The Struggle That Is Phenylketonuria : What Do The Patients and Caregivers Suffer From
Conditions: Psychological Well-Being, Caregiver Burden, Life Stress
Sponsor: Hacettepe University

 
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The Struggle That Is Phenylketonuria : What Do The Patients and Caregivers 
Suffer From 
Abstract 
Objective: To assess the stress levels and life hardships of phenylketonuria patients 
and their parents. 
Study Design: Between January 2020 – June 2020, a total of 156 phenylketonuria 
patients and their parents who arrived for their regular examinations were included. 
Parents were asked to fill the parenting stress index, Zarit burden scale and the 
strengths and difficulties questionnaire and children over the age of eleven were asked 
to fill the Rosenberg self-esteem scale, the stait-trait anxiety inventory and strengths 
and difficulties questionnaire. 
Results: We found a significant negative correlation between Rosenberg self-esteem 
scale and age at diagnosis, (r=-.27, p=.035), age of the mother (r=-.33, p=.009) and 
age of the father (r=-.38, p=.004). There was a significant positive correlation between 
the stait-trait anxiety inventory and age of the patient, (r=.36, p=.006) , age of the 
mother (r=.29, p=.031) and age of the father (r=.38, p=.024). In child form of strengths 
and difficulties questionnaire ; emotional problems part was significantly positively 
correlated with serum phenylalanine levels at diagnosis (r=.35, p=.036); total points 
were significantly positively correlated with serum phenylalanine levels at clinical 
examination (r=-.34, p=.004) and social problems part was significantly negatively 
corelated with the age of the father (r=-.34, p=.047). We found a significant positive 
correlation between Zarit burden scale and number of siblings (r=.195, p=.023). In 
parent form of strengths and difficulties questionnaire; emotional problems part was 
significantly positively correlated with age of the patient (r=.217, p=.032), peer 
problems part was significantly positively correlated with age at diagnosis (r=.211, 
p=.037), behavioral problems (r=.203, p=.045)  and attention deficit and hyperactivity 
(r=.203, p=.045)  parts were significantly positively correlated with serum 
phenylalanine levels at diagnosis.  
Conclusions: Phenylketonuria is hard to cope with both for the patients and their 
parents because of diet obligation, high expenditures for the formulas required for the 
diet, requirement of regular clinical examinations and possible development of mental 
disability and psychiatric disorders Patients and their families should be 
psychologically evaluated and support should be provided if needed.  
Keywords: Phenylketonuria, stress, caregivers burden  
 
 
 
 
 

 
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List of Abbreviations: 
Phe: Phenylalanine 
BH₄ Tetrahydrobiopterin 
PAH Phenylalanine Hydroxylase 
PKU Phenylketonuria 
TAI Trait Anxiety Inventory 
SAI Stait Anxiety Inventory 
SDQ Strengths and Difficulties Questionnaire 
ADHD Attention Deficit and Hyperactivity Disorder 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Introduction 
Phenylalanine is an essential aminoacid. It’s required for protein production 
and cell function in human body.  Thyroxine production is also dependant on 
phenylalanin intake since it’s synthetised in liver from phenylalanine in a reaction 
catalysed by enzyme “Phenylalanine Hydroxylase” . [1] Therefore disruptancies in 
enzyme functions cause phenylalanine abundance. Phenylalanine accumulates in 
body (especially in central nervous system) and it’s excreted by kidneys as 
fenylpiruvic acid. [2] 
This abundance of phenylalanine is called hyperphenylalaninemia and blood 
levels help define the borders of the disease. Biochemical definition is blood 
phenylalanine level above 2 mg/dl (120 μmol/L) but clinical spectrum  is wide and 
symptoms become worse as levels rise. [3] Deficiency of the Phenylalanine 
Hydroxylase (PAH) enzyme (EC 1.14. 16.1)causes the illness which has come to 
known as Phenylketonuria (OMIM #261600) and the urinary products give urine the 
specific musty odor.  Phenylketonuria (PKU) has autosomal recessive inheritance 
pattern and PAH gene is located on 12q23.2. [4] This genetic inheritance pattern 
causes increased number of patients in countries where consanguineous marriage is 
common – such as Turkey. Frequency of phenylketonuria is 1 in every 4.000 children 
in Turkey as opposed to Europe where it’s 1 in every 10.000 children. [2,5-8]. As 
misfortunate as it is, this facilitates observation of the disease and the hardships it 
brings. 
The severity of clinical spectrum is dependant on blood levels of 
phenylalanine. Therefore the disease classification is made according to 
phenylalanine measurements. Blood levels between 2 and 6 mg/dl is defined as mild 
hyperphenylalaninemia, 6-10 mg/dl as mild phenylketonuria, 10-20 mg/dl as 
moderate phenylketouria and levels above 20 mg/dl is defined as classical 
phenylketonuria. [2,9] Disorders of tetrahydrobiopterin (BH₄ ) metabolism which is the 
coenzyme of PAH, causes BH₄ responsive hyperphenylalaninemia. [10] 
The most important factor in the treatment of phenylketonuria is 
phenylalanine-restricted diet, and this treatment should be lifelong. The aim of the 
treatment is to keep the blood phenylalanine level within the recommended range, 6 
mg/dl limit is accepted for children aged under 12 years , 10 mg/dl limit is accepted 
for children and adults aged 12-18 years.  [11] For this purpose, blood phenylalanine 
levels should be measured at regular intervals, physical examination evaluations and 
clinical follow-ups are required in order to monitor the dietary compliance of the 
patients. Apart from diet, some patients can have a partially or completely normal diet 
by taking the pharmacological agent containing tetrahydrobiopterin orally.  [12] 
Reasons such as emotional strain on food restriction, difficulty in giving the child the 
appropriate diet due to the social pressure, difficulty in obtaining dietary products 
because of high costs, and difficulty in complying with the diet in social gatherings 
make dietary continuity difficult. [13]  In addition, patients or their caregivers have a 
lot of financial and temporal losses in order to ensure dietary compliance. [14]  
Therefore, in our study, it was aimed to evaluate the quality of life and stress levels of 
patients diagnosed with phenylketonuria and their parents. 
 
 
 

 
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Methods 
This study was carried out at Hacettepe University, İhsan Doğramacı 
Children's Hospital, Department of Metabolism, between January 2020 and June 
2020. It was planned to include patients who were followed up with the diagnosis of 
phenylketonuria with diet or Sapropterin hydrochloride therapy, who didn’t have BH4 
metabolism disorder or any other health problem. Pregnant patients were also 
excluded. Our aim was to evaluate the quality of life and stress levels of these 
patients and their families. 
The research sample was formed from phenylketonuria patients followed in 
Hacettepe University, İhsan Doğramacı Children's Hospital, Department of 
Metabolism. All parents of the participants and the patients of age had given 
consent.Institutional ethics committee approved the study in accordance with the 
Declaration of Helsinki. After the participants were physically evaluated in the 
Department of Child Metabolism, scales to evaluate their quality of life and stress 
levels were applied to the participants and their parents. In our department, 
phenylketonuria patients are tested for phenylalanine levels every three months for 
routine control. The results of the blood test taken from the patients when they came 
for their routine control and the results of the blood tests taken at the other controls 
were obtained from the database. 
Evaluation Tools 
Rosenberg Self-Esteem Scale was developed by Morris Rosenberg in 1960. It 
evaluates self-esteem and consists of 10 items in total. In the Likert-type scale, which 
includes positively and negatively charged items, 0-1 points are considered as high 
self-esteem, 2-4 points as medium self-esteem, and 5-6 points as low self-esteem. 
[15]  
State-Trait Anxiety Inventory is an inventory that measures state and trait 
anxiety levels of children. It has been developed by Spielberges et. al in 1983. It 
consists of two questionnaires with a total of 40 questions, 20 that assesses the 
anxiety level stately, that is, how the child feels at that moment, and 20 that assesses 
how he feels constantly, that is, in general. The scale is in 3-point Likert type and is 
evaluated with 1-3 points according to symptom severityThe lowest score that can be 
obtained from the scales is 20, and the highest score is 60, higher scores indicate 
higher anxiety. [16] 
 Strengths and Difficulties Questionnaire  was developed by Goodman in 1997 
to assess children's social, emotional and behavioral difficulties. There is a parent 
form for ages 4-17 and a child form for ages 11-17. It consists of 25 questions in 
total. [17]  
Zarit Burden Scale was developed by Zarit et al. in 1980. It is a 5-point Likert-
type scale consisting of 22 questions that aims to measure the distress experienced 
by caregivers. Answers are scored between 0-4. A minimum of 0 and a maximum of 
88 points can be obtained from the scale. The high score indicates the height of the 
distress experienced. [18]  
Parenting Stress Index aims to measure the stress experienced by parents in 
their relationships with their children. It is a 4-point Likert-type scale consisting of 16 

 
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questions in total. A minimum of 16 and a maximum of 64 points can be obtained 
from the scale. A high score from the scale indicates that parental stress is high. [19]  
Statistical Analyses 
Analyses were made using the IBM SPSS Statistics 23 program, a licensed 
product of Hacettepe University. Whether the numerical variables showed a normal 
distribution or not was examined using the Shapiro-Wilk test when n<50, and the 
Kolmogorov-Smirnov test when n>50. Number and percentage are given for 
qualitative variables, mean, standard deviation, median, minimum and maximum 
values are given for qualitative variables.Since the scale scores are in discrete 
numeric data type and the assumption of normality cannot be achieved, the 
relationships with the Spearman correlation coefficient, which is a non-parametric 
coefficient, were examined and the p values were examined. The significance level 
was 0.05, and the relationships with a p value less than 0.05 were considered 
statistically significant. 
When the number of categories was two, if the scores in the categories were 
normally distributed, the "Independent Samples t Test" was performed, and the mean 
and standard deviations were given. For cases where the normal distribution 
assumption was not met, the "Mann-Whitney U Test" was performed, and medians 
and quartiles were given. For the variables with more than two categories, it was 
observed that there was no normal distribution in the categories in general, so the 
"Kruskal Wallis Test" was applied.In cases where the Kruskal Wallis test was applied, 
the "Dunn Multiple Comparison Test" was used to determine which categories were 
different for the results that were significant. 
 
Results 
Participants and Demographics 
Data from a total of 156 phenylketonuria patients who applied to Hacettepe 
University İhsan Doğramacı Children's Hospital Pediatric Metabolism Outpatient Clinic 
between February 2020 and August 2020 were evaluated. The mean age of the 156 
patients included in the study at admission was 10.9 years (±8.), and the median age 
was 10 (0.6-35). 53.2% of the patients were male and 46.8% were female, and the 
male/female ratio was 1.13 (83/73).At the time of examination, the mean age of the 
mothers was 37.8 years (±9), the median age was 37 (20-64), the mean age of the 
fathers was 40.9 years (±9.4), and the median age was 41 (17-68). Among the mothers 
and fathers of the patients, the rate of those with consanguineous marriage was 52.9%. 
The mean number of siblings was 1.23 (±1.2). 
The education levels of the mothers were 2.6% illiterate, 3.3% literate, 30.1% primary 
school graduate, 15% secondary school graduate, 26.1% high school graduate and 
22.9% university graduate. 40.5% of the mothers had a driver's license. Those with 
monthly income below 3000 Turkish Liras (TL) were 38.6% of the whole sample, those 
between 3000-6000 TL were 37.9%, those between 6000-9000 TL were 18.3%, and 
those over 9000 TL were 5.2%.  (Table 1). 
 
The mean age at diagnosis was 3.2 months (±10), and the median age was 0.6 
months (0.07-96). 49.4% of the patients were diagnosed with classical type, 24.4% 

 
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moderate type, 26.3% mild type phenylketonuria. The mean serum phenylalanine 
levels of the patients at the time of diagnosis were 20.61 mg/dl (±11.82), mean serum 
phenylalanine levels measured when they came to the outpatient clinic examination 
were 7.71 mg/dl (±5.91), median serum phenylalanine levels were 7.49 mg/dl (±5.25). 
85.3% of the patients who took a diet and 14.7% of those who did not. The percentage 
of those who adhered to the diet was 72.4% and 12.8% of those who did not. While 
18.6% of the patients were receiving sapropterin dihydrochloride treatment, 81.4% 
were not. (Table 2) 
 
Correlation Analysis of Patients' Scales 
 
  
The scales applied to the patients were the Rosenberg self-esteem scale, the 
state-trait anxiety inventory, the strengths and difficulties questionnaire, and the sub-
dimensions of emotional problems, behavioral problems, attention deficit and 
hyperactivity, peer problems, and social behaviors. 
 
The mean score of the patients on the Rosenberg self-esteem scale was 22.19 
(±5.77), and the median score was 23 (4-30). No significant correlation was found 
between the age of the patient and the scale scores (p=.195). A significant negative 
correlation was found between age at diagnosis and scale scores (r=-.27, p=.035). No 
significant correlation was found with serum phenylalanine level at diagnosis (p=.436), 
serum phenylalanine level during control examination (p=.065) and median serum 
phenylalanine level (p=.27). A significant and negative correlation was found with 
maternal age (r=-.33, p=.009) and father's age (r=-.38, p=.004). No significant 
relationship was found with the number of siblings (p=.352). 
 
The mean score of the patients from the state anxiety inventory (SAI) was 29.61 
(±6.93), and the median score was 29 (20-56). A significant positive correlation was 
found between patient age and scale scores (r=.36, p=.006). There was no significant 
relationship between age at diagnosis and scale scores (p=.14). No significant 
correlation was found with serum phenylalanine level at diagnosis (p=.11), serum 
phenylalanine level during control examination (p=.15) and median serum 
phenylalanine level (p=.25). A significant and positive correlation was found with 
maternal age (r=.29, p=.031) and father's age (r=.38, p=.024). No significant 
relationship was found with the number of siblings (p=.91). 
 
The mean score of the patients in the trait anxiety inventory (TAI) was 33.36 
(±8.51), and the median score was 32 (20-58). No significant correlation was found 
between patient age and scale scores (p=.062). There was no significant relationship 
between age at diagnosis and scale scores (p=.082). No significant correlation was 
found with serum phenylalanine level at the time of diagnosis (p=.18), serum 
phenylalanine level during the control examination (p=.27) and median serum 
phenylalanine level (p=.19). There was no significant relationship between maternal 
age (p=.36) and father's age (p=.61). No significant relationship was found with the 
number of siblings (p=.17). 
 
The sub-steps and the total score of the strengths and difficulties questionnaire 
(SDQ)  were evaluated separately. There were no significant results in terms of age 
and age at diagnosis. A significant and positive correlation was found between the 

 
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serum phenylalanine level at the time of diagnosis and the emotional sub-dimension 
of the questionnaire (r=.35, p=.036). A positive and significant correlation (r=-.34, 
p=.004) was found between the serum phenylalanine level in the control examination 
and the total score. There was no significant relationship between median serum 
phenylalanine levels, maternal age and number of siblings. A negative and significant 
relationship (r=-.34, p=.047) was found between father's age and the social sub-
dimension of the questionnaire. (Table 3) 
 
 
Correlation Analysis of Parents' Scales 
 
The scales applied to the parents are the parental stress index, the Zarit burden 
scale, the strengths and difficulties questionnaire, and the sub-dimensions of emotional 
problems, behavioral problems, attention deficit and hyperactivity, peer problems and 
social behaviors. 
 
The mean score from the parental stress index was 24.64 (±7.5) and the median 
score was 23 (8-46). No significant correlation was found between the patient's age 
(p=.82) and age at diagnosis (p=.23) and scale scores. No significant correlation was 
found with serum phenylalanine level at diagnosis (p=.094), serum phenylalanine level 
during control examination (p=.96) and median serum phenylalanine level (p=.52). 
There was no significant relationship between maternal age (p=.57) and father's age 
(p=.27). No significant relationship was found with the number of siblings (p=.41). 
 
The mean score from the caregiving burden scale was 21.07 (±12.5), and the 
median score was 20 (0-55). No significant correlation was found between the patient's 
age (p=.36) and age at diagnosis (p=.57) and scale scores. No significant correlation 
was found with serum phenylalanine level at diagnosis (p=.055), serum phenylalanine 
level during control examination (p=.32) and median serum phenylalanine level (p=.1). 
There was no significant relationship between maternal age (p=.99) and father's age 
(p=.72). A positive and significant relationship (r=.195, p=.023) was found between the 
number of siblings and the number of siblings. 
 
The sub-steps and the total score of the strengths and difficulties questionnaire 
were evaluated separately. A significant and positive correlation was found between 
the age of the patient and the emotional sub-dimension of the questionnaire (r=.217, 
p=.032). A significant and positive correlation was found between the age at diagnosis 
and the peer problems sub-dimension of the questionnaire (r=.211, p=.037). A 
significant and positive correlation was found between the serum phenylalanine level 
at the time of diagnosis and the behavioral sub-dimension of the questionnaire (r=.203, 
p=.045) and the dimension of attention deficit and hyperactivity (r=.203, p=.045). No 
significant correlation was found between the median serum phenylalanine levels and 
the phenylalanine levels in the control examination and the scales. There was no 
significant relationship between maternal and paternal age and the scales. No 
significant relationship was found with the number of siblings. (Table 4) 
 
 
 
 
 

 
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Comparisons Between Groups 
 
Scale scores of patients and parents were compared according to disease type. 
The Kruskal Wallis test was used to determine whether there was a difference between 
the types in terms of scale scores, since the number of categories was more than 2 
and the assumption of normal distribution was not provided. There was no significant 
difference between the classical type, moderate type and mild type in terms of scale 
scores. It was observed that there was a difference between the classical type and 
mild type in terms of the age of diagnosis of the patients (p=.043). The mean age at 
diagnosis of patients with the classical type was 85.09 months, and the patients with 
the mild type were 63.5 months. 
 
When the scale scores were evaluated in terms of sapropterin intake status, a 
significant difference was found between the patients who received and did not receive 
sapropterin in terms of emotional (p=0.43), behavior (p=0.47), and social (p=0.29) sub-
dimensions of the parent form of the strengths and difficulties questionnaire. 
 
Due to the small sample size, maternal education levels were evaluated in two 
groups as below high school and high school and above. There was no significant 
difference between the two groups in any of the scales. When the groups were 
evaluated in terms of mother's driver's license status, a significant difference was found 
in the patient form of the strengths and difficulties questionnaire in terms of behavior 
(p=0.48) and social (p=0.25) sub-dimensions. 
 
Scale scores were compared in terms of income level. A significant difference 
was found between the group with income less than 3000 TL/month and the group with 
3000-6000 TL/month in terms of stateful trait anxiety inventory (p=.033). A significant 
difference was found between the group with an income level of 3000-6000 TL/month 
and the group with a 6000-9000 TL/month level in terms of the peer sub-dimension of 
the patient form of the strengths and difficulties questionnaire (p=.024). 
 
 
Discussion 
Phenylketonuria is a chronic disease, and it is a difficult disease to cope with 
due to the necessity of diet. Patients face many difficulties in complying with the diet, 
obtaining special foods, coping with the economic burden of special foods and regular 
controls, and adapting to social life. [13,14] Conditions such as hyperactivity, 
depression and anxiety, which can be observed due to the nature of the disease, also 
create a burden on both parents and patients. [20] The stress caused by these 
difficulties effects the quality of life. In this study, the difficulties and stress situations 
faced by patients and parents were evaluated. The results are discussed separately 
for both groups. 
 
Evaluation of Patients' Outcomes 
Scales indicating self-esteem, life difficulties and anxiety were used to evaluate 
the patient group. The Rosenberg self-esteem scale, which measures self-esteem, 
indicates how an individual evaluates oneself. Individuals with high self-esteem have 

 
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positive thoughts about themselves, and as a result, these individuals are self-
confident and resilient in the face of difficulties. Low self-esteem leads to social 
introversion. In the evaluation results of our patient group's self-esteem, it was found 
that there was a negative correlation with the age at which the patient was diagnosed, 
the age of the mother and the age of the father. In a study by Iakovou et al. on the self-
esteem of patients with phenylketonuria, it was shown that patients with higher dietary 
adherence had higher self-esteem and that self-esteem could be increased with 
psychiatric support. [21]  In our study, in the correlation analysis of the self-esteem 
scale with the other scales, it was found that the state and trait anxiety inventory and 
the strengths and difficulties questionnaire were negatively correlated with emotional 
problems, behavioral problems, peer problems, hyperactivity and total scores. 
Decreased self-esteem indicated an increase in momentary or general anxiety and life 
difficulties. The effecting factor here may be that the decrease in the self-esteem of the 
patients may lead to a decrease in their ability to cope with difficulties. In a study by 
Brumm et al., it was shown that low self-esteem can be seen in children and 
adolescents who were treated early. [22] In our study, the patient's advanced age at 
diagnosis indicates low self-esteem. As the diagnosis is delayed and the uncontrolled 
follow-up period is prolonged, it can be concluded that the self-esteem of the patients 
will decrease. 
 
The state anxiety inventory, which is used to evaluate the anxiety levels of the 
patients, is the scale that indicates how the patient is feeling at the moment, and the 
trait anxiety inventory is the scale that indicates how he/she is generally feeling, and 
they measure the states of tension, nervousness, fussiness and uneasiness. [16] In 
our study, there was no correlation between the trait anxiety scale and the variables, 
but a positive correlation was found between the state anxiety scale and the age of the 
patient, mother and father. This indicates that although the patient does not have a 
constant sense of anxiety, anxiety increases linearly with age at the time of admission 
to the outpatient clinic. In a study by Bosch et al., the most effective factor effecting the 
quality of life of patients with phenylketonuria was found to be emotional factors which 
were serum phenylalanine levels, guilt about non-compliance with diet, and serum 
phenylalanine levels during pregnancy. [23] Similarly, in the study of Morawska et al., 
it was found that the child's anxiety during blood draw and the feeling of guilt associated 
with diet incompatibility were the factors that effected the quality of life the most. [24] 
In our study, although the patients did not experience constant anxiety, their anxiety 
levels, which increased as age increased at the time of admission to the outpatient 
clinic.This may be due to the same concern about serum phenylalanine levels and guilt 
about non-compliance with the diet. In this study, as a result of the correlation analysis 
between the trait anxiety scale and other scales, the emotional, behavioral, 
hyperactivity and total scores of the strengths and difficulties questionnaire, negative 
correlation was found with social problem scores.. Especially strong correlations were 
found in emotional, hyperactivity and social scores. Anxiety can be expected to cause 
emotional and social problems. In a systematic review study by Smith and Knowles, it 
was shown that patients with phenylketonuria are prone to anxiety compared to healthy 
controls, and the disease is associated with attention deficit and hyperactivity in many 
studies. [25] 
The strengths and difficulties questionnaire is a scale that indicates the 
difficulties experienced by the patient in certain areas. In our study, it was found that 

 
10
as the serum phenylalanine level of the patient at the time of diagnosis increased, 
emotional problems increased. In a study where Jusiene et al. compared children with 
phenylketonuria with healthy controls, showed that patients with phenylketonuria had 
more emotional and behavioral problems. [26] In a study by Palermo et al., it was 
shown that the difficulty of maintaining the diet causes emotional problems. [27] The 
serum phenylalanine level at the time of diagnosis indicates the level of the patient's 
disease, and the higher it is, the more difficult it will be to control the disease and the 
more dietary phenylalanine restriction will be required. As a result, high phenylalanine 
levels at the time of diagnosis can be expected to cause emotional problems. In our 
study, in the dimension of the questionnaire related to social problem, it was found that 
as the age of the father increased, social problems increased. A linear relationship was 
found between the total score of the questionnaire and the serum phenylalanine levels 
in the control. This indicates the relationship between the problems such as emotional, 
behavioral, peer problems, and hyperactivity that patients encounter in life with serum 
phenylalanine levels. Similarly, in the study of Morawska et al., phenylketonuria 
symptoms and social impact have been found to be associated with emotional and 
behavioral difficulties. [24] 
There are various opinions in studies about the effect of sapropterin use on 
quality of life. Considering that it reduces the need for restriction of phenylalanine in 
the diet, it can be thought that the use of sapropterin will increase the quality of 
life.However, in most of the studies conducted in the literature, no significant difference 
was found in terms of quality of life between users and non-users. [28,29] When the 
patients were evaluated in terms of sapropterin use in our study, a significant difference 
was found between the patients who used and did not use in the emotional problems, 
behavioral problems and social problems sub-dimensions of the strengths and 
difficulties questionnaire. Similarly, in the study of Cazzorla et al. [30], a significant 
difference was found in the quality of life of patients with mild phenylketonuria who 
were treated with sapropterin and those with classical phenylketonuria who were 
followed up with diet therapy. However, in this study, it was thought that this difference 
in the mild group might be due to the lesser severity of the disease. 
Evaluation of Parents' Outcomes 
Factors that determine the low quality of life of the parents of phenylketonuria 
patients have been reported to be high stress levels, depression or anxiety in the 
family, lack of social support, loss of friends, and a young age of the patient. [24] 
Parental stress index, Zarit burden scale and strengths and difficulties questionnaire 
were applied to parents in our study. Parental stress index could not be associated 
with other variables in our parent group. On the other hand, a linear relationship was 
found between the Zarit burden scale and the number of siblings. It was observed that 
the burden of caregiving increased as the number of children in the family increased. 
In a study conducted in our country to evaluate the life difficulties of patients with 
phenylketonuria, it was observed that families were reluctant to have children 
again.[31] In a study conducted in our clinic, it was observed that families had 
difficulties in terms of diet between healthy siblings and children with phenylketonuria. 
[32] In a study by Alaei et al., average phenylalanine levels and some factors affecting 
social status were compared. No relationship was found in terms of family size. [33] In 
our study, there were no corelation in the increase in the number of sibling, the median 
serum phenylalanine levels of the patients and the parental stress index. From this, it 

 
11 
can be concluded that the size of the family does not cause any disruption in the follow-
up of the patients, but creates difficulties in the life of the family. 
Due to the nature of the phenylketonuria disease, attention deficit and 
behavioral problems can be seen in patients with a diagnosis of phenylketonuria. [20] 
In the study of Ford et al., it was also shown that children with phenylketonuria 
experience social exclusion and relationship problems. [20] In our study, a linear 
relationship was found between the behavioral problems, attention deficit and 
hyperactivity sub-dimensions of the strengths and difficulties questionnaire and the 
phenylalanine level at the time of diagnosis. Similarly, it was observed that peer 
problems increased with the advanced age at diagnosis. High serum phenylalanine 
levels at the time of diagnosis are associated with clinically severe disease or late 
diagnosis. For this reason, it can be assumed that patients will have behavioral and 
attentional problems in case of more severe disease state or late diagnosis, and also 
peer problems in case of late diagnosis. 
There are studies conducted to evaluate the effect of social status in 
phenylketonuria. Alaei et al. showed the relationship between social status and dietary 
compliance. A linear relationship was found between the education level, marital and 
working status of the parents and the median phenylalanine levels. [33] Cotugno et al. 
[34] found that phenylalanine intake increased as maternal education level decreased, 
in the study performed in our clinic, Özel et al. showed that the knowledge level of the 
mother and the median serum phenylalanine level were inversely proportional.[35] 
Mahmoudi et al. reported in a study that one of the factors most associated with 
caregivers' quality of life was caregiver’s work. [36] In this study, the mother's education 
level, whether the mother has a driver's license and monthly income were used as 
indicators of social status. No significant difference was found regarding any variable 
related to the education level of the mother. However, it was observed that there was 
a significant difference between behavioral problems and social problems of the 
strengths and difficulties questionnaire in terms of the presence or absence of the 
mother's driver's license. In comparisons made in terms of income level, it was seen 
that there was a significant difference between income levels in terms of peer problems 
of the state anxiety scale and the strengths and difficulties questionnaire. 
When the relationship between the scales was examined in our study, it was 
seen that the Zarit burden scale was correlated with all sub-dimensions of the parent 
form of the strengths and difficulties questionnaire and with the parent stress scale. 
There was also a correlation with all parts of the strengths and difficulties 
questionnaire, except for the peer problems part of the patient form. This indicates that 
the increase in the life difficulties of patients and parents increases the burden of 
caregiving. It can be said that the increase in the burden of caregiving also increases 
the parental stress levels. Finding solutions for emotional, behavioral, social problems, 
peer problems and hyperactivity problems that children face in life will reduce the stress 
levels of families. A systematic review by Edelstein et al. also supports this.[37] He 
reported that stress can be reduced through appropriate support in caregivers of 
children with chronic diseases and that the burden of caregiving can be reduced with 
various interventions. Some recent studies have also indicated the hardships of livinhg 
with phenylketonuria. A meta-analysis made in Latin American patients showed that 
the disease brought high burden with it. [38]  A systematic review by Thomas et al.  in 
Phenlketonuria patients’ caregivers concluded that they had poor to moderate health 
related quality of life. [39] 

 
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Phenylketonuria is one of the most difficult diseases to cope with. It is known 
that behavioral problems of patients increase as a result of uncontrolled disease. In 
this study, it was observed that self-esteem decreased especially in the case of late 
diagnosis. As a result, patients encounter emotional and social problems and 
difficulties in relationships with peers. Especially in patients with late diagnosis and 
poor diet control, providing psychological support even if there is no clinical sign of 
psychiatric disease will increase the patient's self-esteem and make it easier to cope 
with difficultiesThis is a situation that will facilitate the control of the disease. In our 
study, we also observed that the anxiety of coming to the outpatient clinic increases as 
the age of the patients increases, that is, the longer the follow-up period. There may 
be multiple reasons for this, questioning this in the outpatient clinic examinations on 
an individual patient basis. It will be useful to offer solutions for the patient's concerns 
about the outpatient clinic application. One of our findings was that as the age of the 
father increased, the patients' self-esteem decreased and their social problems 
increased. The vast majority of patients apply to our clinic accompanied by their 
mothers for a control examination. Including fathers in the follow-up and treatment 
process, questioning their knowledge about the disease,ensuring the patient's 
participation in the follow-up process can make an important contribution. Another 
finding we found was that the burden of caregiving for families increased as the number 
of children increased. As pediatricians, problems related to healthy siblings, as well as 
siblings with phenylketonuria, are also included in the field of pediatrics. It may be 
appropriate to question the attitudes of the family towards their children and to evaluate 
the attitudes and perceptions of healthy siblings about the disease. As with every 
disease, phenylketonuria is a disease that requires a holistic approach. In this disease, 
it would be appropriate to question the home and family environment in order to provide 
good disease control and to increase the quality of life of the patients and their parents. 
More individualized studies on the subject are needed. 
 
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15
Table 1. Demographic characteristics of the patients included in the study 
Feature 
n (%) 
Number of patients 
156 
Gender (Girl/Boy) 
73 (46.8) /83 (53.2) 
Age (years) 
            Mean ± SD 
median (range) 
  
10.9±8.8  
10 (0.6-35) 
Maternal age (years) 
            Mean ± SD 
median (range) 
  
37.8±9 
37 (20-64) 
Father age (years) 
            Mean ± SD 
median (range) 
  
40.9±9.4 
41 (17-68) 
Number of siblings 
             Mean ± SD 
             median (range) 
 
1.23±1.2 
1 (0-7) 
Kinship between parents 
           There is 
no 
 
81 (52.9) 
72 (47.1) 
Mother's education level 
             Illiterate 
             Literate 
             Primary education 
             secondary education 
             High school 
             University 
 
4 (2.6) 
5 (3.3) 
46 (30.1) 
23 (15) 
40 (26.1) 
35 (22.9) 
mother's license 
            There is 
             no 
 
62 (40.5) 
91 (59.5) 
Income level (monthly) 
             less than 3000 TL 
             3000-6000 TL 
             6000-9000 TL 
 more than 6000 TL 
 
59 (38.6) 
58 (37.9) 
28 (18.3) 
8 (5.2) 
 
 
 
 
 
 
 
 
 
 

 
16
Table 2. Disease characteristics of the patients included in the study 
Feature  
n (%) 
Age at diagnosis (months) 
            Mean ± SD 
median (range) 
  
3.2±10  
0.6 (0.07-96) 
Disease type 
            Classical 
            moderate 
Mild 
 
77 (49.4) 
38 (24.4) 
41 (26.3) 
Serum phenylalanine level at diagnosis              
(mg/dl) 
             Mean ± SD 
             median (range) 
 
 
20.61 (±11.82) 
18.16 (4.03-59.48) 
Serum phenylalanine level (mg/dl) in the 
control examination 
             Mean ± SD 
             median (range) 
 
 
7.71 (±5.91) 
6.3 (0.4-27.73) 
Median serum phenylalanine level (mg/dl) 
  Mean ± SD 
  median (range) 
 
7.49 (±5.25) 
5.94 (37.9) 
Diet status 
            There is 
             no 
 
133 (85.3) 
23 (14.7) 
status of adherence to diet 
           There is 
            no 
Not dieting 
 
113 (72.4) 
20 (12.8) 
23 (14.7) 
Sapropterin dihydrochloride intake status 
            There is 
             no 
 
29 (18.6) 
127 (81.4) 
 
 
 
 
 
 
 
 
 
 
 
 

 
17
Table 3. Correlation analysis results of patients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rosenberg 
TAI 
SAI 
SDQ  
emotion 
SDQ  
behavior 
SDQ 
ADHD 
SDQ 
peer 
SDQ 
social 
SDQ 
total 
Age 
 
-.165 
.358* 
0.67 
-.105 
.150 
-.055 
-.004 
-.269 
-.008 
Age at 
diagnosis 
-.266* 
.195 
.231 
.097 
.193 
-.055 
.148 
-.235 
.115 
Phe level 
at 
diagnosis 
-.100 
.214 
.179 
.351* 
.230 
.243 
-.208 
-.018 
.215 
Median 
Phe levels 
-.141 
.154 
.176 
.200 
.074 
.063 
.116 
.125 
.166 
Phe levels 
at control 
-.234 
.191 
.146 
.281 
.233 
.178 
.211 
-.094 
.338* 
Age of 
mother 
-.329* 
.289* 
.068 
.015 
.225 
-.007 
-.007 
-.243 
.034 
Age of 
father 
-.287* 
.376* 
.123 
.115 
.185 
.102 
.192 
-.338* 
.157 
Number of 
siblings 
-.120 
-.015 
.182 
.022 
-.037 
-.152 
.326 
-.038 
.019 
Phe: Phenylalanine ,TAI: Trait Anxiety Inventory, SAI: Stait Anxiety Inventory, SDQ: Strengths and 
Difficulties Questionnaire, ADHD: Attention Deficit and Hyperactivity Disorder 
*p <0.05 

 
18
Table 4. Parents' correlation analysis results 
 
 
 
 
 
 
Parental 
Stress Scale 
Zarit 
Burden 
Scale 
SDQ  
emotion 
SDQ  
behavior 
SDQ 
ADHD 
SDQ 
peer 
SDQ 
social 
SDQ 
total 
Age 
 
.077 
.19 
.217* 
-.005 
-.024 
.035 
.024 
.087 
Age at 
diagnosis 
.101 
.049 
.177 
.182 
.042 
.211* 
-.056 
.187 
Phe level 
at 
diagnosis 
.163 
.142 
.146 
.203* 
.203* 
-.080 
-.101 
.173 
Median 
Phe levels 
.137 
.055 
.192 
.068 
.060 
.008 
.026 
.110 
Phe levels 
at control 
.084 
.004 
.185 
.156 
.059 
.081 
-.094 
-.076 
Age of 
mother 
.048 
-.001 
.038 
-.26 
-.102 
-.090 
.119 
-.063 
Age of 
father 
.094 
.030 
.126 
.059 
.088 
-.135 
.164 
-.034 
Number of 
siblings 
.070 
.195* 
.071 
-.050 
-.132 
-.074 
-.020 
-.022 
SDQ: Strengths and Difficulties Questionnaire 
*p <0.05