%), c.728G>A (18.2%) and c.898G>T (9.1%). The most common loci in Uyghur patients were c.158G>A (33.3%), c.355C>T (12.5%) and c.1068C>A (8.3%). c. 898G>T might be most unique in Hui patients and c.355C>T most unique in Uyghur patients in Xinjiang. A novel variant of PAH gene, c.828G>C (p.M276I) in exon 7 was identified. Compared with northern, central and northwestern regions of China, PKU patients in Xinjiang had significantly higher incidence of c.158G>A mutation and lower incidence of c.728G>A mutation ( P<0.05). Conclusions:Missense mutations of PAH gene are common in some regions of Xinjiang. The compositions of PAH gene variations are similar to northwest and northern China with significant differences in hotspots of mutations.

Influence of blood phenylalanine level variations on the development of executive functions and social cognition in children with phenylketonuria

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.

Overweight/obesity in adolescents with phenylketonuria: protective and predisposing factors

Abstract Objective: To estimate the prevalence and factors associated with overweight/obesity development in adolescents with early diagnosed phenylketonuria treated exclusively by diet. Methodology: In this cross-sectional study anthropometric measurements, serum phenylalanine levels, and 10 metabolites associated with lipid and carbohydrate metabolism were analyzed in 101 adolescents aged 10-20 years. Adolescents were categorized into overweight/obesity and eutrophic/low body mass index groups. These patients were compared using Student's t-test, Pearson's chi-square test, Wald's chi-square test for multivariate analysis. Further, to verify whether the prevalence of overweight/obesity found in the study population was similar to that in the general population, the authors compared the nutritional status of 46 patients aged 13-17 years with that of healthy students of the same age from the National School Health Survey using the chi-square test for adherence. The significance threshold was p < 0.5. Results: The prevalence of overweight/obesity in adolescents was 27.7%. There was no difference in prevalence between sexes. Older age was a protective factor and Increased Homeostasis Model Assessment Insulin Resistance index and high phenylalanine and low-density lipoprotein cholesterol levels were predictive factors for overweight/obesity. The equality hypothesis was not rejected in the comparison of nutritional states of 46 patients aged 13-17 years and healthy students of the same age. Conclusion: The prevalence of overweight/obesity in phenylketonuria adolescents was similar to what is found in healthy adolescents.

Adecuación del aporte de proteína natural en el tratamiento de la fenilcetonuria: una revisión bibliográfica / Adequacy of natural protein intake in patients with phenylketonuria: bibliographic review

Introducción: la fenilcetonuria (PKU) es el error congénito del metabolismo de las proteínas más frecuente. El tratamiento dietético consiste en un plan de alimentación con una ingesta de proteínas naturales restringida, un sustituto proteico libre o de bajo contenido en fenilalanina (Phe) y el aporte de alimentos muy bajos en proteínas. El objetivo principal de este trabajo fue investigar si es posible aumentar la ingesta de proteína natural (PN) que se indica a los pacientes con PKU manteniendo los dosajes de Phe en sangre en rangos de seguridad. Materiales y método: se buscaron en 6 bases de datos electrónicas artículos publicados. Se identificaron un total de 154 artículos de Pub Med por intervalo de años desde 1999 a 2020. Se eligieron 15 artículos que se adaptaron a los criterios de inclusión y exclusión y respondían al objeto de estudio de esta revisión bibliográfica. Resultados: hay varios factores que pueden influenciar la estimación de la tolerancia de Phe como la severidad del fenotipo del paciente, la edad, el rango de seguridad de Phe en sangre, la prescripción de Phe y la adherencia al sustituto proteico. Si los niveles de Phe en sangre se mantienen en forma constante dentro del rango adecuado y por un período determinado, se debería considerar un incremento de la ingesta de Phe. El aumento de la ingesta de PN deberá ser realizado de manera controlada, individual y evaluando en forma constante el impacto en los dosajes de Phe en sangre. Conclusión: optimizar la ingesta de PN ofrece una mejora en la calidad de vida de pacientes con PKU, facilita la capacidad del paciente para socializar y contribuye a una mejor adherencia a la dieta(AU).

Introduction: phenylketonuria (PKU) is the most frequent inborn error of protein metabolism. The dietary treatment consists of a diet with a restricted natural protein intake, a free or low phenylalanine (Phe) protein substitute, and the intake of low protein food. The main objective of this work is to analyze if it is possible to increase the natural protein (NP) intake prescribed to PKU patients while maintaining blood Phe dosages within safe range. Materials and method: studies published were searched in 6 electronic data- basis. A total of 154 Pub Med articles were identified by range of years from 1999 to 2020. Fifteen articles which met the inclusion and exclusion criteria and responded to the objective of this bibliographic review were chosen. Results: several factors may influence Phe tolerance, such as severity of the patient´s phenotype, age, blood Phe safe range, Phe prescription and adherence to protein substitute. If Phe blood levels remain constantly within safe range and for a certain period, an increase of Phe intake should be considered. Increase of NP intake must be carried out in a controlled manner, individually and constantly evaluating blood Phe levels. Conclusion: optimizing NP intake offers the PKU patient an improvement in quality of life, facilitates the patient´s ability to socialize and contributes to a better adherence to the diet(AU).

Current Scenario and Future Direction of Newborn Screening and Management Program for Phenylketonuria in Bangladesh

Abstract Phenylketonuria (PKU) is a correctable inborn error of metabolism which causes lethal intellectual delay and neurobehavioral anomalies. A screening package, especially for early recognition can support to regulate the PKU process of most patients. New-born screening program in any country focuses at the earliest detection of inheritance deficiency disorders in order to avoid the most severe repercussion by appropriate medication. This screening program needs a concomitant diagnosis and involves additional clinical research. Strategies from developed countries recommend that new-born screening should be done as soon as possible after birth before hospital/clinic discharge because if detected later, it conveys to significantly increase in disability as well as morbidity. Although exact protocol differs among different countries, testing procedures for PKU should be followed universally recognized in the developed world. Unfortunately, new-born screening program in Bangladesh is in lying-in room or possibly in pilot study in particular hospital, because the health-care system is classically targeted mortality (like childbirth complications) and transmittable morbidities (such as COVID-19) but not inborn frailties. Although policies and management of childbirth complications have been successfully lowered infant and mother mortality rates, the number of disabled babies increased tremendously. The study aims to investigate the current status of new-born screening (NBS) program of PKU in the Rajshahi Division Bangladesh, and focus on future plans to manage with life-long treatment. The primary challenges such as financial support for newborn screening, publicity, should be identified and implemented for national PKU-NBS policy as a role model of Bangladesh for developing countries.

Physical, intellectual and genetic characteristics of 53 neonates with phenylketonuria / 预防医学

Objective@#To investigate the physical and intellectual development and mutation characteristics of the phenylalanine hydroxylase (PAH) gene among 53 newborns with phenylketonuria (PKU), so as to provide insights into the management and genetic counseling of PKU@*Methods@#The medical records of 54 children with definitive diagnosis of PKU and standardized therapy until 2 years at the Center for Neonatal Disease Screening of Shanxi Children' s Hospital from 2018 to 2021 were collected. Newborns' body weight and height developments were evaluated using the World Health Organization growth chart (2006 version), and the intellectual development was assessed using the national criteria of Development Behavior Assessment Scale among Children at Ages of 0 to 6 Years (WS/T 580-2017). The gene mutations were detected among neonates and their children, and the physical, intellectual developments and genetic characteristics of neonates with PKU were descriptively analyzed.@*Results@#The 53 PKU cases included 29 male children and 24 female children, 36 cases with classic PKU and 17 cases with mild PKU, and 30 cases from rural areas and 23 cases from urban areas. The study subjects had a median age of 30 (10) d at initial therapy, and a mean blood phenylalanine concentration of (1 507±685) μmol/L at definitive diagnosis. There were 52 cases with normal height developments (98.11%), and all cases had normal weight and intellectual developments. The mean developmental functional quotient (DFQ) was significantly greater among urban children with PKU than among rural children [(94.92±8.57) vs. (87.65±6.57); t=-3.498, P=0.001], and the mean DFQ was significantly higher among children with mild PKU than among those with classic PKU [(95.55±8.76) vs. (88.57±7.11); t=-3.095, P=0.003]. There were 37 mutations detected in the PAH gene, which were mainly distributed in exons 3, 6, 7, 11, 12 and intron 4. Three high-frequency mutation sites were detected, including c.728G>A, c.611A>G and c.1197A>T, including three novel mutations (c.674C>G, c.1316-2A>C and c.1069T>C).@*Conclusions@#Following standardized treatment, the children with PKU have comparable physical and intellectual developments as compared to normal children. c.728G>A, c.611A>G and c.1197A>T were predominant mutations in the PAH gene among these 53 children with PKU, and three novel mutations were identified, including c.674C>G, c.1316-2A>C and c.1069T>C.

25 Years of Newborn Screening in Uruguay

Abstract In the 1960s Guthrie conceived the idea of preventing congenital disease using dried blood spot samples on filter paper to detect them through biochemical tests and then be able to treat environmental factors in time to avoid the devastating effect of the diseases. Uruguay started in 1994 with the detection of congenital hypothyroidism in umbilical cord blood. In 2007 it was extended to Phenylketonuria and Congenital Adrenal Hyperplasia, starting with dried blood spot sample. In 2008, with the incorporation of Mass Spectrometry, a pilot program was started for the detection of aminoacidopathies, beta-oxidation defects and organic acidemias disorders. In the following years, the program expanded to more diseases, reaching a total of 25 disorders that could be detected, 5 of them are investigated on a mandatory basis and others in pilot program. During the 25-year of experience, 974277 umbilical cord blood samples were analyzed and since 2007: 532684 dried blood spot samples. 613 true positive congenital disorders were identified. The coverage has been greater than 98% and the repetition rate for insufficient samples less than 1.9%.

25 Hydroxy Vitamin D Level, Bone Health, Vitamin D and Calcium Intake in Chilean Patients with Phenylketonuria and Hyperphenylalaninemias

Abstract It has been shown that there is a decrease in the concentrations of 25 hydroxyvitamin D (25-OHD) and bone mineral density (BMD) in patients with phenylketonuria (PKU) in their follow-up. Our objective was to determine concentrations of 25-OHD in subjects with PKU and hyperphenylalaninemia (HPA). Transversal analytical study considered three groups: G1-PKU with neonatal diagnosis and formula intake without Phe; G2-HPA, without specific treatment and G3-C control group. Sixteen patients per group (aged 6-23) were included. Levels of 25-OHD, lumbar spine (L2-L4), femur and total BMD, intact parathormone (PTH) and vitamin D (VitD) and calcium intake were calculated. The Kruskal-Wallis statistical test was applied (p-value<0,05). Significant differences were detected in concentrations of 25-OHD between G1-PKU and G2-HPA (38.9 ng/mL; 28 ng/mL, respectively) (NV: >30 ng/mL). G1-PKU had a higher intake of VitD, with differences among groups. There were no significant differences among groups in relation to BMD and intact PTH. In conclusion, G1-PKU under treatment and with good adherence, does not present VitD deficiency and no BMD alterations are observed. In contrast, G2-HPA had a lower intake of VitD and decreased 25-OHD concentrations which could affect the bone architecture in the long term. Further studies on the G2-HPA are suggested.

Update on Dietary Compliance, Nutritional Status, and Neuropsychological Functioning in the Chilean Phenylketonuria cohort

Abstract Since 1992, Chile has had a Newborn Screening Program for Phenylketonuria (PKU), which currently has an incidence of 1:18,916 newborns. The objective of the current study was to describe the 2020 follow up of the Chilean PKU cohort. The variables analyzed were: nutritional status, dietary compliance and neuropsychological functioning. We conducted a descriptive cross-sectional statistical analysis. The 271 subjects with PKU had an average age of diagnosis of 17±8 days and a phenylalanine (Phe) level of 1122±546 umol/L. Approximately 80% of protein requirement came from a protein substitute. For those <18 years of age, 80% had good dietary compliance with Phe level between 120-360 umol/L and those >18 years had a median of 522 umol/L (95%CI 468 - 636). Forty-four percent of the active PKU cohort had overweight/obesity. Eighty-five percent of the cohort >4 years of age had a normal intelligence quotient (IQ) (score 80-120). We observed a negative correlation (p <0.001; 95% CI: - 0.5, -0.2) between IQ score and Phe level. The Chilean protocol and protein substitute subsidy for life, together with the follow-up and continuous education carried out by the clinical team has encouraged compliance.

Parenting Styles and Coping Strategies in PKU Early Detected Children

Abstract Phenylketonuria (PKU) requires tight control to prevent neurocognitive impairment but reports show that patients may present mild cognitive defects related to higher impulsivity. We hypothesize that chronic intervention may influence the parents and child bonding and the child´s resources to face problems. To describe the PKU parenting styles perceived by the children (PS) and their coping strategies (CS) assessing their relationship with impulsivity, 30 early diagnosed and adequately treated PKU children and 30 non PKU aged-paired controls (CG) were compared. The Argentine Children´s Coping Questionnaire, Argentine Scale Perception of the Relationship with Parents, WISC IV Comprehension Subtest, and CPT II test were administered. PKU PS were based on control: strict to pathologic in the mother and acceptable in the father (both p<0.05 vs. CG). Children significantly sought greater support and showed less emotional control when facing conflicts. These characteristics positively correlated with maternal control r:.383 and r:.398 (both p<0.05). Impulsivity was higher in PKU (p<0.05) but didn´t associate with PS or CS. Maternal strict control wasn´t linked to the higher impulsivity found (possibly neurobiologically based). Nevertheless, if both factors are present, patients may develop a psychological and/or behavioral trait of greater dependency and impulsivity that must be considered in their follow-up.

Bone Health in Adults with Phenylketonuria: A Cross-Sectional Study

Abstract Available literature documenting BMD in patients with PKU is mostly reported among heterogeneous populations including adults and children. We aim to describe the bone health status among adults (aged >18 years) affected with Phenylketonuria (PKU) and to evaluate the effect of diet and exercise on bone mineral density (BMD). Sample size of the study population was 27. Enrolled patients underwent multi-site Dual-energy X-ray absorptiometry (DXA) scan and laboratory tests. Nutritional and physical activity records were obtained on each subject to ascertain bone health. BMD in patients with PKU was low normal. 14% of the study subjects were found to have osteoporosis in at least one measured skeletal site. 70% had low BMD in one or more of the measured skeletal sites. BMD score was lowest at radius. Moderate correlation was observed between femoral and radial BMD and serum calcium level. Dietary intake of vitamin A was moderately correlated with BMD T-scores in femur. Our results indicate that BMD in patients with PKU is low normal with better BMD with vitamin A intake, trend towards better bone health with physical exercise and Sapropterin intake.

Monitoring of Phenylalanine Levels in Patients with Phenylketonuria Using Dried Blood Spots: a Comparison of Two Methods

Abstract Phenylketonuria (PKU) is caused by deficient activity of phenylalanine hydroxylase (PAH), responsible for the conversion of phenylalanine (Phe) to tyrosine (Tyr). Monitoring of patients with PKU requires the measurement of Phe in plasma using high-performance liquid chromatography (HPLC) or in dried blood spots (DBS) using different techniques to adjust treatment strategy. The objective of this study was to evaluate Phe levels in DBS measured by two different methods and compare them with Phe levels measured in plasma by HPLC. We analyzed 89 blood samples from 47 PKU patients by two different methods: fluorometric method developed in-house (method A) and the commercially available PerkinElmer® Neonatal Phenylalanine Kit (method B) and in plasma by HPLC. The mean Phe levels by method A, method B, and HPLC were 430.4±39.9μmol/L, 439.3±35.4μmol/L, and 442.2±41.6μmol/L, respectively. The correlation values between HPLC and methods A and B were 0.990 and 0.974, respectively (p < 0.001 for both). Our data suggest that methods A and B are useful alternatives for monitoring Phe levels in patients with PKU, with method A being in closer agreement with the reference standard (HPLC).

Identification of mutations in the pah gene in pku patients in the state of mato grosso / Identificação de mutações no gene da pah em pacientes com fenilcetonúria do estado de mato grosso

ABSTRACT Objective: To identify phenylalanine hydroxylase (PAH) mutations in patients with phenylketonuria (PKU) from the Newborn Screening Service in Mato Grosso, Midwest Brazil. Methods: This is a cross-sectional descriptive study. The sample consisted of 19 PKU patients diagnosed by newborn screening. Molecular analysis: DNA extraction using the "salting-out" method. Detection of IVS10nt-11G>A, V388M, R261Q, R261X, R252W, and R408W mutations by the restriction fragment length polymorphism (RFLP) technique. Results: Two mutant alleles were identified in four patients (21.1%), one allele in five patients (26.2%), and none in the remaining ten patients (52.6%). A total of 13/38 alleles were detected, corresponding to 34.2% of the PAH alleles present. The most prevalent variant was V388M (13.2% of the alleles), followed by R261Q (10.1%) and IVS10nt-11G>A (7.9%). Three variants (R261X, R252W, and R408W) were not found. The most frequent mutation types were: missense mutation in eight alleles (18.4%) and splicing in four alleles (10.5%). The model proposed by Guldberg to determine a genotype/phenotype correlation was applied to four classical PKU patients with two identified mutations. In three of them, the predicted moderate/moderate or moderate PKU phenotype did not coincide with the actual diagnosis. The prediction coincided with the diagnosis of one classic PKU patient. The estimated incidence of PKU for Mato Grosso, Brazil, was 1:33,342 live births from 2003 to 2015. Conclusion: The only mutations found in the analyzed samples were the IVS10nt-11G>A, V388M, and R261Q. The genotype/phenotype correlation only occurred in four (5.3%) patients.

RESUMO Objetivo: Identificar mutações da fenilalanina hidroxilase (PAH) em pacientes com PKU (fenilcetonúria) do Serviço de Triagem Neonatal em Mato Grosso. Métodos: Estudo de corte transversal. Amostra composta de 19 pacientes com PKU através do exame de triagem neonatal biológica. Análise molecular: a) extração de DNA pela metodologia "salting out". B) detecção de mutações IVS10nt-11G>A, V388M, R261Q, R261X, R252W e R408W pela técnica de polimorfismo de comprimento de fragmento de restrição (RFLP). Resultados: Dois alelos foram identificados em quatro pacientes (21,1%), um alelo em cinco pacientes (26,2%) e nenhum nos dez pacientes restantes (52,6%). Um total de 13/38 alelos foram identificados, correspondendo a 34,2% dos alelos PAH presentes. A variante mais prevalente foi a V388M (13,2% dos alelos), seguida de R261Q (10,1%) e IVS10nt-11G>A (7,9%). Três variantes (R261X, R252W e R408W) não foram encontradas. Os tipos de mutações mais frequentes foram: troca de sentido em oito alelos (18,4%) e emenda em quatro alelos (10,5%). O modelo proposto por Guldberg para determinar uma correlação genótipo/fenótipo foi aplicado para quatro pacientes clássicos de PKU, com duas mutações identificadas. Em três, o fenótipo previsto de PKU moderada/moderada ou moderada não coincidiu com o diagnóstico real. A predição coincidiu com o diagnóstico de um paciente PKU clássico. A incidência de PKU estimada para Mato Grosso, Brasil foi de 1:33.342 nascidos vivos para o período de 2003 a 2015. Conclusões: Foram encontradas apenas as mutações IVS10nt-11G>A, V388M, R261Q nas amostras analisadas. A correlação genótipo/fenótipo ocorreu em quatro (5,3%) pacientes.

Fenilcetonuria de diagnóstico precoz: Bases fisiopatológicas del daño neuronal y opciones terapéuticas / Early diagnosis of phenylketonuria. Physiopathology of the neuronal damage and therapeutic options

La fenilcetonuria, también conocida como PKU, es el error congénito más frecuente del metabolismo de los aminoácidos. La forma grave o PKU clásica no tratada, causa una discapacidad intelectual, aunque los programas de detección en el período neonatal, el diagnóstico y el tratamiento evitan la aparición de los síntomas. A pesar de un diagnóstico y tratamiento temprano hemos observado cierta neurotoxicidad en los pacientes con PKU tratados. Analizamos los demás factores implicados, aparte de la toxicidad por las elevadas concentraciones cerebrales de fenilalanina (Phe), se revisan los defectos de síntesis de neurotransmisores, las alteración de la mielinización cerebral, el efecto de la elevación de Phe en los procesos de transporte y distribución de los aminoácidos neutros con una síntesis anómala de proteínas cerebrales, la deficiencia plasmática y cerebral de tirosina, la neurotoxicidad de los metabolitos de Phe, el defecto de la biosíntesis del colesterol o el aumento del estrés oxidativo. Las alteraciones de la sustancia blanca en los pacientes con PKU tienen un papel importante en las manifestaciones neurológicas. El tratamiento de la PKU es para toda la vida y se basa en la reducción del aporte de alimentos que contienen Phe combinado con la administración de una fórmula especial, o en el tratamiento con tetrahidrobiopterina (BH4). Se analizan nuevas opciones terapéuticas.

Phenylketonuria, also known as PKU, is the most frequent congenital inborn error of metabolism. The severe form or classic PKU untreated causes intellectual disability, although with the early detection programs in the neonatal period, diagnosis and treatment prevent the appearance of the symptoms. Despite early diagnosis and treatment we have observed some neurotoxicity in treated PKU patients. We analyzed the factors involved apart from the toxicity due to the high cerebral concentrations of phenylalanine (Phe), the defects of synthesis of neurotransmitters, the alteration of cerebral myelination, the effect of the elevation of Phe in the processes of transport and distribution of neutral amino acids with an abnormal synthesis of brain proteins, plasma and cerebral tyrosine deficiency, the neurotoxicity of Phe metabolites, the defect of cholesterol biosynthesis or the increase of oxidative stress. White matter alterations in early treated PKU patients have an important role in neurological manifestations. The treatment of PKU is for life and is based on the reduction of foods containing Phe combined with the administration of a special formula or tetrahydrobiopterin (BH4) treatment. New therapeutic options will be analyzed.

Obtención de hidrolizados proteicos bajos en fenilalanina a partir de suero dulce de leche y chachafruto (Erythrina edulis Triana) / Obtaining protein products low in phenylalanine from milk whey and chachafruto (Erythrina edulis Triana)

La fenilcetonuria (PKU) es causada por una actividad deficiente de la enzima fenilalanina hidroxilasa. En los pacientes con esta deficiencia la fenilalanina (Phe) no puede ser convertida en tirosina, aumentando sus niveles en sangre y de otros metabolitos neurotóxicos, provocando un retraso mental irreversible. El tratamiento fundamentalmente se basa en una dieta controlada de Phe. Sin embargo, los alimentos libres o bajos en Phe son escasos. El objetivo de esta investigación es obtener hidrolizados proteicos con bajo contenido de Phe a partir del suero dulce de leche en polvo y harina de E. edulis Triana. El aislado proteico (96,01% proteína cruda) se obtuvo por solubilización y precipitación de las proteínas de la harina, mientras que las proteínas del suero (15,69% proteína cruda) fueron tratadas en su matriz original. Las proteínas del suero y el asilado fueron hidrolizadas enzimáticamente con pepsina y proteasa de Streptomyces griseus. La concentración de Phe se determinó por fluorometría y por HPLC, de lo cual la Phe de las proteínas del suero es liberada una hora antes que las del chachafruto, debido a que las proteínas del suero en parte fueron hidrolizadas en la elaboración del queso. Además, los resultados de la utilización del carbón activados como captor de Phe indican la reducción total del contenido de este aminoácido en los hidrolizados y la reducción de la concentración de otros aminoácidos(AU)

henylketonuria (PKU) is caused by a low activity of the enzyme phenylalanine hydroxylase. In patients with this deficiency, phenylalanine (Phe) cannot be converted to tyrosine, increasing blood levels and other neurotoxic metabolites, causing irreversible mental retardation. The treatment is fundamentally based on a controlled diet of Phe. However, free or low-Phe foods are scarce. The objective of this research is to obtain protein hydrolysates with low Phe content from sweet milk powder and E. edulis Triana flour. The protein isolate (96.01% crude protein) was obtained by solubilization and precipitation of the flour proteins, while the whey proteins (15.69% crude protein) were treated in their original matrix. Serum and asylated proteins were enzymatically hydrolyzed with pepsin and Streptomyces griseus protease. The concentration of Phe was determined by fluorometry and by HPLC, from which the Phe of whey proteins is released one hour earlier than those of chachafruto, due to the fact that the whey proteins were partially hydrolyzed in the elaboration of the cheese. In addition, the results of the use of charcoal activated as Phe captor indicate the total reduction of the content of this amino acid in the hydrolysates and the reduction of the concentration of other amino acids(AU)

Análise da densidade mineral óssea em pacientes com fenilcetonúria e sua correlação com parâmetros nutricionais / Bone mineral density assessment in patients with phenylketonuria and its correlation with nutritional parameters

Introdução: Redução da densidade mineral óssea (DMO) está associada à Fenilcetonúria (PKU), mas a causa desta associação não é completamente entendida. O objetivo desse estudo foi avaliar a ingestão de nutrientes relacionados ao metabolismo ósseo (cálcio, fósforo, magnésio, potássio), e sua associação com a DMO em pacientes com PKU. Métodos: Estudo transversal, observacional. Foram incluídos 15 pacientes (PKU Clássica=8; Leve=7; mediana de idade=16 anos, IQ=15-20), todos em tratamento com dieta restrita em fenilalanina (Phe) e 13 em uso de fórmula metabólica. Foi realizado recordatório alimentar de 24 horas de um dia e demais dados (histórico de fraturas, parâmetros antropométricos, DMO e níveis plasmáticos de Phe, Tyr, cálcio) foram obtidos por revisão de prontuário. Resultados: Nenhum paciente apresentou histórico de fraturas e seis realizavam suplementação de cálcio (alteração prévia da DMO=5; baixa ingestão=1). A mediana dos níveis de Phe foi 11,6 mg/dL (IQ=9,3-13,3). Em relação ao recordatório alimentar, dez indivíduos apresentaram inadequado consumo de carboidratos; 14, de lipídeos; 9, de cálcio; 11, de magnésio; 13, de fósforo; e todos de potássio. A mediana da DMO foi de 0,989 g/cm2 (IQ=0,903-1,069), sendo duas classificadas como reduzidas para idade, ambas de pacientes com PKU Leve que recebiam suplementação de cálcio. Não foi observada correlação entre níveis de Phe, DMO e demais variáveis analisadas. Conclusão: Redução da DMO não foi frequente na amostra, embora ingestão inadequada de cálcio assim o seja. Estudos adicionais são necessários para esclarecer o efeito da Phe e da ingestão dietética sobre o metabolismo ósseo na PKU. (AU)

Introduction: Reduced bone mineral density (BMD) is associated with phenylketonuria (PKU), but this association is not completely understood. This research aimed to evaluate intake of nutrients related to bone metabolism (calcium, phosphorus, magnesium, potassium) and its association with BMD in patients with PKU. Methods: In this cross-sectional, observational study, 15 patients with PKU (Classical=8, Mild=7; median age=16 years, IQ=15-20 years) were included, all of them on phenylalanine (Phe) restricted diet and 13 being supplemented with a metabolic formula. A 24-hour dietary recall was performed and remaining data (history of fractures, anthropometric parameters, BMD and plasma Phe, tyrosine and calcium levels) were obtained through medical chart review. Results: No patient had any fractures and six received calcium supplements, five due to previous change in BMD and one due to inadequate nutritional intake. Median Phe level was 11.6 mg/dL (IQ=9.3-13.3). In relation to dietary recall, all individuals had inadequate intake of some nutrient (carbohydrate=10; lipids=14; calcium=9; magnesium=11; phosphorus=13; potassium=15). The median BMD was 0.989 g/cm2 (IQ=0.903-1.069). Two cases were classified as low BMD for age, both in patients with mild PKU receiving calcium supplements. Conclusion: Reduced BMD was not common in this sample, although inadequate calcium intake was frequently reported. Additional studies are needed to clarify the effect of Phe and dietary intake on bone metabolism in patients with PKU.(AU)

Linguistic Validation of the Phenylketonuria - Quality of Life (PKU-QOL) Questionnaire Into Brazilian Portuguese

Abstract The phenylketonuria - quality of life (PKU-QOL) questionnaire was developed to assess the impact of phenylketonuria (PKU) and its treatment on the health-related quality of life (HRQL) of patients and their caregivers. Available in four versions (child, adolescent, adult and parent), it was developed and validated in eight countries. The objective of this study was to linguistically validate the PKU-QOL questionnaire in Brazilian Portuguese for use in Brazil by clinicians who take care of PKU patients. The translation method used a standard linguistic validation process. The British English version served as a basis for translation. No major cultural or semantic issues were found during the process. The main difficulty was the use of the acronym "PKU" in the first translations. During the cognitive interviews, respondents made the confusion between the disease itself and the food supplement since it is written "PKU" or "COMIDA-PKU" on the packaging of the product. To overcome this issue, it was decided to use fenilcetonuria (fenil) or fenil alone throughout all versions. The PKU-QOL will be valuable for Brazilian healthcare providers in individualizing treatment and managing patients with PKU.

Study of the phenylalanine hydroxylase gene variants in patients with phenylketonuria from Jiangxi province / 中华医学遗传学杂志

Objective@#To delineate the variants spectrum of phenytalanine hydroxylase (PAH) gene among 78 unrelated patients with phenylketonuria (PKU) from Jiangxi province.@*Methods@#The 13 exons and flanking intronic regions of the PAH gene were subjected to PCR amplification and sequencing.@*Results@#A total of 143 variants were detected among the 156 alleles, which included 54 types of variants, which yielded a detection rate of 91.7%. Common variants have included R243Q (26/143, 18.2%), R408Q (10/143, 7.0%), EX6-96A>G (8/143, 5.6%), IVS4-1G>A (7/143, 4.9%), R241C (7/143, 4.9%) and V399V (7/143, 4.9%). In addition, 6 novel variants were detected, which included IVS4-3T>G, Q172H, C284Y, V291L, V329del, and L430R. The variants consisted of missense, splicing, nonsense and deletion variants, which have mainly located in exons 7 (45, 31.5%), 12 (17, 11.9%), 11 (16, 11.2%) and 6 (14, 9.8%).@*Conclusion@#Variants of the PAH gene identified in Jiangxi province mainly involve exons 7, 12, 11 and 6, with the most common variants being R243Q and R408Q. Six novel variants were identified.

Mutation spectrum and new mutation of phenylalanine hydroxylase gene in Guangxi region / 中华实用儿科临床杂志

Objective To investigate the characteristics of the phenylalanine hydroxylase( PAH)gene muta﹣tions in patients With phenylketonuria(PKU)in Guangxi region,in order to provide clinical data for genetic counseling and prenatal gene diagnosis. Methods Thirty－seven children diagnosed as PKU in the Maternal and Children＇s Hos﹣pital of Guangxi Zhuang Autonomous Region Were enrolled in the study betWeen January 2009 and December 2017. Ve﹣nous blood Was collected and the PAH gene sequence Was determined by Sanger sequencing after amplification With the polymerase chain reaction technique. The neW gene mutations Were defined based on the national and international literature revieW and databases. MeanWhile,100 healthy individuals Were selected as the control group for gene sequen﹣cing to confirm Whether the mutation Was a neW one. Results Thirty－seven cases of PKU Were detected for 68 muta﹣tions,With the detection rate being 91. 89%(68／74). Six mutations Were identified in exon 7,Which accounted for 31. 08% of all,exon 12(18. 92%),exon 8(10. 81%)and exon 6(10. 81%)folloWed. A total of 25 different muta﹣tions Were identified Which including 14 missense mutations(56. 00%),7 nonsense mutations(28. 00%),3 splicing junction mutations(12. 00%),and 1 deletion mutation(4. 00%). The most common mutations included c. 1223G＞A (p. R408Q),c. 728G＞A(p. R243Q)and c. 721C＞T( p. R241C),accounting for 14. 86%,13. 51%,and 10. 81%, respectively. After querying international databases,including PAH mutation database and Human Gene Mutation Data﹣base and forecasting softWare,three kinds of mutations c. 314C＞ T(p. T105I),c. 583A＞ G(p. K195E),c . 851G＞A(p. C284Y)Were verified as novel PAH gene mutations. Conclusions The mutation spectrum of the PAH gene in Guangxi has been identified. And 3 kinds of mutations have been identified. This may accumulate valuable information for gene diagnosis and prenatal diagnosis of PKU in Guangxi region.