Psychosocial adaptation of children and adolescents with phenylketonuria in Korea

Abstract

Phenylketonuria (PKU) is one of the most common inherited metabolic disorders. If recognized and treated early, patients can avoid severe complications and maintain normal intellectual functioning. However, despite early and intensive treatment, several studies have reported an increased prevalence of psychiatric and behavioral symptoms, particularly in adulthood. The aim of this study was to investigate psychiatric manifestations in children and adolescents with PKU. The Korean version of the Child Behavior Checklist (K-CBCL) was used to assess psychopathology in 50 children with PKU and 50 healthy controls. Recent and mean phenylalanine (Phe) levels, as well as demographic information, were collected through retrospective chart review. Patients with PKU showed significantly higher scores in social, school, aggressive behavior, externalizing problems, and total behavior on the K-CBCL than healthy controls. Significant differences were found in total competence (p < 0.001), total behavior (p = 0.004), attention (p = 0.031), and emotional lability (p = 0.031) between clinical and non-clinical ranges. Later age at diagnosis was associated with increased anxiety, depression, thought problems, attention deficits, and emotional lability. Internalizing problems (p = 0.025), thought problems (p = 0.016), and delinquent behavior (p = 0.006) were positively correlated with recent and mean Phe levels. Internalizing problems (p = 0.004), attention (p = 0.008), and social problems (p = 0.016) were associated with variation in blood Phe levels. Children with PKU may experience greater psychosocial challenges than healthy children. Careful monitoring and control of Phe levels may reduce the risk of psychiatric symptoms in this population.

1. Introduction

Phenylketonuria (PKU; OMIM 212600) is an inherited metabolic disorder caused by pathogenic variants encoding phenylalanine hydroxylase (PAH), an enzyme that converts phenylalanine to tyrosine [1,2]. Insufficient PAH activity causes abnormal accumulation of phenylalanine in the body, leading to reduced levels of tyrosine and tryptophan. In the normal metabolic process, tyrosine and tryptophan serve as precursors for the neurotransmitters dopamine and serotonin, respectively. Reduced levels of these amino acids in the blood, brain, and nervous system following reduced PAH activity lead to intellectual disability, convulsions, and the appearance of yellow hair and white skin [3,4]. The first documented case of PKU was reported in 1937 by a Norwegian physician, Asbjørn Følling, in siblings with a developmental disorder and urine smelling like that of a mouse. Subsequently, neonatal screening became feasible in the 1960s with the development of a dried blood spot (DBS) method, which revolutionized PKU diagnosis, allowing the implementation of a phenylalanine-controlled diet in potential patients even before manifestation of the symptoms, preventing severe nervous system complications [[5], [6], [7], [8]]. During the 1960s and 1980s, strict dietary control before the age of 4, a stage prior to the completion of brain development, was thought to prevent neurological abnormalities. However, in the 1900s and subsequent years, various psychosocial abnormalities were reported in patients who received early treatments, highlighting the necessity for continued stringent dietary therapy to control phenylalanine even during adulthood [[9], [10], [11]].

Since 1997, neonatal screening has been conducted on all newborns in South Korea, enabling subsequent early detection and treatment of PKU patients [12,13]. Early detection and treatment have markedly reduced the incidence of intellectual disability in patients with PKU; however, failure to maintain strict dietary therapy results in complications caused by abnormal phenylalanine levels [6,7]. In addition, patients with PKU and their families often face psychosocial challenges in social and school environments. These problems are based on life-long dietary management [8,14]; attention disorders and depressive symptoms, in particular, have been commonly reported in clinical studies compared to cognitive dysfunction [[6], [7], [8], [9],11]. In patients with a rare chronic disease, addressing psychosocial problems is crucial; however, limited studies exist, particularly in children with PKU.

The aim of this study was to investigate the psychosocial characteristics of PKU, detected and treated in South Korea, and compare them with healthy controls. The findings of this study are anticipated to contribute to enhanced systematic management of PKU in the future.

2. Materials and methods

2.1. Participants

2.1.1. Patient group

This study enrolled patients with PKU and their guardians who visited the outpatient clinic of the Pediatrics Department at Soonchunhyang University Hospital, Seoul, between July 2020 and March 2022. Fifty-five patients aged 6–14 years were enrolled in the study. The exclusion criteria were a known co-morbid psychiatric diagnosis (e.g., ADHD, autism spectrum disorder) or current psychiatric treatment. It was also confirmed that no participants were attending a special school. The inclusion criterion was a minimum of eight blood phenylalanine level records over the past two years, which aligns with the standard clinical guideline of quarterly monitoring for this age group. Using a patient questionnaire approved by the Institutional Review Board (IRB) at Soonchunhyang University Hospital Seoul, signed consent for participation was obtained from each patient before completing the questionnaire and after providing adequate explanations on the contents of the study and patient privacy protection to the guardians. The questionnaire applied the Korean Version of the Child Behavior Checklist (K-CBCL), a widely used tool in the screening of psychiatric problems in children [14,15]. Of the 55 questionnaires distributed, five were excluded due to incomplete responses. The final analysis was therefore conducted on the data from the 50 fully completed questionnaires. The mean age of the participants was 9.1 ± 2.8 years. All patients received the following tests at diagnosis: PAH genetic test, BH₄ (tetrahydrobiopterin) load test, and blood phenylalanine test via plasma amino acid analysis, which revealed that the participants consisted of 35 classic PKU patients and 15 BH₄ responsive PKU patients. All 15 patients with BH₄ responsive PKU were receiving active treatment with sapropterin in conjunction with a protein-restricted diet. By examining the medical records retrospectively, the time of diagnosis and blood phenylalanine levels in the past 2 years were determined. All patients had been diagnosed through the national newborn screening (NBS) program, with a mean age at diagnosis of 14 days (range 7–21 days). The most recent measurement of blood phenylalanine level based on the date of the questionnaire was also determined. The study was approved by the Institutional Review Board (IRB) at Soonchunhyang University Hospital Seoul (approval number: 2023–12-006).

2.1.2. Control group

Although it was not feasible to match the patient and control groups based on age and gender, 50 unrelated healthy children aged 6–14 years (31 males and 19 females; mean age at 8.94 ± 3.01 years) with no physical or psychological disorder were recruited as the control group. These included patients who visited the outpatient clinic of the Pediatrics Department at Soon Chun Hyang University Hospital Seoul for vaccination or health examination and randomly selected healthy students at a local primary school. Similar to the patient group, the guardians of the children in the control group completed the IRB-approved questionnaire (K-CBCL) after obtaining a signed consent.

2.2. Experimental procedures

2.2.1. Instruments

The Child Behavior Checklist (CBCL) is a behavior assessment scale developed by Achenback et al. [10] in 1983 and is widely used for the assessment and examination of psychosocial and mental disorders in children and adolescents. The Korean version of CBCL (K-CBCL) was developed as a standardized scale for Korean children and adolescents, and its validity and utility have been verified in previous studies [14,15]. The K-CBCL is subdivided into the social competence scale and the scale of problem behavior syndrome. The social competence scale assesses the overall social competence, by which the levels of social competence, academic achievement, and total competence are measured. The scale of problem behavior syndrome consists of the following items: total behavior problems, internalizing problems, externalizing problems, withdrawn behavior, somatic complaints, social problems, anxious/depressed state, thought problems, attention problems, delinquent behavior, aggressive behavior, and emotional lability. The clinical range for the scores obtained using the K-CBCL was defined as follows: ≤30 T (upper and lower 2 percentiles) for social competence and academic achievement; ≤36 T (upper and lower 5 percentiles) for total competence; ≤63 T (upper and lower 90 percentiles) for total behavior problems, internalizing problems, and externalizing problems; ≤65 T (upper and lower 95 percentiles) for all other items.

2.2.2. Blood phenylalanine levels

Dietary treatment for all patients was aimed at maintaining target blood phenylalanine levels between 2 and 6 mg/dL, regardless of age. This was achieved through a prescribed diet consisting of a phenylalanine-free formula and low-protein foods, such as low protein pre-cooked rice. We calculated the mean blood phenylalanine levels in patients with PKU aged 6–14 years over the past 2 years. We also analyzed the most recent phenylalanine level, for which blood samples were collected as close to the K-CBCL completion date as possible, typically within a one-to-two-week timeframe. To compare the individuals with large variations in phenylalanine levels and those with minor variations, the participants were divided into three groups: Group 1 with individuals whose blood phenylalanine levels in the past 2 years consistently remained within normal range; Group 2 with individuals whose phenylalanine levels fell outside the normal range at ≤25 % frequency; Group 3 with individuals whose phenylalanine levels fell outside the normal range at >25 % frequency. Blood samples were collected using either plasma amino acid analysis or blood spot analysis, with the criteria set between 2 and 6 mg/dL [2,5]. Our standard method is plasma amino acid analysis; however, due to access restrictions during the COVID-19 pandemic, dried blood spot (DBS) samples were used for remote monitoring in some cases. Approximately 70 % of samples were from plasma and 30 % from DBS.

2.2.3. Statistical analysis

An a priori power calculation was performed to determine the required sample size. Base on an anticipated medium effect size (Cohen's d = 0.5), an alpha of 0.05, and a power of 80 %, a sample size 50–55 patients was adequate, especially considering the rarity of the disease in Korea. SPSS version 20.0 (SPSS Inc. Chicago, IL, USA) was used for statistical analysis. The measured values were expressed as mean ± standard deviation in the case of normal distribution. Through descriptive statistics, the differences between the patient and control groups regarding demographic variables were compared. The mean values of the subscales of K-CBCL between the two groups were compared using the Student's t-test and Fisher's exact test. The chi-square test was used to comparatively analyze each item regarding the percentage of clinical patients. To analyze the psychopathologic predictors in PKU patients, linear regression analysis was performed with Bonferroni correction.

3. Results

3.1. Differences in demographic variables between the patient and control groups

The distribution of demographic variables for the patient and control groups is presented in Table 1. The two groups did not vary significantly in demographic variables, including age, gender, parents' economic status, and educational years (Table 1).

Table 1.

Demographics and baseline characteristics of the study subjects.

	PKU group (n = 50)	Control group (n = 50)	p value
Sex (n, %)
Male	30 (60.0)	31 (62.0)	0.838
Female	20 (40.0)	19 (38.0)
Mean age (SD) (year)	9.1 (2.83)	8.9 (3.01)	0.785
Economic status (n, %)			0.911
Upper class	3 (6.0)	2 (4.0)
Upper middle class	9 (19.0)	6 (12.0)
Middle class	27 (54.0)	31 (62.0)
Lower middle class	8 (16.0)	8 (16.0)
Lower class	3 (6.0)	3 (6.0)
Paternal educational year (n, %)			0.133
>13	38 (76.0)	30 (60.0)
9–12	12 (24.4)	19 (38.0)
<8	0 (0.0)	1 (2.0)
Maternal educational year (n, %)			0.579
>13	27 (54.0)	27 (54.0)
9–12	23 (46.0)	23 (46.0)
<8	0 (0.0)	0 (0.0)

p value <0.05 by Fisher's exact test.

3.2. Differences in psychosocial characteristics between the patient and control groups

Comparing the mean values of the subscales of K-CBCL between the patient and control groups showed that social competence (p = 0.009), academic achievement (p = 0.004), and total competence (p < 0.001) had significantly higher mean values in patients with PKU than in healthy controls. In contrast, externalizing problems (p = 0.030), social problems (p = 0.006), attention problems (p < 0.001), aggressive behavior (p = 0.006), and emotional lability (p = 0.002) had significantly lower mean values in patients with PKU than in healthy controls. No significant difference was observed between the group for total behavior problems (p = 0.085), internalizing problems (p = 0.514), anxious/depressed state (p = 0.223), withdrawn behavior (p = 0.656), somatic complaints (p = 0.287), thought problems (p = 0.068), and delinquent behavior (p = 0.627) (Table 2).

Table 2.

Mean T-score of K-CBCL between PKU and healthy control groups.

	PKU group (n = 50) Mean (SD)	Control group (n = 50) Mean (SD)	p value
Social competence scale
Social	56.44 (8.58)	51.00 (11.61)	0.009
School	53.54 (9.29)	47.96 (9.77)	0.004
Total competence scale	57.42 (9.69)	50.64 (10.96)	<0.001
Behavior problems scale
Total behavior problem	46.94 (11.05)	50.84 (11.35)	0.085
Internalizing problem	48.08 (11.32)	49.50 (10.34)	0.514
Externalizing problem	47.00 (10.15)	51.48 (10.24)	0.030
Anxious/depressed	53.28 (5.91)	54.64 (5.14)	0.223
Withdrawn	53.92 (6.26)	54.44 (5.33)	0.656
Somatic complaints	52.88 (5.86)	54.16 (6.09)	0.287
Social problem	52.84 (5.89)	56.40 (6.63)	0.006
Thought problem	52.70 (5.17)	54.80 (6.17)	0.068
Attention	52.08 (4.09)	56.36 (6.76)	<0.001
Delinquent behavior	53.46 (6.23)	54.04 (5.66)	0.627
Aggressive behavior	51.76 (4.53)	54.78 (6.05)	0.006
Emotional lability	56.50 (7.72)	51.98 (6.41)	0.002

p value <0.05 by Fisher's exact test.

When cases of clinically significant levels and cases of clinically insignificant levels were distinguished, the comparative analysis showed significant differences between the patient and control groups for total competence (p < 0.001), total behavior problems (p = 0.004), attention problems (p = 0.031), and emotional lability (p = 0.031). However, no significant difference was observed between the group in the percentage of clinically significant individuals for social competence (p = 0.310), academic achievement (p = 1.000), internalizing problems (p = 0.356), externalizing problems (p = 0.074), anxiety/depression (p = 1.000), withdrawn behavior (p = 0.678), somatic complaints (p = 0.436), thought problems (p = 0.678), delinquent behavior (p = 1.000), and aggressive behavior (p = 0.160) (Table 3).

Table 3.

Distribution of subjects in clinical spectrum and non-clinical spectrum.

	PKU group		Control group		p value
	NC, n (%)	C, n (%)	NC, n (%)	C, n (%)
Social competence scale
Social	49 (98.0)	1 (2.0)	42 (84.0)	8 (16.0)	0.310
School	48 (96.0)	2 (4.0)	47 (94.0)	3 (6.0)	1.000
Total competence scale	47 (94.0)	3 (6.0)	41 (82.0)	9(18.0)	<0.001
Behavior problems scale
Total behavior problem	47 (94.0)	3 (6.0)	35 (70.0)	15(30.0)	0.004
Internalizing problem	46 (92.0)	4 (8.0)	42 (84.0)	8 (16.0)	0.356
Externalizing problem	47 (94.0)	3 (6.0)	40 (80.0)	10 (20.0)	0.074
Anxious/depressed	48 (96.0)	2 (4.0)	47 (94.0)	3 (6.0)	1.000
Withdrawn	46 (92.0)	4 (8.0)	48 (96.0)	2 (4.0)	0.678
Somatic complaints	48 (96.0)	2 (4.0)	45 (90.0)	5 (10.0)	0.436
Social problem	45 (90.0)	5 (10.0)	41 (82.0)	9 (18.0)	0.387
Thought problem	48 (96.0)	2 (4.0)	46 (92.0)	4 (8.0)	0.678
Attention	48 (96.0)	2 (4.0)	40 (80.0)	10 (20.0)	0.031
Delinquent behavior	46 (92.0)	4 (8.0)	46 (91.0)	4 (8.0)	1.000
Aggressive behavior	48 (96.0)	2 (4.0)	43 (86.0)	7 (14.0)	0.160
Emotional lability	40 (80.0)	10(20.0)	48 (96.0)	2 (4.0)	0.031

NC, subjects in non-clinical spectrum; C, subjects in clinical spectrum.

p value <0.05 by Chi-square test.

3.3. Predictors of psychosocial characteristics in patients with PKU

To identify the predictors of psychosocial problems in Korean patients with PKU, the diversity in demographic variables, time of diagnosis, the PKU type (typical or BH₄ responsive), and recent blood phenylalanine levels and their mean were examined using a linear regression analysis for each item of K-CBCL (Table 4, Table 5). The results showed no correlation for age, gender, parents' economic status, and educational years. However, with increasing age at the time of diagnosis, the scores of total behavior problems (p = 0.01), anxious/depressed state (p = 0.02), thought problems (p = 0.02), attention problems (p = 0.01), and emotional lability (p = 0.04) in the K-CBCL were significantly higher.

Table 4.

Regression analysis between demographic variables and the K-CBCL findings.

		Social	School	Total Compet	Total behavior	Int. prob	Ext. prob	Anxious depress	With drawn	Somatic complain	thought plobl	Atten prob	Delinq prob	Agg prob	Emot lability
Age	β	0.27	0.31	0.57	−0.55	−0.68	−0.22	−0.77	0.51	−0.38	−0.44	0.87	0.11	1.11	1.32
	p	0.75	0.36	0.41	0.11	0.45	0.11	0.35	0.17	0.99	0.38	0.84	0.38	0.54	0.71
Sex	β	0.87	1.34	1.54	0.17	0.09	2.13	−0.98	0.26	0.77	−0.87	−0.11	1.23	0.47	1.46
	p	0.91	0.77	0.33	0.21	0.29	0.38	0.88	0.37	0.26	0.08	0.55	0.43	0.18	0.92
Economic status	β	0.23	0.27	0.09	−0.14	0.24	−0.92	0.03	0.01	0.07	−0.01	0.35	−0.24	−0.62	0.11
	p	0.20	0.65	0.58	0.09	0.88	0.07	0.18	0.87	0.20	0.38	0.45	0.22	0.14	0.21
Paternal education	β	0.08	−0.05	−0.03	−0.18	−0.04	−0.27	−0.12	−0.17	0.08	0.07	0.03	0.12	0.22	0.33
	p	0.79	0.17	0.67	0.74	0.77	0.08	0.19	0.17	0.09	0.89	0.16	0.82	0.18	0.24
Maternal education	β	0.62	2.10	0.04	0.22	0.83	0.24	5.20	3.10	−0.13	0.11	0.454	0.11	−0.13	−0.30
	p	0.27	0.77	0.08	0.39	0.81	−0.73	0.32	0.07	0.26	0.39	0.55	0.72	0.19	0.91
Age of diagnosis	β	0.22	0.33	0.40	0.58	0.24	0.55	0.36	0.75	0.56	0.56	0.60	0.55	−0.12	0.57
	p	0.11	0.09	0.06	0.01⁎	0.74	0.17	0.02⁎	0.33	0.09	0.02⁎	0.01⁎	0.66	0.11	0.04⁎
Type of PKU	β	−0.08	−0.11	0.13	−0.28	0.22	−0.38	0.02	0.31	−0.18	−0.21	−0.11	0.33	0.43	−0.11
	p	0.89	0.77	0.23	0.24	0.41	0.33	0.11	0.27	0.31	0.87	0.11	0.22	0.98	0.44

^⁎Significant correlations between demographics, clinical findings and K-CBCL results are shown as bold, p value <0.05.

Table 5.

CBCL findings and their association with phenylalanine measures and age.

		Mean scores	Model and fit parametersa
		(SD)	Recent phenylalanine level			Mean phenylalanine level
			β (phe)	β CI	p-value	β (phe)	β CI	p-value
Social competence scale
Social		51.00 (11.62)	−0.68	−1.824/0.463	0.237	−0.541	−1.785/0.709	0.385
School		47.96 (9.77)	−0.48	−1.425/0.448	0.300	−0.310	−1.329/0.702	0.543
Total competence scale		50.64 (10.96)	−0.946	−2.016/0.123	0.082	−0.435	−1.622/0.751	0.464
Behavior problems scale
Total behavior problem		50.84 (11.35)	1.467	0.437/2.497	0.006	1.098	−0.064/2.261	0.063
Internalizing problem		49.50 (10.34)	1.020	0.048/1.992	0.040	1.199	0.159/2.239	0.025
Externalizing problem		51.48 (10.24)	1.311	0.429/2.193	0.004	0.602	−0.424/1.627	0.244
Withdrawn		54.44 (5.33)	0.200	−0.305/0.705	0.429	0.423	−0.111/0.958	0.118
Somatic complaints		54.16 (6.09)	0.412	−0.193/1.017	0.177	0.845	0.228/1.462	0.008
Social problem		56.40 (6.63)	0.796	0.245/1.348	0.006	0.758	0.150/1.365	0.016
Thought problem		54.80 (6.17)	0.715	0.137/1.292	0.016	0.394	−0.260/1.048	0.232
Attention		56.36 (6.76)	0.996	0.413/1.579	0.001	0.750	0.080/1.420	0.029
Delinquent behavior		55.24 (6.78)	0.889	0.262/1.516	0.006	0.301	−0.267/0.869	0.292
Aggressive behavior		54.78 (6.05)	0.935	0.403/1.468	0.001	0.284	−0.325/0.894	0.352
Emotional lability		54.14 (5.71)	0.419	−0.117/0.955	0.123	0.367	−0.217/0.950	0.213

Β = parameter estimates; β CI = 95 % confidence interval for parameter estimates.

a = multiple linear regression with the independent variable phe, controlling for age.

p value <0.05 adjusted by onset-age and type of disease.

With increasing blood phenylalanine levels in patients with PKU, the scores of internalizing problems (p = 0.025), somatic complaints (p = 0.008), social problems (p = 0.016), and attention problems (p = 0.029) were significantly higher. For these items, correlations for recent blood phenylalanine levels were examined in a multiple linear regression analysis after adjustments for age and PKU type. The results showed strong correlations with blood phenylalanine levels, while significantly high scores were also found for total behavior problems (p = 0.006), externalizing problems (p = 0.004), thought problems (p = 0.016), delinquent behavior (p = 0.006), and aggressive behavior (p = 0.001) (Table 5).

We also analyzed the correlation between the variability of blood phenylalanine levels and psychiatric problems in patients with PKU. The results demonstrated significantly higher scores of internalizing problems (p = 0.004), social problems (p = 0.008), and attention problems (p = 0.008) in Group 3 with a high level of variability (Table 6).

Table 6.

CBCL findings and their association with stability of phenylalanine measures and age.

		Group 1		Group 2		Group 3		p-value
		NC, n (%)	C, n (%)	NC, n (%)	C, n (%)	NC, n (%)	C, n (%)
Social competence scale
Social		16 (89)	2 (11)	22 (88)	3 (12)	4 (57)	3 (43)	0.130
School		17 (94)	1 (6)	24 (96)	1 (4)	6 (86)	1 (14)	0.529
Total competence scale		15 (83)	3 (17)	22 (88)	3 (12)	4 (57)	3 (43)	0.177
Behavior problems scale
Total behavior problem		13 (72)	5 (28)	20 (73)	3 (27)	4 (57)	3 (43)	0.143
Internalizing problem		15 (83)	3 (17)	23 (91)	1 (9)	2 (29)	5 (71)	0.004
Externalizing problem		15 (83)	3 (17)	23 (91)	1 (9)	4 (57)	3 (43)	0.149
Withdrawn		18 (100)	0 (0)	24 (100)	0 (0)	6 (86)	1 (14)	0.308
Somatic complaints		16 (89)	2 (11)	24 (100)	0 (0)	5 (71)	2 (29)	0.146
Social problem		16 (89)	2 (11)	23 (100)	0 (0)	2 (29)	5 (71)	0.008
Thought problem		15 (83)	3 (17)	22 (100)	0 ()	4 (57)	3 (43)	0.069
Attention		16 (89)	2 (11)	23 (100)	0 (0)	2 (29)	5 (71)	0.008
Delinquent behavior		17 (94)	1 (6)	24 (100)	0 (0)	6 (86)	1 (14)	0.469
Aggressive behavior		15 (83)	3 (17)	22 (88)	3 (12)	4 (57)	3 (43)	0.177
Emotional lability		18 (100)	0 (0)	22(91)	1(9)	5 (71)	2 (29)	0.633

Group 1, all phe levels were in the normal range; Group 2, ≤25 % out of normal range of phe levels; Group 3, >25 % out of normal range of phe levels.

NC, subjects in non-clinical spectrum; C, subjects in clinical spectrum.

p value <0.05 adjusted by onset-age and type of disease.

To quantify the differences in metabolic control, the median of the mean blood phenylalanine levels for each group was analyzed. The results showed a clear stepwise increase in phenylalanine levels across the group: Group 1 (median 3.5 mg/dL, IQR 2.75), Group 2 (median 4.9 mg/dL, IQR 4.3), Group 3 (median 7.1 mg/dL, IQR 5.7).

4. Discussion

Recent studies on adult patients with PKU having psychosocial issues revealed psychological, neurological, and behavioral problems in those diagnosed early, with a higher incidence of anxiety, depression, and separation anxiety disorders [16,17]. In addition, the cognitive functions, specifically, executive function and processing speed, showed a notable reduction and were strongly correlated with blood phenylalanine levels [18,19]. However, there is a notable scarcity of research conducted on children and adolescents, with almost no studies focusing on this age group.

Despite the fact that South Korea has been screening newborns for PKU since 1985 and offering free PKU screening for all newborns since 1997 [13,14], facilitating early diagnosis and treatment intervention for approximately 200 patients with PKU, there has been no research on the psychosocial issues experienced by these patients, which serves as the motivation for the current study.

Before CBCL data analysis, the patient and control groups were shown not to vary in demographic variables, including age, gender, parents' economic status, and total educational years, ensuring that there are a few factors with maximum effects on psychosocial variables.

This study demonstrated that the scores of social competence, academic achievement, and total competence were significantly lower in patients with PKU than in healthy controls when comparing social competence indicators (Table 2). Specifically, the total competence score was notably low to identify the respective individuals as the clinical group (Table 3). Our results were consistent with previous reports [20,21], where despite the lack of severe intellectual reduction, relatively low intelligence level and cognitive dysfunction were noted as potential causes.

Analysis of the indicators of behavior problems revealed that the patients with PKU scored lower than healthy controls in externalizing problems, social problems, attention problems, aggressive behavior, and emotional lability. Specifically, the scores of total behavior problems, attention problems, and emotional lability were significantly reduced, identifying the respective individuals as part of the clinical group (Table 3). These observations were similar to the previous international studies that reported high incidences of attention disorders, social incompetence, mood disorders, and anxiety among patients with PKU [17,18]. Interestingly, our study did not find a significant difference in anxiety/depression scores, in contrast to some previous reports. We attribute this encouraging finding to Korea's successful universal newborn screening program. As all patients in our cohort received an early diagnosis and continuous treatment, the development of internalizing symptoms like anxiety may have been effectively mitigated. Notably, attention disorders have been reported to show 5–15 % incidence even in healthy children and adolescents. In patients with PKU, the accumulation of blood phenylalanine in the brain affects the metabolic process, reducing the secretion of neurotransmitters dopamine and serotonin [9,10,14]. Moreover, the higher functions of conceptualization or mathematical ability were reported to decrease simultaneously due to general influence on the prefrontal lobe [15,20]. Similarly, we observed that the level of attention decreased in patients with PKU compared to healthy controls. Notably, cognitive dysfunction and psychosocial abnormalities reported in PKU patients with convulsions in previous studies occurred as a result of repeated convulsions and not only as an outcome of disease characteristics; however, no patient with convulsions was included in this study [20,21].

Compared to healthy controls, patients with PKU exhibited higher levels of psychosocial and psychological problems, prompting an analysis of predictors and influencing factors of these problems (Table 4). While previous studies primarily focused on adults, the scores of anxious/depressed states, attention problems, and emotional lability increased when the diagnosis was delayed [21], aligning with the results of this study. Notably, factors such as gender, parents' economic status, and educational background did not show a significant impact.

Current PKU treatment aims to maintain normal blood phenylalanine levels through a phenylalanine-controlled diet, with KUVAN being administered in some BH₄ responsive cases. However, implementing strict dietary therapy becomes challenging in school-age and adolescent patients, who are exposed to various foods outside their homes. This study analyzed the mean blood phenylalanine levels in patients with PKU over the past 2 years and the recent levels during the study to examine their correlations with the subscales of K-CBCL. At higher phenylalanine levels, the scores of internalizing problems (p = 0.025), somatic complaints (p = 0.008), social problems (p = 0.016), and attention problems (p = 0.029) were significantly higher. In the multiple linear regression analysis after adjustments for age and PKU type, the scores of problem behavior (p = 0.006), thought problems (p = 0.016), delinquent behavior (p = 0.006), and aggressive behavior (p = 0.001) were also observed to be significantly correlated with blood phenylalanine levels at higher levels. In a recent international study, although the target participants were adults, the scores of internalizing problems and somatic complaints were significantly high. Despite the lack of statistical significance, the scores of attention problems and anxiety tended to increase as the most recent blood phenylalanine levels increased [[19], [20], [21], [22]]. The deviation in this study is thought to be due to the target participants being children and adolescents and the results being obtained through the questionnaire completed by the participants' guardians.

Furthermore, we also compared the individuals whose blood phenylalanine levels have never fallen outside the normal range in the past 2 years and whose levels have often fallen outside the normal range. The results revealed that, in Group 3 with >25 % frequency, the scores of internalizing problems (p = 0.004), social problems (p = 0.008), and attention problems (p = 0.008) were significantly high (Table 6). An international study has demonstrated the effect of high variability in blood phenylalanine levels on IQ [23], but no study has yet reported any association with psychosocial aspects. The results of this study revealed that stronger correlations with psychosocial problems were exhibited by individuals with a higher level of variability in blood phenylalanine levels (i.e., those that fell outside the normal range more frequently). These findings are expected to contribute to the development of guidelines for the treatment and follow-up monitoring of PKU patients.

Previous studies conducted on children with PKU have reported an association with attention problems most frequently [19,20]. We identified a similar significant correlation between attention problems and blood phenylalanine levels.

It is indisputable that early diagnosis and dietary intervention with phenylalanine-controlled diet at a neonatal age prevents severe neurological abnormalities associated with PKU [7,8]. However, as this study has shown, failure to maintain normal blood phenylalanine levels continuously will lead to potential internalizing problems, somatic complaints, and social problems, particularly attention problems.

This study had a few limitations. The possibility of accompanied psychosocial problems caused by cognitive dysfunction cannot be ruled out due to the lack of IQ tests on each patient. There is also a possibility of substantially reduced learning ability, although a subscale of K-CBCL reflected learning to confirm the absence of patients with markedly low scores. Moreover, we did not compare the dysmyelination in the prefrontal lobe and cerebral ventricles, in addition to blood phenylalanine levels, as reported in previous studies [21,23]. Third, a mix of plasma and DBS samples was used to measure blood phenylalanine levels due to circumstances of the COVID-19 pandemic. Given that phenylalanine level from DBS can be up to 20 % lower than from plasma, this methodological variability could have affected the classification of patients into the different metabolic control groups.

We implemented K-CBCL for the first time in South Korea to investigate psychosocial abnormalities in patients with PKU, a rare inherited metabolic disorder, and revealed that, even with early diagnosis and dietary intervention, a subsequent inadequate control of blood phenylalanine levels could induce internalizing problems, somatic complaints, and social problems, specifically attention disorders. The findings of this study could serve as a foundation for recommending strict dietary therapy to patients with PKU.

Future research involving IQ tests, brain MRI scans, and long-term follow-up studies comparing the outcomes of children with PKU as they transition into adulthood will provide more comprehensive data on psychosocial challenges in PKU patients. The combination of novel treatment methods [24], including phenylalanine ammonia lyase (PAL) to lower blood phenylalanine levels (although not yet approved for use in Korea, it is being used clinically in the US and Europe), that are currently undergoing clinical trials and dietary therapy has the potential to improve the treatment outcomes in PKU, preventing and controlling psychosocial problems.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of generative AI in scientific writing

We have nothing to declare.

CRediT authorship contribution statement

Jeongho Lee: Writing – review & editing, Writing – original draft, Supervision, Methodology, Investigation, Data curation, Conceptualization. Eun Sook Suh: Writing – review & editing, Supervision, Conceptualization.

Declaration of competing interest

None.

Data availability

Data will be made available on request.