Psychiatric symptoms and disorders in phenylketonuria

doi:10.1016/j.ymgme.2009.10.182

Molecular Genetics and Metabolism

Volume 99, Supplement, 2010, Pages S59-S63

https://doi.org/10.1016/j.ymgme.2009.10.182 Get rights and content

Abstract

Psychological and psychiatric problems are well documented across the lifespan of individuals with early-treated phenylketonuria (PKU). Early-treated children and adolescents tend to display attentional problems, school problems, lower achievement motivation, decreased social competence, decreased autonomy, and low-self-esteem. As they enter adulthood, early-treated individuals may carry forward low self-esteem and lack of autonomy but also tend to develop depressed mood, generalized anxiety, phobias, decreased positive emotions, social maturity deficits, and social isolation. The correlation between level of metabolic control and severity of symptoms suggests a biological basis of psychiatric dysfunction. Additionally, psychosocial factors such as the burden of living with a chronic illness may contribute to psychological and psychiatric outcomes in PKU. The lack of a PKU-specific psychiatric phenotype combined with the observation that not everyone with PKU is affected highlights the complexity of the problem. More research on psychiatric and psychological outcomes in PKU is required. Of particular importance is the routine monitoring of emotional, behavioral, and psychosocial symptoms in individuals with this metabolic disorder. Longitudinal studies are required to evaluate the impact of new and emerging therapies on psychiatric and psychosocial functioning in PKU. Unidentified or untreated emotional and behavioral symptoms may have a significant, lifelong impact on the quality of life and social status of patients.

Section snippets

Background

Phenylketonuria (PKU; OMIM 261600 and 261630),¹ an inherited disorder of amino acid metabolism, provides insights into the biochemical and psychosocial etiology of psychiatric disorders. In PKU, mutations in the phenylalanine hydroxylase (PAH; EC 1.14.16.1) gene prevent the breakdown of

Psychiatric and psychological functioning in untreated PKU

The psychiatric and psychological functioning of individuals with untreated PKU has been studied since the disease was initially described by Følling in 1934. Følling characterized patients as anxious, shy, angry, prone to temper tantrums, irritated, unsociable, and catatonic [22]. Patients with untreated PKU were known to demonstrate severe behavioral disturbances including psychotic, autistic, and aggressive disorders [23]. These individuals are among the most difficult patients to manage in

Psychiatric and psychological functioning in children with early-treated PKU

With the introduction of newborn screening in 1963 and widespread initiation of dietary treatment, the severe psychiatric disturbances associated with untreated PKU were eliminated. Pediatric studies enhanced understanding of the impact of diet discontinuation on the developing brain and psychiatric functioning. Not surprisingly, the effects of dietary discontinuation became evident not only in cognitive functioning, but also in emotional and behavioral adjustment.

Among early-treated children

Psychiatric and psychological functioning in adults with early-treated PKU

Concerns regarding emotional well-being in early-treated adults with PKU who had discontinued treatment in middle childhood first appeared in professional journals in the 1990s. Ris et al. [37], [38] studied 25 early-treated adult patients. Although patients with PKU were indistinguishable from sibling controls on most psychosocial outcome measures, 20% reported significant psychiatric symptoms on the SCL-90-R [37], [40], a widely used self-report symptom checklist. Obsessive–compulsive

Limitations and future directions

Investigations examining psychiatric and psychological functioning in individuals with PKU often included heterogeneous samples, owing to the variation in the Phe levels of participants and their treatment histories (i.e., age at which dietary treatment was implemented, duration of treatment, and quality of Phe control). Studies on adults with PKU have generally been based on small samples of compliant patients, which limit statistical power to detect subtle effects and raise the concern of

Conclusions

Children and adults with PKU experience psychiatric symptoms and display disturbed emotional and behavioral functioning. As noted in Table 1, the list of symptoms covers a broad range. A review of the literature demonstrates, however, that the prevalence and severity of problems generally correlates with the timing and degree of exposure to elevated blood Phe levels. Children with poor metabolic control during the early, critical years are most likely to be affected and to exhibit more serious

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Cited by (108)

Pegvaliase therapy for phenylketonuria: Real-world case series and clinical insights
2024, Molecular Genetics and Metabolism
The aim of this study is to present a series of case studies on the real-life use of pegvaliase in Italy in managing patients affected by phenylketonuria (PKU) and provide practical insight and support to healthcare professionals currently approaching and facing this novel enzyme substitution therapy.
A panel of 11 PKU experts from seven leading Italian treatment centers attended online virtual meetings with the aim of reviewing their clinical and practical experiences with pegvaliase based on occurred cases. In selecting the cases, specific consideration was given to the nationwide representation of the centers involved and to the number of patients with PKU managed. Cases were thoroughly reviewed, with comprehensive discussions enabling the identification of key take-home messages regarding pegvaliase therapy.
The panel discussed 18 cases, 11 males and 7 females (age range 17–43 years). At the last follow-up (up to 111 weeks after pegvaliase initiation), 11 out of 18 patients (61%) reached Phe levels below 600 μmol/l. Outcomes varied significantly across cases. All cases underscore the potential of pegvaliase in reducing Phe levels, enhancing the quality of life, and promoting social skills and independence. Additionally, the cases highlight the challenges associated with pegvaliase therapy, including managing adverse events and ensuring patient motivation and adherence.
This is the first report about the Italian experience of managing patients affected by PKU with pegvaliase. Given the limited real-world data on the use of pegvaliase in PKU management, this case series offers valuable insights into the practical implementation and management of pegvaliase therapy in this Country. Continued research and data collection will be crucial to confirm and progress with this treatment. Despite potential challenges, pegvaliase therapy represents a substantial promise in managing PKU in Italy. Patient education, personalized treatment approaches, and careful monitoring are important to ensure optimal patient outcomes.
Possible role of tryptophan metabolism along the microbiota-gut-brain axis on cognitive & behavioral aspects in Phenylketonuria
2023, Pharmacological Research
Cognitive and psychiatric disorders are well documented across the lifetime of patients with inborn errors of metabolism (IEMs). Gut microbiota impacts behavior and cognitive functions through the gut-brain axis (GBA). According to recent research, a broad spectrum of GBA disorders may be influenced by a perturbed Tryptophan (Trp) metabolism and are associated with alterations in composition or function of the gut microbiota. Furthermore, early-life diets may influence children's neurodevelopment and cognitive deficits in adulthood. In Phenylketonuria (PKU), since the main therapeutic intervention is based on a life-long restrictive diet, important alterations of gut microbiota have been observed. Studies on PKU highlight the impact of alterations of gut microbiota on the central nervous system (CNS), also investigating the involvement of metabolic pathways, such as Trp and kynurenine (KYN) metabolisms, involved in numerous neurodegenerative disorders. An alteration of Trp metabolism with an imbalance of the KYN pathway towards the production of neurotoxic metabolites implicated in numerous neurodegenerative and inflammatory diseases has been observed in PKU patients supplemented with Phe-free amino acid medical foods (AA-MF). The present review investigates the possible link between gut microbiota and the brain in IEMs, focusing on Trp metabolism in PKU. Considering the evidence collected, cognitive and behavioral well-being should always be monitored in routine IEMs clinical management. Further studies are required to evaluate the possible impact of Trp metabolism, through gut microbiota, on cognitive and behavioral functions in IEMs, to identify innovative dietetic strategies and improve quality of life and mental health of these patients.
Pegvaliase dose escalation to 80 mg daily may lead to efficacy in patients who do not exhibit an optimal response at lower doses
2022, Molecular Genetics and Metabolism Reports
In 2018, pegvaliase was approved as the first enzyme substitution treatment for phenylketonuria (PKU) and is now the second medication available for PKU patients since the approval of sapropterin dihydrochloride in 2007. Historically, dietary management has been the mainstay of treatment for PKU. While sapropterin response rate is limited to approximately 50% of PKU patients, pegvaliase has the potential to reduce phenylalanine levels in all PKU patients (Vockley et al., 2014; Longo et al., 2019 [1,3]). Current FDA labeling for pegvaliase includes a dose maximum of 60 mg daily (Longo et al., 2019; BioMarin Pharmaceutical Inc., 2020 [3,4]). We report a case series of four phenylalanine hydroxylase (PAH) deficient patients, previously treated with dietary management only, who initiated treatment with pegvaliase and were titrated to 80 mg daily dosing. The safety profile in these four cases did not differ from lower maintenance dosing (Longo et al., 2019 [3]). Subsequent decreases in Phe levels were observed on 80 mg maintenance dosing, allowing for individualized dietary liberalization in three out of four patients. We conclude that pegvaliase dosing must be personalized to achieve therapeutic goals and that some patients may require higher doses than those included on the product label.
Use of pegvaliase in the management of phenylketonuria: Case series of early experience in US clinics
2021, Molecular Genetics and Metabolism Reports
To present a case series that illustrates real-world use of pegvaliase based on the initial experiences of US healthcare providers.
Sixteen healthcare providers from 14 centers across the US with substantial clinical experience in treating patients with phenylketonuria (PKU) with pegvaliase in the two-plus years since FDA approval (May 2018) provided cases that exemplified important lessons from their initial experiences treating patients with pegvaliase. Key lessons from each case and takeaway points were discussed in both live and virtual meetings.
Fifteen cases of adults with PKU (eight males, seven females), representing a spectrum of age (18 to 53 years), previous PKU care, comorbidities, and socioeconomic situations were reviewed and discussed. Full extended case reports are included in the Supplement. The cases showed that treating patients with a daily injectable can be challenging due to a patient's financial problems, treatment challenges, and neuropsychological and psychiatric comorbidities, which can be identified before starting pegvaliase, but do not prohibit successful treatment. The authors agreed that patient education on adverse events (AEs), time to efficacy, dietary changes, and food preparation is an ongoing process that should start prior to initiating pegvaliase treatment. Treatment goals and planned dietary changes once efficacy is reached should be defined prior to treatment initiation and re-evaluated throughout the course of therapy. Each patient's titration schedule and dietary adjustments are unique, depending on occurrence of AEs and individual goals of treatment. Despite the AE profile of pegvaliase, all but two patients remained motivated to continue treatment and achieved efficacy (except one patient in whom titration was still ongoing). AEs occurring early in the treatment pathway may require prolongation of the titration phase and/or concomitant medication use, but do not seem indicative of future tolerability or eventual efficacy. Close follow-up of patients during titration and maintenance to help with dietary changes is important.
This case series provides real-world experience on the use of pegvaliase. Until data from registries and independent research become available, the data presented herein can support appropriate management of patients receiving pegvaliase in clinical practice.
Executive functioning, adaptive skills, emotional and behavioral profile: A comparison between autism spectrum disorder and phenylketonuria
2020, Molecular Genetics and Metabolism Reports
Influential theories maintain that some of Autism Spectrum Disorder (ASD) core symptoms may arise from deficits in executive functions (EF). EF deficits are also considered a neuropsychological marker of early treated individuals with phenylketonuria (PKU). Aims of this study were: to verify the occurrence and patterns of specific EF impairments in both clinical groups; to explore the coexistence of EF alterations with adaptive, behavioral and emotional problems in each clinical condition.
We assessed EF, adaptive, behavioral and emotional profile in 21 participants with ASD, 15 early treated PKU individuals, comparable for age and IQ, and 14 controls, comparable for age to the clinical groups (age range: 7–14 years).
ASD and PKU participants presented two different, but partially overlapping patterns of EF impairment. While ASD participants showed a specific deficit in cognitive flexibility only, PKU individuals showed a more extensive impairment in EF with a weaker performance in two core EF domains (inhibition, cognitive flexibility) as compared to healthy controls. Psychological and adaptive profile was typical in PKU participants, while ASD participants experienced behavioral (externalizing symptoms), emotional (internalizing symptoms) and adaptive disorders (general, practical, social domains).
Present results support the view of a relative disengagement of adaptive and emotional-behavioral profile with respect to EF skills and suggest that other dysfunctions contribute to the multidimensional phenotype of ASD participants.
Adult patient perspectives on phenylketonuria care: Highlighting the need for dedicated adult management and services
2020, European Journal of Medical Genetics
Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by an inability to metabolize the amino acid phenylalanine (Phe). If left untreated, an accumulation of Phe results in neurodevelopmental, neurological and psychological impairments. Advancements in detection and treatment of PKU have improved outcomes and life expectancy for these patients, emphasizing the need for life-long, specialized care. Due to the paucity of adult-focused PKU clinics, patients who are well into adulthood are still being treated in pediatric centers. This retrospective study evaluates the perceived expectations, benefits and challenges of 50 adult PKU patients (mean age 31.3 ± 10.4 years) transitioning from a pediatric to adult care setting using a transition questionnaire administered at the first clinic visit at the adult PKU care center. Patients reported a lack of access to adult resources and adult-specific PKU educational material in their pediatric PKU clinic. In contrast, the established relationships with the pediatric health care team and familiarity with treatment plans were aspects of pediatric care that patients enjoyed. The results from this study will contribute to the optimization of adult PKU patient care, establishment of strategies for transitioning adults with PKU and other metabolic disorders from pediatric to adult care, and support the need to establish adult-only PKU care facilities.

View all citing articles on Scopus

^☆

References to electronic databases: Phenylketonuria, OMIM 261600 and 261630. Phenylalanine hydroxylase, EC 1.14.16.1.

Funding statement: Dr. Brumm has received consulting fees and speaker’s fees from BioMarin Pharmaceutical Inc. Dr. Bilder and Dr. Waisbren have served as consultants for BioMarin Pharmaceutical Inc.

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Psychiatric symptoms and disorders in phenylketonuria☆

Abstract

Section snippets

Background

Psychiatric and psychological functioning in untreated PKU

Psychiatric and psychological functioning in children with early-treated PKU

Psychiatric and psychological functioning in adults with early-treated PKU

Limitations and future directions

Conclusions

J. Pediatr.

J. Pediatr.

J. Pediatr.

Mol. Genet. Metab.

Hyperphenylalaninemia: phenylalanine hydroxylase deficiency

Phenylpyruvic oligophrenia

Arch. Neurol. Psychiatry

Phenylpyruvic oligophrenia (phenylketonuria)

Res. Publ. Assoc. Res. Nerv. Ment. Dis.

The variability in manifestations of untreated patients with phenylketonuria (phenylpyruvic aciduria)

Pediatrics

The neuropathology of phenylketonuria: human and animal studies

Eur. J. Pediatr.

Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU

Neuropsychol. Rev.

Neuropsychological outcome of subjects participating in the PKU Adult Collaborative Study: a preliminary review

J. Inherit. Metab. Dis.

The neurochemistry of phenylketonuria

Eur. J. Pediatr.

Phenylketonuria: white-matter changes assessed by 3.0-T magnetic resonance (MR) imaging, MR spectroscopy and MR diffusion

Radiol. Med.

Visual evoked potentials in phenylketonuria: association with brain MRI, dietary state, and IQ

J. Neurol. Neurosurg. Psychiatry

Neutral amino acid transport at the human blood–brain barrier

Fed. Proc.

Dietary problems of phenylketonuria: effect on CNS transmitters and their possible role in behavior and neuropsychological function

J. Inherit. Metab. Dis.

Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria: a model for the study of phenylalanine and brain function in man

J. Clin. Invest.

Measurement of neurotransmitter metabolites in the cerebrospinal fluid of phenylketonuric patients under dietary treatment

J. Inherit. Metab. Dis.

Essential Psychopharmacology: Neuroscientific Basis and Practical Applications

Personality characteristics in patients with phenylketonuria treated early

Pediatr. Res.

Psychosocial aspects of phenylketonuria

Eur. J. Pediatr.

Behavioural and emotional problems in early-treated adolescents with phenylketonuria in comparison with diabetic patients and health controls

J. Inherit. Metab. Dis.

Psychopathology of patients treated early for phenylketonuria

Acta Paediatr.

Psychiatric disorders in adult patients with early-treated phenylketonuria

Pediatrics