Quality of Life and Adherence to Treatment in Patients with Phenylketonuria in the Federal District - BrazilABSTRACT
In phenylketonuria (PKU), low adherence to treatment is associated with poor health-related quality of life (HRQoL). The HRQoL of 51 patients with PKU was examined using the PKU-QOL questionnaires, correlating them to two indicators of adherence to treatment using nonparametric tests, according to the results of normality tests. Children, adolescents, and adults achieved adherence to treatment percentages of 62.5%, 63.6%, and 18.8%, respectively. Significant correlations between PKU-QOL scores were observed in several age groups, except in children, due to the reduced sample size (n=4). PKU negatively affects the HRQoL of patients and their caregivers. Improvements in dietary treatment, with the provision of manufactured special low-protein foods, more palatable Phe-free or low-Phe protein substitutes, and improved pharmacological therapies are necessary.
KEYWORDS:
Quality of life; Adherence to treatment; Phenylketonuria
RESUMO
Na fenilcetonúria (PKU), a baixa adesão ao tratamento está associada à má qualidade de vida relacionada à saúde (QVRS). Examinou-se a QVRS de 51 pacientes com fenilcetonúria (FNC) com os questionários PKU-QOL, correlacionando-os a dois indicadores de adesão ao tratamento com uso de testes não paramétricos, conforme os resultados dos testes de normalidade. Crianças, adolescentes e adultos obtiveram percentuais de adesão ao tratamento de 62,5%, 63,6% e 18,8%, respectivamente. Correlações significativas entre as pontuações do PKU-QOL foram observadas em várias faixas etárias, exceto em crianças, devido ao reduzido tamanho amostral (n=4). A PKU afeta negativamente a QVRS dos pacientes e de seus cuidadores. Melhorias no tratamento dietético, com o fornecimento de alimentos especiais com baixo teor de proteína industrializados, de substitutos proteicos livres de Phe ou com baixo teor de Phe mais palatáveis, e nas terapias farmacológicas são necessárias.
PALAVRAS-CHAVE:
Qualidade de vida; Adesão ao tratamento; Fenilcetonúria
Phenylketonuria (PKU, OMIM # 261600) is an autosomal recessive inborn error of metabolism (IEM) of phenylalanine (Phe) caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH), which converts phenylalanine to tyrosine. If left untreated, PKU results in increased concentrations of Phe in the blood and brain, causing severe intellectual disability, epilepsy, and behavioral problems (van Wegberg et al., 2025). According to the International Database of Patients and pathogenic variants Causing HPA/PKU including BH4 Responsive Phenotype (BIOPKU), it is known that there are 3457 pathogenic variants (February 27, 2025) in the gene that encodes PAH and are associated with its deficiency, and most of them are missenses and result in misfolding of proteins or impairment of the catalytic functions. Current estimates account for 0.45 million people worldwide having PKU. In Latin America, the prevalence varies, for example, in Argentina (1:15,715), Brazil (1:25,000), and Peru (1:46,970) (Hillert et al., 2020).
PKU became a model for other IEMs, as it was the first disorder in which severe neurocognitive dysfunction could be prevented by early initiation of treatment, and a diet rather than a drug was the intervention. It was also the first disease for which early diagnosis was possible due to population-based neonatal screening (Blau et al., 2010). The goals of PKU treatment are: optimized neurocognitive functioning and development, psychosocial well-being and adequate growth, and nutritional status and quality of life (van Spronsen et al., 2021). The dietary restriction of phenylalanine individualized according to tolerance, being the basis of the treatment of phenylketonuria in conjunction with the use of phenylalanine-free amino acid supplements or a combination of glycomacropeptides with low phenylalanine content and the addition of amino acids (GMP-AA), vitamins, and minerals to meet nutritional needs. The use of special low-protein foods (SLPF) to meet energy needs is also recommended. Some patients respond and are treated with sapropterin dihydrochloride; patients with high residual PAH enzyme activity are more likely to respond to sapropterin, but a minority of patients with classic PKU may also benefit from this treatment. In the future, treatments may include enzyme replacement and gene therapy (van Wegberg et al., 2025). Phenylalanine has a preponderant presence in foods with a high protein content, so a wide variety of foods, such as legumes, most cereals, and foods rich in proteins of high biological value, such as meat in general, fish, eggs, and dairy (MacDonald, van Wegberg, et al., 2020). Thus, a wide variety of foods are excluded or consumed in limited quantities in the PKU diet.
Adherence to this restrictive diet can be difficult, as specialty products, which are low in protein, are often expensive, difficult to obtain, and may require more time to prepare. Furthermore, many people find the diet limited, unpalatable, and socially restrictive (Ford et al., 2018). Because of these challenges, many people with PKU do not fully adhere to the recommended diet (MacDonald et al., 2010). Poor adherence to recommendations impairs metabolic control. Compromised metabolic control, in turn, is associated with poor health-related quality of life (HRQoL) (Alptekin et al., 2018). Thus, the rigorous and demanding dietary treatment and the mild cognitive abnormalities seen in patients with PKU treated early may also affect the HRQoL of patients and their families (Bosch et al., 2015).
The assessment of HRQoL in phenylketonuria (PKU) using generic questionnaires is considered a limitation, as it may not detect the possible negative consequences of deficiencies or imperceptible problems experienced by patients, such as planning and organization difficulties, reduced brain processing speed (Demirdas et al., 2013), the objection to using the Phe-free protein supplement, the limitations imposed by a restricted diet, the financial burden of purchasing special foods. All these issues can affect adherence to treatment, social relationships, work performance, and, consequently, the quality of life. The main objective of this study was to examine the HRQoL of patients with Phenylketonuria using PKU-QOL questionnaires and to investigate the correlation between their domains and indicators of adherence to treatment. This is the first time that the HRQoL of patients with phenylketonuria has been measured using a specific, linguistically validated PKU questionnaire in Brazil.
Methods
Observational, analytical, cross-sectional, non-interventional study carried out with 51 individuals, 24 children (0 -11 years old), 11 adolescents (12 - 17 years old) and 16 adults (> 18 years old) with PKU (hyperphenylalaninemia, mild, moderate or classic PKU), treated early or not with the use of a phenylalanine-free amino acid formula for more than 12 months. Patients were invited to participate in the research during routine appointments at the PKU and Allied Disorders Outpatient Clinic in the Hospital de Apoio de Brasília of the State Health Secretariat of the Federal District (Secretaria de Estado de Saúde do Distrito Federal (SES-DF)). Inclusion criteria were having participated in the consultations and having collected blood samples on filter paper, analyzed using a tandem mass spectrometer (MSMS) for at least one year and using a protein supplement free of phenylalanine, and exclusion criteria were irregular outpatient follow-up (more than 12 months of absence from routine appointment), inability of patients and parents to understand the study questionnaires, presence of chronic or severe disabling diseases unrelated to PKU, non-use of Phe-free protein supplement or its irregular use, with voluntary suspension for more than 6 months, and pregnancy.
The median Phe of the Quadrennial 2018-2021, collected through a review of medical records and the application of the PKU-QOL questionnaire, was carried out between December 2021 and August 2022. After obtaining Institutional Review Board (CAAE: c52663221. 9.0000.5553) approval and subsequent signing of the free and informed consent form, patients and family members were able to participate voluntarily. For the classification of PKU severity, the 2012 Scientific Review Conference held by the National Institutes of Health (NIH) was used as a reference, which classified patients based on the peak Phe concentration in the blood without treatment (hyperphenylalaninemia (360-600 μmol/L), mild (600-900 μmol/L), moderate (900-1200 μmol/L) or classic PKU (> 1200 μmol/L)(Camp et al., 2014) (Camp et al., 2014), if Phe levels at diagnosis were not available, patients were classified as ''PKU of undefined type''.
Quality of life was assessed using the PKU-QOL questionnaires (PKU-QOL© Biomarin Pharmaceutical Inc. - 2015/ Mapi Research Trust) (Regnault et al., 2015) and linguistically validated for children, adolescents, adults with PKU, and their caregivers (Vicente et al., 2019). The PKU-QoL questionnaires, developed by MAPI, are freely available for use in unfunded academic research, downloadable from the website of the MAPI Research Trust, Lyon, France (https://eprovide.mapi-trust.org/instruments /phenylketonuria-impact-and-treatment-quality-of-life-questionnaire). The PKU-QOL comprises four modules: 1) PKU symptoms; 2) PKU in general; 3) Phe-free amino acid supplement administration; 4) Dietary protein restriction. (Bosch et al., 2015). Blood samples collected on filter paper, analyzed in tandem mass spectrometer (MSMS) (TQD, Waters, USA), were used to measure the level of phenylalanine and assess adherence to treatment. The median concentrations of Phe in the blood were evaluated by the Median Phenylalanine in the four years 2018-2021. Patients were considered adherent or non-adherent based on the median concentration of phenylalanine in the period analyzed. The target blood Phe levels in all patients should be maintained in the range of 120-360 μmol/l. (Vockley, J., Andersson, H. C., Antshel, K. M., Braverman, N. E., Burton, B. K., Frazier, D. M., … Berry, 2014).
Qualitative variables were presented as absolute frequency (n) and percentage (%). Quantitative variables were presented using central tendency and dispersion measures: mean, median, standard deviation, minimum, maximum, and interquartile range. Quality-of-life data were evaluated separately among the four groups (children, adolescents, adults, and caregivers) who answered the PKU-QOL questionnaire, considering that it presented different questions depending on the respondent. The questionnaire result was associated with adherence to treatment in the four years 2018-2021. The results were evaluated in relation to adherence through the non-parametric Mann-Whitney U tests. A non-parametric test was used, considering that the quantitative variables did not show an approximately normal distribution according to the Shapiro-Wilk test. The correlation between the quantitative variables was verified using Spearman's rho correlation coefficient (Cohen, 1992). The Kruskal-Wallis non-parametric test of independent samples was used to compare data on phenylalanine concentration between age groups. In cases significant for the Kruskal-Wallis test, Dunn's post hoc test was performed for comparison in pairs. The results were presented according to the respondents and the age groups of patients who completed the quality of life questionnaire (Child, Adolescent, Adult, and Parents). Data analyses were performed using the IBM SPSS program (Statistical Package for the Social Sciences), 23, 2015. The significance level used throughout the study was 5%.
Results
Of the 51 participants (patients, parents, and close relatives) invited to participate in the research, 100% accepted and completed the questionnaires in their entirety; there was no abandonment of treatment in the analyzed period. The mean age of children patients was 5.6 ± 2.8, adolescents 14.2 ± 1.5, and adults 27.1 ± 8.2. The sociodemographic characteristics of patients are summarized in Table 1. Interviews were conducted with mothers (64.7%), patients (23.5%), close relatives (9.8%), and fathers (2%). During data collection, all patients received a protein supplement through an administrative process, according to the corresponding age group.
A progressive increase in median Phe concentrations was identified with advancing age. In the first few years of life, the median Phe in the blood of the group was above the recommended range (Table 2). Throughout the entire follow-up period, among children and adolescents, the proportion of samples with Phe blood test concentrations above the recommended range had slight variation, changing from an average of 40.7% during childhood to 44.7% in adolescence. However, there was a significant increase in adulthood (>18 years), 84.47%. 20.8% of children (<12 years old) and 25% of adults had an inadequate blood Phe test collection frequency (Table 3). When grouping the mean concentrations of Phe into four periods (Figure 1), up to the 3rd year, from the 4th to the 10th year, from the 11th to the 17th year and above the 18th year of life, there was a significant increase in the mean concentration of Phe (P = 0.008, Kruskal-Wallis test), with values above the 18th year being significantly higher than Phe values up to the 3rd year (P = 0.017, Dunn test) and values from the 4th to the 10th year of life (P = 0.038, Dunn's test).
Box plot of mean phenylalanine concentration over age range in patients diagnosed with phenylketonuria using a phenylalanine-free metabolic formula in the Federal District, Brazil. SD = standard deviation.
Quality-of-life data were evaluated separately between the four groups that answered the PKU-QOL questionnaire (Child, Adolescent, Adult, and Parents), considering that it had different questions depending on the respondent; the median scores are shown in Figure 2. Only 8 of the 39 parameters examined had a mild impact on all age groups; 61.5% (24/39) had a moderate impact, 28.2% (11/39) had a major impact, and 5.1% (2/39) had a very severe impact on HRQoL. 79.5% of the domains had a moderate-to-very-severe impact on at least one of the categories analyzed. The domains Slow thinking, Emotional impact of PKU, Practical impact of PKU, Impact of child anxiety - blood test, Anxiety - blood Phe levels, Anxiety - blood Phe levels during pregnancy, Guilt if poor adherence to supplements, Taste - supplements, Practical impact of Dietary Protein Restriction, Overall impact of Dietary Protein Restriction and Guilt if dietary protein restriction not followed had a greater or very severe impact. The significant result of the correlation analysis between the domains of the PKU-QOL questionnaire, the Self-Rated status Health domain, and the median of Phe in the Quadrennial (2018-2021) was described. There was no significant correlation between the PKU-QOL Child domains and the adherence variable analyzed. In this age group, the absence of significant results may be mainly associated with the small sample size of this group.
When comparing the scores of the PKU-QOL - Adolescents, Adult, and Parents domains with the Self-Rated Health status of the samples, statistically significant differences were found for different domains. In adolescents, there was a positive and strong correlation between the Self-rated Status Health score and the domains Headaches (p=0.038, rs =0.630), Stomachaches (p=0.017, rs= 0.696), Lack of concentration (p =0.002, rs=0.820), Slow thinking (p =0.003, rs=0.803), Emotional impact of PKU (p =0.001, rs=0.833), Social impact of PKU (p =0.005, rs= 0.777), Overall impact of PKU (p =0.016, rs=0.700), Adherence to supplements (p =0.031, rs=0.647), Social impact of dietary protein restriction (p =0.004, rs=0.787), Overall impact of dietary protein restriction (p= 0.035, rs= 0.638), Food enjoyment (p= 0.004, rs= 0.793), suggesting a worse perception of health status; as well as a significative emotional, social and general impact of the disease, a social and general impact of protein restriction in the diet and greater difficulty in adhering to the metabolic formula in the analyzed period.
Among the adult respondents, there was a positive and robust correlation between the Self-rated status Health score and the domains Anxiety - Phe levels (p=0.019, rs=0.719), Financial impact of PKU (p =0.045, rs =0.642), and Overall difficulty following dietary protein restriction (p=0.030, rs =0.682). Among the caregivers (mothers, fathers and those responsible for the patient's daily care), there was a positive correlation between the scores of the item Self-rated Health status of the children in the domains of Headaches (p=0.025, rs= 0.438), Tiredness (p=0.010, rs=0.498), Lack of concentration (p= 0.019, rs= 457), Slow thinking (p=0.025, rs=0.440), Irritability(p =0.000, rs=0.636), Aggressiveness (p =0.006, rs= 0.520), Moodiness (p =0.000, rs=0.712), Impact of supplements on family (p =0.010, rs=0.497), Adherence to dietary protein restriction (p= 0.004, rs= 0.543), Child Food enjoyment (p=0.038, rs=0.408), Management of dietary protein restriction (p=0.002, rs=0.582), suggesting a worse perception of the quality of live with increasing correlation scores in the domains of symptoms, administration of the Phe-free amino acid supplements, and restriction of protein in the diet during the period of analysis.
As for the association between Median Phe for the 2018-2021 Quadrennial and the PKU-QOL domains scores, among adolescents, there was a negative correlation with the Tiredness domain (p=0.021, rs = - 0.682). Among adults, there was a positive and relevant association for Practical impact of PKU (p=0.038, rs=0.659) and Food temptation (p=0.031, rs=0.678). Caregivers also demonstrated a positive and significant association for Anxiety (p= 0.031, rs = 0.424).
Discussion
The European Phenylketonuria Guideline recommends assessing quality of life in the outpatient setting, preferably using the PKU-QOL, annually or at least once during childhood, adolescence, and adulthood, or in periods of major life change (van Wegberg et al., 2025). This is the first Brazilian study that correlates adherence to the diet, measured by blood levels of Phe, with quality of life measured by the specific PKU-QOL questionnaire. Some studies also evaluated QoL in various age groups, considering the severity of the disease, metabolic control, or adherence to treatment (Barta et al., 2020; Bosch et al., 2015; Huijbregts et al., 2018; Vieira Neto et al., 2018). Adherence to the diet was measured in Brazil. A Brazilian multicenter study conducted with 51 children (6 -18 years) found an adherence rate of 70% in the first year of life, 30% of the patients had median Phe levels above the upper limit of the recommended target range (360µmol/L). Using generic quality of life questionnaires, no significant differences were found in the HRQoL scores of adherent and non-adherent children and adolescents. In the last year of this investigation, the percentage of children with adequate median Phe concentrations dropped to 31.4% (Vieira Neto et al., 2018). Disease-specific quality of life assessment instruments focus on a particular area of interest, detecting biological and psychosocial aspects of a condition; their utility is that they are sensitive enough to detect characteristic aspects of the impact of a disease on quality of life (Aguiar et al., 2008). Generic instruments, in turn, can be applied to healthy people or people affected by a disease, and address multidimensional aspects of a patient's life, such as mobility, social integration, body image, and physical safety (WHO, 1995), and can also be used to assess quality of life in PKU by comparing the affected and non-affected population.
In this analysis, the adherence percentages found for children aged 0 to 11 years (62.5%), adolescents (63.6%) and adults (18.8%) showed similar behavior but were significantly lower than that described in a multicenter study European who found an adherence rate of 88% in children aged up to 1 year, 74% children aged 1 to 10 years, 89% adolescents and 65% for adults (>18 years)(Ahring et al., 2011) and to that reported by MacDonald et al (2011), except for children and adolescents, considering the average percentage of individuals with at least 70% of Phe concentrations within the target range for children aged 0 to 5 years, 6 to 10 years, 11 to 17 years and over 18 years, finding percentage adherence of 57.0%, 56.5% and 57.1% and 39.4%, respectively ( MacDonald et al., 2011). Compared to a study conducted in the United States, there was worse adherence in the adult age group, and similarly, in adolescence, adherence to the recommendations was 33% in adults over 30 years of age and greater than 60% of adolescents (13 to 17 years of age). More than 70% of adult PKU patients do not adhere to target Phe concentrations (Jurecki et al., 2017). These differences in adherence can be explained by the differences in the age groups evaluated, the number of patients in the sample, and the reality of different treatment resources between countries.
Direct assessment of blood Phe concentration is perhaps the best overall measure of adherence to treatment, but there is no universal consensus on the number of Phe concentrations that should fall within the target range and frequency or time of measurement (MacDonald et al., 2010). As for the median scores of the PKU-QOL domains, adolescents had a moderate impact (or moderate symptom) in the domains headaches, tiredness, irritability, mood, and anxiety, and adults had symptoms of tiredness, moodiness, and irritability; these results may be associated with a non-adherence rate of 36.4% and 81. 2%, respectively, for adolescents and adults. Elevated levels of Phe in the blood are directly associated with neuropsychiatric problems (eg, anxiety, hyperactivity, neurological abnormalities, headaches, tremors, irritability, moodiness) (Bilder et al., 2016); thus, the occurrence of moderate scores for these symptoms may be associated with non-adherence to treatment.
Children, adolescents and caregivers had a high score on the Emotional impact of PKU domain, a result similar to the study by Bosch et al.(2015), expressing a concern about how phenylketonuria (PKU) can affect their daily lives and the their health, about the transmission of the disease to their offspring, the difficulties of living with the disease and the indignation with the occurrence of the condition in their lives, revealing an impact on self-esteem and difficulty disease acceptance. A cross-sectional observational study with 59 parents and 11 adolescents revealed that the eating pleasure domain was the most impacted, with a higher severity score in the group of adolescents (62.5, IQR: 25-75), and the emotional impact was classified as moderate severity by both teenagers and parents (Becsei et al., 2021). This research finds low scores (25, IQR: 0-50) to Food enjoyment in adolescents.
The domain Anxiety - blood Phe levels scored high or severe in almost all age groups, except for children. Anxiety, along with depression, is one of the most frequently self-reported symptoms in adult and pediatric patients with PKU (Ford et al., 2018). In PKU, not only is tyrosine synthesis reduced due to PAH deficiency. When Phe levels are elevated, there is competitive binding to the LAT1 transporter, resulting in preferential transport of Phe across the blood-brain barrier and a relative lack of other LNAAs (tryptophan and tyrosine, for example), essential to produce serotonin, norepinephrine, and dopamine (González et al., 2016). The domain “Anxiety - blood Phe levels” obtained a positive and significant performance in adults when correlated with self-assessment of their health status, highlighting the concern and awareness of this age group regarding the harmful effects of high Phe levels on health, with a tendency to a worse perception of health status with increased intensity of anxiety related to phenylalanine levels.
In this research, there was a severe perception of anxiety by caregivers when carrying out Phe control tests through the Impact of child anxiety - blood test and Anxiety - blood Phe levels domain. Caregivers of children with PKU may perceive that their child's development may be threatened during the first months and years after diagnosis, with the development of chronic stress due to concerns about their child's health and problems with adherence to treatment (Hoghughi & Long, 2004). In this research a severe perception of anxiety by caregivers with the performance of Phe control tests by the Impact of child anxiety - blood test domain was found, this data corroborates with a study carried out by Morawska et al (2020) who found a more significant impact of PKU on the HRQoL of parents related to their children's anxiety during blood tests, to guilt related to poor adherence to dietary restrictions and the formula supplementation, impacting maternal HRQoL (Morawska et al., 2020).
A greater and more frequent impact in almost all groups, except for children, was found in the Guilt if poor adherence to supplements domain, revealing the concern of parents when the patient stops taking the Phe-free amino acid formula and the feeling of regret of adolescents and adults when they do not use the Phe-free supplement as recommended. This is probably due to awareness of the importance of using the Phe-free formula for the treatment. Luna et al (2023) found lower scores in adults for the domains Guilt if poor adherence to supplements (59.5 ± 35.94) and Guilt if dietary protein restriction not followed (60 ± 31.83) and higher scores for food pleasure (85 ± 20.51 ) and taste-supplements (53.25± 32.85)(Luna et al., 2023), when comparing the scores in Figure 2. These differences may be related to some factors such as the availability of therapeutic resources, better compliance with the dietary plan, family support, and knowledge about the disease.
As for dietary restriction, this research found that the domain Guilt, if dietary protein restriction was not followed, received scores that indicate a very severe or severe impact, except in children, who had a moderate score. This is due to the high frequency of guilt perception of adolescents, adults, and caregivers for not following the dietary restriction. The high frequency of guilt perception of patients and caregivers (mothers, fathers, or direct caregivers) identified with PKU-QOL for not following the dietary restriction indicates the need for these people to be supported by the multidisciplinary care team. For this domain, adolescents and adults also obtained high scores, a greater and more frequent impact, revealing knowledge of the negative impacts on health of non-adherence to dietary treatment. In adults, insufficient knowledge about PKU, the temptation to eat protein-rich foods, once the patient has developed a taste for them, and socioeconomic status are likely influences for the very difficult adherence to the PKU diet. Recent data from the United Kingdom indicate that 43% of adult patients report not following the PKU diet (Ford et al., 2018) and a survey conducted in Austria identified high rates of adult patients without follow-up for more than 2 years, 63.7% of adult patients with PKU diagnosed by the National Austrian Newborn Screening Program (NANSP) between 1966 and 1999 (n = 177), dropping out of treatment and poor adherence are a major concern in the long-term treatment of PKU (Beghini et al., 2021).
Abandonment of treatment by female adults can have serious problems due to insufficient metabolic control during pregnancy in women with PKU, since this causes Maternal Phenylketonuria Syndrome. Adult women with phenylketonuria, got a high score in the domain Anxiety - blood Phe levels during pregnancy (Figure 2), evidencing the concern of these people with the consequences of the maternal phenylketonuria syndrome because the high blood Phe levels during pregnancy have a teratogenic effect that can result in growth retardation, microcephaly, intellectual disabilities and birth defects, including congenital heart defects (van Wegberg et al., 2025).
Stacked column chart of Median Scores For The PKU-QOL Child, Adolescent, Adult, and Parent Domains in the Federal District, Brazil. Lower PKU-QOL scores represent a more positive outcome; 0 (no impact/no symptom) and 100 (extremely severe impact/very frequent symptom). DPR = dietary protein restriction. SLPF = specialty Low Protein Food. Q1= 1st quartile or 25th percentile. Q3 = 3rd quartile or 75th percentile.
The Taste-supplements domain had a median score with the greatest impact on adolescents, due to the perception of the taste of the Phe-free protein supplement as something unpleasant to the palate. More palatable metabolic formulas with low phenylalanine peptides with added amino acids (casein glycomacropeptide - CGMP) (Daly et al., 2022) and formulations with Physiomimic Technology TM, in which a coating is added to the protein substitute (MacDonald, Ashmore, et al., 2020), were developed to provide greater adherence and diversity to the treatment. A variety of options for protein substitutes in different presentations with low or free phenylalanine content and SLPF have been made available on the market to reduce adherence problems due to the taste and lack of food diversity faced by individuals with PKU, but most of these innovations are not yet available in Brazil.
There is recognition that dietary management is associated with a significant burden for the patient, particularly if patients have eaten protein-rich foods and/or find Phe-free L-amino acid supplements unpleasant (van Wegberg et al., 2025). In Brazil, the challenge of following a diet restricted in phenylalanine has an additional adversity due to the unavailability of SLPF for the dietary treatment of phenylketonuria in a subsidized and continuous way by a State program, due to its high cost (Wood et al., 2021), which is an impediment for most families undergoing treatment. The use of low-protein foods can favorably modify metabolic control, as demonstrated by Handoom et al. (2018). In patients with PKU, phenylalanine levels were significantly reduced after the use of SLPF (p < 0.0001) (Handoom et al., 2018). Unlike what happens in Brazil, the therapeutic use of special low protein foods is recognized both in the American treatment and follow-up guidelines (Vockley, J., Andersson, H. C., Antshel, K. M., Braverman, N. E., Burton, B. K., Frazier, D. M., … Berry, 2014) as in European (van Wegberg et al., 2025), as an important part of treatment. Availability of low-protein foods is a key element in the successful implementation of a low-Phe diet, as many regular staples such as bread, flour, and wheat flour-based pasta are not allowed on a low-Phe diet. In this way, they are replaced by equivalent low-protein foods made from food starches (wheat, potato, and corn starch). Most of these special foods have a phenylalanine content ≤ 25 mg per 100 g, or no source of phenylalanine/protein has been identified in the list of product ingredients, and are an important source of energy, increasing food diversity and helping with diet adherence (Wood et al., 2021). This way, the need emerges to create national technical programs to supply these foods as part of the treatment.
Among adolescents, the Practical impact of PKU domain had a great impact, this can be explained by the transition of care and the increased demand from parents so that patients acquire greater independence regarding diet management, preparation of meals with low phenylalanine content (weighing, measuring Phe content, cooking), the use of the protein substitute and tasks related to disease management (appointments, visits to the pharmacy, for example). The high impact on these domains may be related to the fact that adolescents and adults, in particular, perceive dietary restriction as a limitation to activities of daily living, find it difficult to prepare protein substitutes, are more prone to social pressures, and be able to perceive their condition as stable (MacDonald et al., 2010; Thimm et al., 2013). In adolescents, there was also a negative and significant association between the four-year (2018-2021) median of Phe and the Tiredness domain. Knowledge about the relationship between this symptom and phenylalanine levels is limited; more studies are needed. A study carried out with 111 Italian PKU adults found reports of fatigue in 25% (n=28) of the sample at least twice a week or even every day (Cazzorla et al., 2018).
The positive and significant correlation found in adults between the Self-rated Health status score and the Financial impact of PKU domains (P=0.045, rs =0.642) ratifies the fact that treatment for PKU incurs a substantial burden of time and cost for people with PKU and their families(Rose et al., 2019). The median Phe for the four-year period (2018-2021) in adults was positively correlated with the Practical Impact of PKU and Food Temptation domains. The tendency found may be associated with the desire to eat foods not recommended for PKU and to think about foods that are not part of the diet, which may be related to the exposure and social pressure that adults experience to taste foods rich in phenylalanine in their daily lives. The practical impact refers to the patient's perception that they spend a lot of time on administrative tasks related to clinical follow-up (filling in reminders, scheduling appointments, for example), that PKU affects their professional life, as they have difficulty concentrating, memorizing and performing tasks, and that they feel the burden of having to attend appointments and perform all the tasks necessary to keep their phenylalanine under control every day.
The study has limitations. Quality of life questionnaires portray the perception of patients and their caregivers about phenylketonuria and its treatment; the care team must evaluate these perceptions. The cross-sectional design of the study does not allow for causal conclusions; all associations discussed are of a correlative nature. Data interpretation must be carried out with caution; the sample investigated is small, and the period analyzed is four years. Due to the application of a specific questionnaire, there was the absence of a control group to demonstrate comparability between treatment groups with dietary or drug therapy and a control group without specific treatment. This is a limitation because comparative results between the control and exposed groups could improve the internal validity of non-randomized studies by evaluating residual bias in effect estimates. The purpose of this study was not to evaluate the correlation between the domains of quality of life and Phe levels at the time of application of the questionnaire. Another limitation was conducting this study during the COVID pandemic (Schmidt et al., 2021). A suggestion to minimize these limitations is to carry out a longitudinal study to explore the effects of adherence to treatment on the HRQoL over time.
Conclusion
Studies on the impact of metabolic diseases on health-related quality of life (HRQoL) of patients with PKU are growing and timely. Few studies in the literature have examined the quality of life of patients with PKU using the PKU-QOL questionnaire. Adherence to treatment in PKU negatively affected HRQoL in the sample studied; there was a worse perception of health status, emotional, social, and general repercussions of the disease and its treatment. This result may be related to the methodology used and the reality of different treatment resources. In Brazil, there is no availability of protein supplements with low phenylalanine content or phenylalanine-free with better palatability, the provision of special low protein foods (SLPF), pharmacological treatment with sapropterin in an expanded form for all responders, and intense activities of food and nutritional education in phenylketonuria. The challenges associated with the treatment of PKU must have multidisciplinary, effective interventions for better health and well-being in this population. Longitudinal and multicentric investigations on the treatment and quality of life in phenylketonuria would be important to elucidate the perception of health and propose individual and collective health actions for its treatment in the Federal District and Brazil.
References
-
Aguiar, C. C. T., Vieira, A. P. G. F., Carvalho, A. F., & Montenegro-, R. M Junior. (2008). [Assessment instruments for a Health-Related Quality of Life in diabetes mellitus]. Arquivos Brasileiros de Endocrinologia e Metabologia, 52(6), 931-939. https://doi.org/10.1590/s0004-27302008000600004
» https://doi.org/10.1590/s0004-27302008000600004 -
Ahring, K., Bélanger-Quintana, A., Dokoupil, K., Gokmen-Ozel, H., Lammardo, A. M., MacDonald, A., Motzfeldt, K., Nowacka, M., Robert, M., & van Rijn, M. (2011). Blood phenylalanine control in phenylketonuria: a survey of 10 European centres. European Journal of Clinical Nutrition, 65(2), 275-278. https://doi.org/10.1038/ejcn.2010.258
» https://doi.org/10.1038/ejcn.2010.258 -
Alptekin, I. M., Koc, N., Gunduz, M., & Cakiroglu, F. P. (2018). The impact of phenylketonuria on PKU patients’ quality of life: Using of the phenylketonuria-quality of life (PKU-QOL) questionnaires. Clinical Nutrition ESPEN, 27, 79-85. https://doi.org/10.1016/j.clnesp.2018.06.005
» https://doi.org/10.1016/j.clnesp.2018.06.005 -
Barta, A. G., Sumánszki, C., Turgonyi, Z., Kiss, E., Simon, E., Serfőző, C., & Reismann, P. (2020). Health Related Quality of Life assessment among early-treated Hungarian adult PKU patients using the PKU-QOL adult questionnaire. Molecular Genetics and Metabolism Reports, 23, 100589. https://doi.org/10.1016/j.ymgmr.2020.100589
» https://doi.org/10.1016/j.ymgmr.2020.100589 -
Beghini, M., Resch, F. J., Möslinger, D., Konstantopoulou, V., Karall, D., Scholl-Bürgi, S., Brunner-Krainz, M., Plecko, B., Spenger, J., Kautzky-Willer, A., Scherer, T., & Hufgard-Leitner, M. (2021). Project “Backtoclinic I”: An overview on the state of care of adult PKU patients in Austria. Molecular Genetics and Metabolism, 133(3), 257-260. https://doi.org/10.1016/j.ymgme.2021.05.003
» https://doi.org/10.1016/j.ymgme.2021.05.003 -
Bik-Multanowski, M., Didycz, B., Mozrzymas, R., Nowacka, M ., Kaluzny, L., Cichy, W., Schneiberg, B., Amilkiewicz, J., Bilar, A., Gizewska, M., Lange, A., Starostecka, E., Chrobot, A., Wojcicka-Bartlomiejczyk, B. I., & Milanowski, A. (2008). Quality of life in noncompliant adults with phenylketonuria after resumption of the diet. Journal of Inherited Metabolic Disease, 31(S2), 415-418. https://doi.org/10.1007/s10545-008-0978-7
» https://doi.org/10.1007/s10545-008-0978-7 -
Bilder, D. A., Noel, J. K., Baker, E. R., Irish, W., Chen, Y., Merilainen, M. J., Prasad, S., & Winslow, B. J. (2016). Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria. Developmental Neuropsychology, 41(4), 245-260. https://doi.org/10.1080/87565641.2016.1243109
» https://doi.org/10.1080/87565641.2016.1243109 -
Blau, N., van Spronsen, F. J., & Levy, H. L. (2010). Phenylketonuria. The Lancet, 376(9750), 1417-1427. https://doi.org/10.1016/S0140-6736(10)60961-0
» https://doi.org/10.1016/S0140-6736(10)60961-0 -
Bosch, A. M., Burlina, A., Cunningham, A., Bettiol, E., Moreau-Stucker, F., Koledova, E., Benmedjahed, K., & Regnault, A. (2015). Assessment of the impact of phenylketonuria and its treatment on quality of life of patients and parents from seven European countries. Orphanet Journal of Rare Diseases, 10(1), 80. https://doi.org/10.1186/s13023-015-0294-x
» https://doi.org/10.1186/s13023-015-0294-x -
Camp, K. M., Parisi, M. A., Acosta, P. B., Berry, G. T., Bilder, D. A., Blau, N., Bodamer, O. A., Brosco, J. P., Brown, C. S., Burlina, A. B., Burton, B. K., Chang, C. S., Coates, P. M., Cunningham, A. C., Dobrowolski, S. F., Ferguson, J. H., Franklin, T. D., Frazier, D. M., Grange, D. K., … Young, J. M. (2014). Phenylketonuria scientific review conference: State of the science and future research needs. Molecular Genetics and Metabolism , 112(2), 87-122. https://doi.org/10.1016/j.ymgme.2014.02.013
» https://doi.org/10.1016/j.ymgme.2014.02.013 -
Cazzorla, C., Bensi, G., Biasucci, G., Leuzzi, V., Manti, F., Musumeci, A., Papadia, F., Stoppioni, V., Tummolo, A., Vendemiale, M., Polo, G., & Burlina, A. (2018). Living with phenylketonuria in adulthood: The PKU ATTITUDE study. Molecular Genetics and Metabolism Reports , 16, 39-45. https://doi.org/10.1016/j.ymgmr.2018.06.007
» https://doi.org/10.1016/j.ymgmr.2018.06.007 -
Cazzorla, C., Cegolon, L., Burlina, A. P., Celato, A., Massa, P., Giordano, L., Polo, G., Daniele, A., Salvatore, F., & Burlina, A. B. (2014). Quality of Life (QoL) assessment in a cohort of patients with Phenylketonuria. BMC Public Health, 14(1), 1243. https://doi.org/10.1186/1471-2458-14-1243
» https://doi.org/10.1186/1471-2458-14-1243 -
Cohen, J. (1992). A power primer. Psychological Bulletin, 112(1), 155-159. https://doi.org/10.1037/0033-2909.112.1.155
» https://doi.org/10.1037/0033-2909.112.1.155 -
Daly, A., Pinto, A., Evans, S., &MacDonald, A . (2022). Glycomacropeptide in PKU-Does It Live Up to Its Potential? Nutrients, 14(4), 807. https://doi.org/10.3390/nu14040807
» https://doi.org/10.3390/nu14040807 -
Demirdas, S., Maurice-Stam, H., Boelen, C. C. A., Hofstede, F. C., Janssen, M. C. H., Langendonk, J. G., Mulder, M. F., Rubio-Gozalbo, M. E., van Spronsen, F. J., de Vries, M., Grootenhuis, M. A., & Bosch, A. M. (2013). Evaluation of quality of life in PKU before and after introducing tetrahydrobiopterin (BH4); a prospective multi-center cohort study. Molecular Genetics and Metabolism , 110, S49-S56. https://doi.org/10.1016/j.ymgme.2013.09.015
» https://doi.org/10.1016/j.ymgme.2013.09.015 -
Ford, S., O’Driscoll, M., &MacDonald, A . (2018). Living with Phenylketonuria: Lessons from the PKU community. Molecular Genetics and Metabolism Reports, 17, 57-63. https://doi.org/10.1016/j.ymgmr.2018.10.002
» https://doi.org/10.1016/j.ymgmr.2018.10.002 -
Gassió, R., Campistol, J., Vilaseca, M., Lambruschini, N., Cambra, F., & Fusté, E. (2007). Do adult patients with phenylketonuria improve their quality of life after introduction/resumption of a phenylalanine-restricted diet? Acta Paediatrica, 92(12), 1474-1478. https://doi.org/10.1111/j.1651-2227.2003.tb00834.x
» https://doi.org/10.1111/j.1651-2227.2003.tb00834.x -
González, M. J., Gassió, R., Artuch, R., & Campistol, J. (2016). Impaired Neurotransmission in Early-treated Phenylketonuria Patients. Seminars in Pediatric Neurology, 23(4), 332-340. https://doi.org/10.1016/j.spen.2016.11.007
» https://doi.org/10.1016/j.spen.2016.11.007 -
Handoom, B., Megdad, E., Al-Qasabi, D., Al Mesned, M., Hawary, R., Al-Nufiee, S., Al-Hassnan, Z., Alsayed, M. D., & Eldali, A. (2018). The effects of low protein products availability on growth parameters and metabolic control in selected amino acid metabolism disorders patients. International Journal of Pediatrics and Adolescent Medicine, 5(2), 60-68. https://doi.org/10.1016/j.ijpam.2018.04.001
» https://doi.org/10.1016/j.ijpam.2018.04.001 -
Hillert, A., Anikster, Y., Belanger-Quintana, A., Burlina, A., Burton, B. K., Carducci, C., Chiesa, A. E., Christodoulou, J., Đorđević, M., Desviat, L. R., Eliyahu, A., Evers, R. A. F., Fajkusova, L., Feillet, F., Bonfim-Freitas, P. E., Giżewska, M., Gundorova, P., Karall, D., Kneller, K., … Blau, N. (2020). The Genetic Landscape and Epidemiology of Phenylketonuria. The American Journal of Human Genetics, 107(2), 234-250. https://doi.org/10.1016/j.ajhg.2020.06.006
» https://doi.org/10.1016/j.ajhg.2020.06.006 -
Hoghughi, M., & Long, N. (2004). Handbook of Parenting: Theory and Research for Practice SAGE Publications Ltd. https://doi.org/10.4135/9781848608160
» https://doi.org/10.4135/9781848608160 -
Huijbregts, S. C. J., Bosch, A. M ., Simons, Q. A., Jahja, R., Brouwers, M. C. G. J., De Sonneville, L. M. J., De Vries, M. C., Hofstede, F. C ., Hollak, C. E. M., Janssen, M. C. H ., Langendonk, J. G ., Rubio-Gozalbo, M. E ., Van der Meere, J. J., Van der Ploeg, A. T., &van Spronsen, F. J . (2018). The impact of metabolic control and tetrahydrobiopterin treatment on health related quality of life of patients with early-treated phenylketonuria: A PKU-COBESO study. Molecular Genetics and Metabolism , 125(1-2), 96-103. https://doi.org/10.1016/j.ymgme.2018.07.002
» https://doi.org/10.1016/j.ymgme.2018.07.002 -
Jurecki, E. R., Cederbaum, S., Kopesky, J., Perry, K., Rohr, F., Sanchez-Valle, A., Viau, K. S., Sheinin, M. Y., & Cohen-Pfeffer, J. L. (2017). Adherence to clinic recommendations among patients with phenylketonuria in the United States. Molecular Genetics and Metabolism , 120(3), 190-197. https://doi.org/10.1016/j.ymgme.2017.01.001
» https://doi.org/10.1016/j.ymgme.2017.01.001 -
Luna, P. M., López-Paz, J. F., García, M., Amayra, I., Martínez, O., Pérez, M., Rodríguez, A. A., Pérez-Núñez, P., Ceberio, I., Mansilla, N., & Soria, C. (2023). Cognitive Functioning in Adults with Phenylketonuria in a Cohort of Spanish Patients. Behavioural Neurology, 2023, 9681740. https://doi.org/10.1155/2023/9681740
» https://doi.org/10.1155/2023/9681740 -
MacDonald, A ., Ashmore, C., Daly, A ., Pinto, A ., &Evans, S . (2020). An Observational Study Evaluating the Introduction of a Prolonged-Release Protein Substitute to the Dietary Management of Children with Phenylketonuria. Nutrients , 12(9), 2686. https://doi.org/10.3390/nu12092686
» https://doi.org/10.3390/nu12092686 -
MacDonald, A ., Gokmen-Ozel, H ., van Rijn, M ., & Burgard, P. (2010). The reality of dietary compliance in the management of phenylketonuria. Journal of Inherited Metabolic Disease , 33(6), 665-670. https://doi.org/10.1007/s10545-010-9073-y
» https://doi.org/10.1007/s10545-010-9073-y -
MacDonald, A ., Nanuwa, K., Parkes, L., Nathan, M., & Chauhan, D. (2011). Retrospective, observational data collection of the treatment of phenylketonuria in the UK, and associated clinical and health outcomes. Current Medical Research and Opinion, 27(6), 1211-1222. https://doi.org/10.1185/03007995.2011.576237
» https://doi.org/10.1185/03007995.2011.576237 -
MacDonald, A ., van Wegberg, A. M. J. J., Ahring, K ., Beblo, S., Bélanger-Quintana, A ., Burlina, A., Campistol, J., Coşkun, T., Feillet, F., Giżewska, M., Huijbregts, S. C., Leuzzi, V., Maillot, F., Muntau, A. C., Rocha, J. C., Romani, C., Trefz, F., van Spronsen, F. J ., Rocha, J. C ., …van Spronsen, F. J . (2020). PKU dietary handbook to accompany PKU guidelines. Orphanet Journal of Rare Diseases , 15(1), 171. https://doi.org/10.1186/s13023-020-01391-y
» https://doi.org/10.1186/s13023-020-01391-y -
Morawska, A., Mitchell, A. E., Etel, E., Kirby, G., McGill, J., Coman, D., & Inwood, A. (2020). Psychosocial functioning in children with phenylketonuria: Relationships between quality of life and parenting indicators. Child: Care, Health and Development, 46(1), 56-65. https://doi.org/10.1111/cch.12727
» https://doi.org/10.1111/cch.12727 -
Regnault, A., Burlina, A ., Cunningham, A., Bettiol, E., Moreau-Stucker, F., Benmedjahed, K., &Bosch, A. M . (2015). Development and psychometric validation of measures to assess the impact of phenylketonuria and its dietary treatment on patients’ and parents’ quality of life: the phenylketonuria - quality of life (PKU-QOL) questionnaires. Orphanet Journal of Rare Diseases , 10(1), 59. https://doi.org/10.1186/s13023-015-0261-6
» https://doi.org/10.1186/s13023-015-0261-6 -
Rose, A. M., Grosse, S. D., Garcia, S. P., Bach, J., Kleyn, M., Simon, N.-J. E., & Prosser, L. A. (2019). The financial and time burden associated with phenylketonuria treatment in the United States. Molecular Genetics and Metabolism Reports , 21, 100523. https://doi.org/10.1016/j.ymgmr.2019.100523
» https://doi.org/10.1016/j.ymgmr.2019.100523 -
Schmidt, S. J., Barblan, L. P., Lory, I., & Landolt, M. A. (2021). Age-related effects of the COVID-19 pandemic on mental health of children and adolescents. European Journal of Psychotraumatology, 12(1). https://doi.org/10.1080/20008198.2021.1901407
» https://doi.org/10.1080/20008198.2021.1901407 -
Singh, R. H., Cunningham, A. C., Mofidi, S., Douglas, T. D., Frazier, D. M., Hook, D. G., Jeffers, L., McCune, H., Moseley, K. D., Ogata, B., Pendyal, S., Skrabal, J., Splett, P. L., Stembridge, A., Wessel, A., & Rohr, F. (2016). Updated, web-based nutrition management guideline for PKU: An evidence and consensus based approach. Molecular Genetics and Metabolism , 118(2), 72-83. https://doi.org/10.1016/j.ymgme.2016.04.008
» https://doi.org/10.1016/j.ymgme.2016.04.008 -
Thimm, E., Schmidt, L. E., Heldt, K., & Spiekerkoetter, U. (2013). Health-related quality of life in children and adolescents with phenylketonuria: unimpaired HRQoL in patients but feared school failure in parents. Journal of Inherited Metabolic Disease , 36(5), 767-772. https://doi.org/10.1007/s10545-012-9566-y
» https://doi.org/10.1007/s10545-012-9566-y -
van Spronsen, F. J ., Blau, N., Harding, C., Burlina, A ., Longo, N., &Bosch, A. M . (2021). Phenylketonuria. Nature Reviews Disease Primers, 7(1), 36. https://doi.org/10.1038/s41572-021-00267-0
» https://doi.org/10.1038/s41572-021-00267-0 -
van Wegberg, A. M. J., MacDonald, A ., Ahring, K ., Bélanger-Quintana, A ., Beblo, S., Blau, N ., Bosch, A. M ., Burlina, A ., Campistol, J ., Coşkun, T ., Feillet, F ., Giżewska, M ., Huijbregts, S. C ., Leuzzi, V ., Maillot, F ., Muntau, A. C ., Rocha, J. C ., Romani, C ., Trefz, F ., &van Spronsen, F. J . (2025). European guidelines on diagnosis and treatment of phenylketonuria: First revision. Molecular Genetics and Metabolism, 145(2), 109125. https://doi.org/10.1016/j.ymgme.2025.109125
» https://doi.org/10.1016/j.ymgme.2025.109125 -
Vicente, F., Jurecki, E., Giovannetti, D., Ferreira, A. R., Leite, E., Giugliani, L., & Acquadro, C. (2019). Linguistic Validation of the Phenylketonuria - Quality of Life (PKU-QOL) Questionnaire Into Brazilian Portuguese. Journal of Inborn Errors of Metabolism and Screening, 7. https://doi.org/10.1590/2326-4594-jiems-2018-0001
» https://doi.org/10.1590/2326-4594-jiems-2018-0001 -
Vieira, E. Neto, Maia, H. S. Filho, Monteiro, C. B., Carvalho, L. M., Tonon, T., Vanz, A. P., Schwartz, I. V. D., & Ribeiro, M. G. (2018). Quality of life and adherence to treatment in early-treated Brazilian phenylketonuria pediatric patients. Brazilian Journal of Medical and Biological Research, 51(2). https://doi.org/10.1590/1414-431x20176709
» https://doi.org/10.1590/1414-431x20176709 -
Vockley, J., Andersson, H. C., Antshel, K. M., Braverman, N. E., Burton, B. K., Frazier, D. M ., … Berry, S. A. (2014). Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genetics in Medicine, 16(2), 188-200. https://doi.org/10.1038/gim.2013.157
» https://doi.org/10.1038/gim.2013.157 -
WHO. (1995). The World Health Organization quality of life assessment (WHOQOL): Position paper from the World Health Organization. Social Science & Medicine, 41(10), 1403-1409. https://doi.org/10.1016/0277-9536(95)00112-K
» https://doi.org/10.1016/0277-9536(95)00112-K -
Wood, G., Pinto, A ., Evans, S ., Daly, A ., Adams, S., Costelloe, S., Gribben, J., Ellerton, C., Emm, A., Firman, S., Ford, S ., French, M., Gaff, L., Giuliano, E., Hill, M., Hunjan, I., Newby, C., Mackenzie, A., Pereira, R., …MacDonald, A . (2021). Special Low Protein Foods Prescribed in England for PKU Patients: An Analysis of Prescribing Patterns and Cost. Nutrients , 13(11), 3977. https://doi.org/10.3390/nu13113977
» https://doi.org/10.3390/nu13113977
Research data is available on request from the corresponding author.
