Quality of Life in Patients with Phenylketonuria: A Systematic Review

Abstract

The impact of phenylketonuria (PKU) on Quality of life (QoL) has been a topic of interest in recent research. This article reviews current researches on the impact of PKU on QoL. The review examines factors that may influence QoL, such as age, metabolic control, and treatment adherence. In this systematic review study, relevant articles were identified using a search strategy built with the keywords phenylketonuria, PKU, or hyperphenylalaninemia (or their synonyms) and QoL in Web of Science, Scopus, and PubMed databases. After identifying the articles, duplicates, reviews, scientific abstracts, articles published in languages other than English, and non relevant studies were excluded. The search strategy identified 951 records from databases, and after excluding duplicates, irrelevant studies, and those published in non English languages, 26 records were left that contained data on 1816 patients with PKU/hyperphenylalaninemia. The studies included both children/adolescents and adults. Overall, the studies found that the QoL of PKU patients was comparable to normative data, but some aspects such as emotional health and school functioning were lower. Metabolic control was found to significantly correlate with QoL. Younger patients and men had better QoL in several studies, while late treated patients and those with lower education had worse outcomes. It is concluded that QOL in patients with PKU is similar to the general population. However, given the chronic nature of the condition, it is important to pay special attention to their QoL. Poor QOL is associated with female gender, lower education, older age, and poor metabolic control.

INTRODUCTION

Phenylketonuria (PKU) is an uncommon genetic disorder caused by a deficiency of phenylalanine hydroxylase, which impairs the body’s ability to metabolize phenylalanine. If untreated, PKU can result in serious neurological problems, seizures, and intellectual disability. Nevertheless, timely diagnosis and treatment can enable many PKU patients to live healthy and fulfilling lives.[1] Newborn screening programs for this inherited metabolic condition were first introduced in Europe and the USA during the 1960s.[2]

Although protein restriction is the primary treatment for PKU, assessing treatment efficacy based solely on metabolic control may not be sufficient due to the chronic nature of the disease and the required treatment. Patients with PKU must adhere to a lifelong low-phenylalanine diet to maintain normal blood phenylalanine levels, but compliance with treatment often decreases after childhood. Even with adequate treatment, individuals with PKU still exhibit some degree of intellectual impairment compared to healthy individuals.[3,4,5]

Due to the chronic and demanding nature of PKU and the need for ongoing care to prevent complications, individuals with PKU may experience a reduced quality of life (QoL).[6] As a result, an essential aspect of living with PKU is the QoL that the patient experiences. In recent years, there has been growing interest in understanding the impact of PKU on patients’ QoL. QoL is a multidimensional concept that encompasses physical, psychological, and social well-being. Assessing QoL in patients with PKU can provide valuable insights into the burden of the disease and help identify areas where interventions may need to improve patient outcomes.[7]

Several studies conducted to explore the QoL of patients with PKU; however, the findings are inconsistent. Some studies have reported that patients with PKU have lower QoL scores compared to healthy controls,[6,7,8,9] while others have found no significant differences in QoL between patients with PKU and controls.[10,11,12,13] These controversial results highlight the need for a systematic review of the literature to synthesize the available evidence and provide a more comprehensive understanding of the impact of PKU on QoL.

The purpose of this paper is to conduct a systematic review of the literature on the QoL in individuals with PKU. We will specifically examine the methods used to evaluate QoL and the various factors that can affect it, such as dietary restrictions, social support, and access to medical care. By providing a comprehensive analysis of the available evidence, this review will enable healthcare providers to offer support that is more effective to PKU patients and promote their optimal QoL and well-being. Moreover, this review could also guide future research on QoL in individuals with PKU.

MATERIALS AND METHODS

The study was conducted as a systematic review following the 2020 guideline of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). This study was conducted between May and June 2023 to investigate whether health-related QoL is impacted in patients with PKU due to the disease and its complications. To achieve this, a search was conducted through international databases for all studies that reported aspects of QoL in patients with PKU or hyperphenylalaninemia.

Search strategy

A systematic search of electronic databases including Web of Science, Scopus, and PubMed was conducted. The search was limited to studies published in the English language from January 2000 to June 2023. A combination of keywords and medical subject headings (MeSH) terms related to PKU and QoL such as PKU, hyperphenylalaninemia, QoL, health-related QoL, and their synonyms were used. The search strategy was modified according to the guidelines in each database [Appendix 1]. The reference lists of eligible studies were also evaluated to identify additional relevant articles.

Appendix 1.

Search strategy

Database	Search strategy
Web of Science	#1
	TI=(Classic Phenylketonuria OR Non- Classic Phenylketonuria OR BH4 Deficiency OR DHPR Deficiency OR Dihydropteridine Reductase OR Phenylalanine Hydroxylase OR Dihydropteridine Reductase Deficiency OR Dihydropteridine Reductase Deficiency Disease OR Folling Disease OR Folling’s Disease OR Hyperphenylalaninemia OR Biopterin Metabolism defect OR BH4-Deficiency OR Non-Phenylketonuric Hyperphenylalaninemia OR Tetrahydrobiopterin Deficiency OR Hyperphenylalaninemia, Non-Phenylketonuric OR Oligophrenia Phenylpyruvica OR PAH Deficiency OR Atypical PKU OR Phenylalanine Hydroxylase Deficiency OR Phenylalanine Hydroxylase Deficiency Disease OR Phenylketonuria OR QDPR Deficiency OR Quinoid Dihydropteridine Reductase Deficiency OR Tetrahydrobiopterin Deficiency OR phenylketonuria I OR phenylketonuria II OR phenylketonuria type 2 OR phenylketonuria)
	#2
	AB=(Classic Phenylketonuria OR Non- Classic Phenylketonuria OR BH4 Deficiency OR DHPR Deficiency OR Dihydropteridine Reductase OR Phenylalanine Hydroxylase OR Dihydropteridine Reductase Deficiency OR Dihydropteridine Reductase Deficiency Disease OR Folling Disease OR Folling’s Disease OR Hyperphenylalaninemia OR Biopterin Metabolism defect OR BH4-Deficiency OR Non-Phenylketonuric Hyperphenylalaninemia OR Tetrahydrobiopterin Deficiency OR Hyperphenylalaninemia, Non-Phenylketonuric OR Oligophrenia Phenylpyruvica OR PAH Deficiency OR Atypical PKU OR Phenylalanine Hydroxylase Deficiency OR Phenylalanine Hydroxylase Deficiency Disease OR Phenylketonuria OR QDPR Deficiency OR Quinoid Dihydropteridine Reductase Deficiency OR Tetrahydrobiopterin Deficiency OR phenylketonuria I OR phenylketonuria II OR phenylketonuria type 2 OR phenylketonuria)
	#3
	#1 OR #2
	#4
	ALL=(Quality of life OR HRQOL OR Health-Related Quality Of Life OR Life Quality)
	#5
	#3 AND #4
Scopus	Modified: TITLE-ABS-KEY ( “classic phenylketonuria” OR “non-classic phenylketonuria” OR “BH4 deficiency” OR “DHPR deficiency” OR “dihydropteridine reductase” OR “phenylalanine hydroxylase” OR “dihydropteridine reductase deficiency” OR “dihydropteridine reductase deficiency disease” OR “folling disease” OR “folling' s disease” OR “hyperphenylalaninemia” OR “biopterin metabolism defect” OR “BH4-deficiency” OR “non-phenylketonuric hyperphenylalaninemia” OR “tetrahydrobiopterin deficiency” OR “hyperphenylalaninemia, non-phenylketonuric” OR “oligophrenia phenylpyruvica” OR “PAH deficiency” OR “atypical PKU” OR “phenylalanine hydroxylase deficiency” OR “phenylalanine hydroxylase deficiency disease” OR “phenylketonuria” OR “QDPR deficiency” OR “quinoid dihydropteridine reductase deficiency” OR “tetrahydrobiopterin deficiency” OR “phenylketonuria I” OR “phenylketonuria II” OR “phenylketonuria type 2” OR “phenylketonuria” ) AND
	ALL ( “quality of life” OR “health-related quality of life” OR “life quality” )
PubMed	1#
	Classic Phenylketonuria[Title/Abstract] OR Non- Classic Phenylketonuria[Title/Abstract] OR BH4 Deficiency[Title/Abstract] OR DHPR Deficiency[Title/Abstract] OR Dihydropteridine Reductase[Title/Abstract] OR Phenylalanine Hydroxylase[Title/Abstract] OR Dihydropteridine Reductase Deficiency[Title/Abstract] OR Dihydropteridine Reductase Deficiency Disease[Title/Abstract] OR Folling Disease[Title/Abstract] OR Folling’s Disease[Title/Abstract] OR Hyperphenylalaninemia[Title/Abstract] OR Biopterin Metabolism defect[Title/Abstract] OR BH4-Deficiency[Title/Abstract] OR Non-Phenylketonuric Hyperphenylalaninemia[Title/Abstract] OR Tetrahydrobiopterin Deficiency[Title/Abstract] OR Hyperphenylalaninemia, Non-Phenylketonuric[Title/Abstract] OR Oligophrenia Phenylpyruvica[Title/Abstract] OR PAH Deficiency[Title/Abstract] OR Atypical PKU[Title/Abstract] OR Phenylalanine Hydroxylase Deficiency[Title/Abstract] OR Phenylalanine Hydroxylase Deficiency Disease[Title/Abstract] OR Phenylketonuria[Title/Abstract] OR QDPR Deficiency[Title/Abstract] OR Quinoid Dihydropteridine Reductase Deficiency[Title/Abstract] OR Tetrahydrobiopterin Deficiency[Title/Abstract] OR phenylketonuria I[Title/Abstract] OR phenylketonuria II[Title/Abstract] OR phenylketonuria type 2[Title/Abstract] OR phenylketonuria[Title/Abstract] OR phenylketonuria[MeSH Terms]
	2#
	Quality of life OR HRQOL OR Health-Related Quality Of Life OR Life Quality OR Quality of life[MeSH Terms]
	#1 AND #2

Eligibility criteria

English language studies that evaluate QoL in individuals with PKU using validated QoL instruments or self-reported measures were included. Studies that focus on other metabolic disorders or those that do not report QoL outcomes were not included. Studies must have been published in peer-reviewed journals. Studies published before the year 2000 were excluded, as were scientific abstracts, guidelines, reviews, editorials, case reports, retracted articles, and articles with full texts in other languages.

Study selection and data extraction

Two independent reviewers screened the titles and abstracts of all identified studies for eligibility. Full-text articles were obtained for all potentially eligible studies and reviewed for inclusion and data extraction. Non-relevant articles based on the full text were ignored. Articles not related to PKU or those in which the QoL was not reported were excluded. Qualitative studies, validity studies, and interventional studies in which the baseline QoL of the PKU patients was not reported were also excluded. The study selection process is shown in Figure 1. Finally, eligible studies underwent further review and data extraction.

Figure 1.

Study selection flowchart

Data were extracted using a standardized data extraction form, including study characteristics, participant demographics, QoL assessment tools, and results.

Quality assessment

The quality of the included studies was assessed using Newcastle-Ottawa Scale for observational studies. Any discrepancies between reviewers are resolved through discussion and consensus.

RESULTS

Out of 951 records retrieved, 318 were duplicates. After removing the duplicates, 24 articles published before 2000 were ignored. Non-relevant articles, conference abstracts, and articles published in languages other than English were also excluded. After removing articles based on the abstract, 109 records remained and were sought for retrieval and review. However, 83 articles were excluded due to reasons listed in Figure 1, and only 26 remained [Table 1].

Table 1.

Quality of life data in Patients with PKU

Of the remaining articles, 20 were from European countries,[8,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28] one from Australia,[9] one from Brazil,[6] one from Iran,[7] one from the USA,[29] one from New Zealand[30], and one from Egypt.[1]

The total number of patients included was 1804, with 932 females. Children and adolescents were reported in ten studies,[1,6,9,14,15,17,22,25,27,30] while ten studies only included adults.[7,10,11,13,16,18,19,20,26,28] Six studies included both adults and children.[8,12,21,23,24,29]

Table 1 displays the SF-36, pediatric quality of life inventory (PedsQL), TNO-AZL, and World Health Organization QoL questionnaire as commonly used questionnaires. In German studies, pediatric patients were often assessed using KINDL. The table also includes information on the degree of metabolic control and disease severity, if mentioned.

Some studies have found a significant relationship between the degree of metabolic control and QoL.[13,15,22,23,24,30] Younger patients generally had better outcomes compared to older patients,[1,10,17] while late-treated patients had worse outcomes.[7] A study in Turkey reported worse outcomes for children.[8] Women tended to have poorer QoL.[10,23,28] In Brazil, a study using the PedsQL revealed that patients had significantly lower scores compared to controls.[6] Another study showed that PKU patients received more special education during primary school.[19]

An adult study found that PKU patients displayed more anxious relationship styles, and partial adherence was associated with lower mental and physical QoL scores.[16] In the Netherlands, a study showed that children had lower autonomy, cognition, and positive emotions scores, while adolescents had lower scores across all domains compared to controls.[23] Another study found that children aged 8–12 reported higher physical functioning scores, while those aged 13–17 had higher scores on total and psychosocial functioning in the PedsQL. Adult patients reported lower scores in the TAAQOL cognitive domain. Mothers of children aged 5–7 also reported a trend towards lower HRQoL scores on the “school and social functioning” scales.[21]

DISCUSSION

This systematic review aimed to investigate the QoL in patients with PKU or hyperphenylalaninemia. The majority of the articles included in the data extraction were conducted in European countries, with only a few outside Europe. The results of the review showed that despite the negative impact of PKU on QoL particularly in terms of social functioning, psychological well-being, and physical health, the studies generally reported an acceptable QoL in patients with high blood phenylalanine levels, whether they had classical PKU requiring lifelong treatment and dietary restrictions or hyperphenylalaninemia.

Adolescents with poor treatment adherence were found to report more symptoms, while those with better adherence had lower enjoyment of food.[15] Some studies have reported lower health-related QoL scores in PKU patients.[6,23,30]

One study conducted in seven European countries found that, except for social functioning, the results for children were comparable to normative data.[12] Mental functioning according to SF-36 scores was slightly worse in adults with PKU, and tiredness was the highest symptom score reported by patients. The emotional impact of PKU and its management, anxiety about blood phenylalanine levels, and guilt related to poor adherence to dietary restrictions or Phe-free amino acid supplement intake had the highest PKU-QOL impact scores.

There was no clear association between the severity of PKU and symptoms, but a consistent pattern emerged regarding the impact of Phe-free amino acid supplement intake based on the severity of PKU. In adolescents, there was an association between the impact of dietary restriction and the severity of PKU. The parent version showed that children with classical PKU had poorer dietary adherence and experienced a greater impact from the diet than those with mild or moderate PKU.

Correlations with metabolic control

Some studies have investigated the correlation between QoL and metabolic control in patients with PKU.

In a study, it was found that blood phenylalanine (Phe) levels over the last 10 years were significantly correlated with certain aspects of PKU such as practical impact and treatment adherence. Phe levels over the last year were significantly correlated with the social impact of dietary protein restriction, adherence to treatment, practical impact, and overall impact of PKU. Concurrent Phe levels were correlated with an overall impact of PKU and some other aspects of QoL, with a greater impact observed in the group with poorer adherence. Lifetime Phe levels were correlated with the emotional impact of PKU. Classical patients did not differ significantly from other patients except for financial impact.[13]

Another study found that lifetime metabolic control was negatively correlated with pain, anger, sexuality, and sleep in adults, while concurrent Phe levels were negatively associated with sexuality.[23] A study in Germany also found that metabolic control was correlated with mood.[20] Patients’ self-assessments revealed a positive correlation between poor metabolic control and conduct problems. Parents of PKU patients rated everyday functioning significantly lower than parents of healthy children. Metabolic control in PKU patients was correlated with QoL measured with the KINDL-R, particularly in the field of everyday functioning as answered by parents.[22] Phe levels during the last year and concurrent levels were significantly associated with QoL regardless of severity in one study,[24] while the Worries score was inversely associated with plasma tyrosine levels and the General well-being score in another study.[29]

It is suggested that there appears to be a positive correlation between QoL and metabolic control in patients with PKU. Good metabolic control is associated with higher levels of QoL and better overall well-being. However, other factors such as social support including educational courses[7,24] for both patients and parents, and psychological interventions may also play a significant role in improving QoL for PKU patients, regardless of their metabolic control. Further research is needed to better understand these complex relationships and to develop interventions to improve the QoL of PKU patients.

Differences by gender

In the reviewed studies, some have investigated gender differences in the QoL of patients with PKU. While some studies have found significant gender differences, others have not.

According to a study conducted on adults in Germany, men had better QoL scores, but overall, patients had acceptable results.[28] Conversely, in another study, adult women reported lower QoL scores.[23]

In yet another study, women reported lower levels of positive mood and psychological functioning, but higher scores in the “social well-being” category although not significant according to the defined P-value.[10]

In another study conducted on adults, males and those with lower education or employment status had lower QoL scores compared to students.[24]

The reasons for these gender differences are not entirely clear. One possible explanation is that females may be more susceptible to the emotional and social impacts of PKU due to societal expectations and gender roles. Females may also face additional challenges related to pregnancy and childbirth, which can affect their metabolic control and QoL.[12] Another possible explanation is that males may be more likely to engage in physical activities, which can improve their physical functioning and overall QoL.

Overall, while some studies have found gender differences in the QoL of PKU patients,[10,28] the evidence is not entirely consistent. Further research is needed to better understand the factors that contribute to these differences and to develop interventions to improve the QoL of both male and female PKU patients.

Differences by age

The impact of age on the QoL of PKU patients has been reported in some studies.

In a study, adolescents had lower scores than younger patients in family cohesion and parental impact-time, indicating reduced QoL.[17] Another study found that older patients with late-treated PKU may have worse mental health, while higher education was associated with better results.[7] Patients over 25 years old reported more PKU-specific symptoms.[10] In a study in the USA, the total QoL score was negatively correlated with age.[29] A study showed that the QoL in most dimensions of children with PKU was similar to reference values, except for a reduction in positive emotions. Higher phenylalanine levels during the first year of life had a long-term negative impact on some dimensions of QoL.[25] In Egypt, QoL tended to decrease as the patient got older, but under-five children who received a special diet and supplements had higher median physical, emotional, and total scores compared to those who did not.[1]

In contrast, in one study in Turkey, children showed worse results, with the most frequent symptom being slow thinking. The most frequent problem, in general, was lack of concentration and tiredness.[8]

However, not all studies have found significant age-related differences in QoL among PKU patients.[25] The reasons for these age-related differences are not entirely clear. One possible explanation is that as patients age, they may become more aware of the challenges associated with PKU, which can lead to a decline in QoL. Older patients may also face additional challenges related to aging, such as comorbidities and social isolation. On the other hand, younger patients may be more resilient and adaptable to the challenges of PKU.

However, it is suggested that age appears to be an important factor in determining the QoL of patients with PKU. Further research is needed to better understand the factors that contribute to these age-related differences and to develop interventions to improve the QoL of patients across all age groups.

Differences in disease severity

The severity of PKU can vary widely, depending on factors such as the degree of residual enzyme activity and adherence to dietary restrictions. Several studies have investigated the impact of disease severity on the QoL of PKU patients.

One study found that disease severity was significantly related to physical and social functioning scores,[1] while another study found no significant difference between groups in terms of disease severity. However, classical patients may experience a more severe impact of guilt related to poor adherence.[9] In a study from New Zealand, patients with PKU had worse scores on the PedQL compared to those with HPA.[30]

In a study by Bosch et al.[12] in seven European countries, no association between the severity of PKU and its symptoms was found. However, they did report a consistent pattern regarding the impact of Phe-free amino acid supplement intake according to the severity of PKU. In adolescents, there was an association between the impact of dietary restriction and PKU severity, with children with classical PKU having poorer adherence to diet and a greater impact from the diet.

Patients with milder forms of PKU may have fewer dietary restrictions and may be less likely to experience cognitive impairment, which could contribute to better QoL outcomes.[1,30]

However, other studies have found that even patients with mild or moderate PKU can experience significant impairments in QoL.[17]

The reasons for these differences in QoL outcomes are not completely clear. One possible explanation is that even patients with mild or moderate PKU may experience some degree of cognitive impairment or other symptoms related to the condition, which could contribute to lower QoL scores.[17] Additionally, the burden of adhering to a strict diet may be challenging for patients with any form of PKU, which could also contribute to lower QoL outcomes.

It seems that disease severity appears to be an important factor in determining the QoL of patients with PKU.[1] Patients with milder forms of PKU may have better QoL outcomes than those with classic PKU,[9,30] but even patients with mild or moderate PKU can experience impairments in QoL. Further research is needed to better understand the factors that contribute to these differences in QoL outcomes and to develop interventions to improve the QoL of all patients with PKU.

Impact of tetrahydrobiopterin (BH4)

Tetrahydrobiopterin (BH4) is a cofactor that is essential for the proper function of enzymes involved in phenylalanine metabolism. BH4 supplementation has been shown to improve the activity of these enzymes and reduce the levels of phenylalanine in the blood of PKU patients.[12]

Some studies have investigated the impact of BH4 on the QoL of PKU patients. One study found that BH4 supplementation led to significant improvements in the QoL in adult PKU patients.[23] Another study reported similar improvements in children with PKU.[24] Overall, BH4 appears to be a promising treatment option for PKU patients, with the potential to improve both metabolic control and QoL.

Pregnancy and QOL

Pregnancy in women with PKU requires careful management of blood phenylalanine levels to prevent fetal complications. Elevated maternal phenylalanine levels during pregnancy can lead to intellectual disability, microcephaly, and other developmental abnormalities in the fetus. However, strict dietary control can be challenging for pregnant women with PKU and may impact their QoL.[12,13]

In some studies, the impact of PKU on the QoL of pregnant women has been investigated. One study found that pregnant women with PKU had lower scores on measures of social support and QoL compared to healthy controls.[12]

Despite the challenges associated with managing PKU during pregnancy, it is important to emphasize that strict dietary control can lead to positive outcomes for both the mother and the fetus.

However, pregnancy in women with PKU requires careful management of blood phenylalanine levels to prevent fetal complications. Although strict dietary control can be challenging, it is important to emphasize the potential benefits for both the mother and the fetus. Further research is needed to better understand the impact of PKU on the QoL of pregnant women and to develop interventions to support their mental health and well-being.

Limitations

Our review was limited to a small number of databases and only included articles written in English, with no assessment of articles written in other languages. Conference papers were not included in our review. Furthermore, different studies used different questionnaires to evaluate QoL, which made it difficult to conduct further quantitative analysis.

CONCLUSION

While the overall quality of life (QoL) in patients with PKU is generally acceptable, research has shown that it could harm the QoL of patients, particularly in terms of social functioning, psychological well-being, and physical health. Therefore, it is important to consider QoL as a measure of health in patients undergoing treatment for PKU. Female patients, older patients, and those who are diagnosed later tend to have worse outcomes. Improvements in metabolic control have been associated with better QoL.

In addition, interventions such as BH4 supplementation and good metabolic control during pregnancy have been shown to improve QoL in PKU patients. Further research is needed to develop and evaluate interventions to improve the QoL of PKU patients.

Ethical approval

The protocol of the study was approved by the ethics committee of Isfahan University of Medical Sciences with the ethics code of IR.MUI.MED.REC.1402.063.

Financial support and sponsorship

This study was funded by the Vice Chancellor of Research, Isfahan University of Medical Sciences, Isfahan, Iran, with a research project number of 340229.

Conflicts of interest

There are no conflicts of interest.