A Neuropsychiatric Perspective of Phenylketonuria I: Overview of Phenylketonuria and Its Neuropsychiatric Sequelae

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
Psychosomatics (Impact Factor: 1.86). 11/2012; 53(6):517-23. DOI: 10.1016/j.psym.2012.04.010
Source: PubMed


Phenylketonuria (PKU) is an autosomal recessive metabolic genetic disorder that is associated with neuropsychiatric sequelae of varying severity. The natural history, epidemiology, and a history of the medical understanding and approaches to treatment of PKU are presented. Neurocognitive and neuropsychiatric sequelae of patients with untreated, early-treated, and continuously-treated PKU are described, and possible mechanisms for the symptoms are proposed. The authors propose an integrated approach to management of patients with PKU.

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    • "Despite the favorable clinical outcome of earlytreated PKU (ETPKU) subjects, when compared with late-or untreated patients, a lower Intelligence Quotient (IQ) than expected and minor neuropsychological and psychiatric problems23456789 remain challenging aspects of the disease. In ETPKU children and adolescents a higher incidence of the following have been reported: anxiety and depressive symptoms, social isolation , physical complaints, hyperactivity101112, attention problems13141516 , low self-esteem, lower achievement motivation and impul- siveness [17]. Among adult PKU patients, depressive mood and anxiety are the most frequently described psychiatric symptoms181920, but obsessive-compulsive symptom [8,21], phobia, and panic attacks [22] are also reported. "
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    ABSTRACT: Background and objectives: Psychiatric symptoms are a challenging aspect in adolescent and adult early treated phenylketonuric (ETPKU) patients. To assess the occurrence of psychiatric disorders we explored the presence of symptoms requiring intervention and further investigated the link between psychiatric disorders, the quality of biochemical control and cognitive functioning. Patients and methods: Forty-six ETPKU patients (aged 12 to 44) and 30 age-matched healthy controls were subjected to cognitive and psychiatric assessment by means of self-report questionnaires and psychiatric interview. Psychiatric diagnoses, if detected, were made according to DSM-5 criteria. Concomitant IQ, historical and concurrent biochemical metabolic controls were included in the statistical analysis. Results: Twenty-five out of 46 ETPKUs showed clinical scores on at least one scale of the psychiatric assessment (7/30 in controls); anxiety and withdrawal were the most frequent self-reported symptoms. Seventeen patients (and no controls) met criteria for a psychiatric diagnosis, most of them belonging to the Anxiety Disorders category. The occurrence of psychiatric symptoms was not associated with the life-long and concurrent quality of metabolic control but patients with good metabolic control (≤500μM) in the first 11years of life showed higher frequency of psychiatric diagnosis (Fisher's exact p=.0300). Discussion/conclusion: ETPKUs show a higher than normal vulnerability to psychiatric disorders, which cannot be explained by the usual biochemical alterations influencing intellectual outcome. Our data support the hypothesis that the burden of the disease acts as psychological stress for children and their families. Possible involvement of neuromediators in the pathogenesis of these complex symptoms requires further investigation.
    Full-text · Article · Nov 2015 · Molecular Genetics and Metabolism
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    • "There is a need for clinical outcomes data on ADHD symptoms and executive functioning in PKU. In their two-part neuropsychiatric perspective on PKU, Bone et al. [10] and Angelino et al. [25] call for consistent and integrated mental health screening and treatment to manage these and other neuropsychiatric sequelae in individuals with PKU. The PKU ASCEND study, the largest controlled clinical outcomes study to date in PKU, was conducted to evaluate the therapeutic effects of sapropterin versus placebo on PKU-associated symptoms of ADHD and executive and global functioning in individuals who had a therapeutic blood Phe response to sapropterin therapy. "
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    ABSTRACT: Symptoms of attention deficit hyperactivity disorder (ADHD), particularly inattention, and impairments in executive functioning have been reported in early and continuously treated children, adolescents, and adults with phenylketonuria (PKU). In addition, higher blood phenylalanine (Phe) levels have been correlated with the presence of ADHD symptoms and executive functioning impairment. The placebo-controlled PKU-ASCEND study evaluated the effects of sapropterin therapy on PKU-associated symptoms of ADHD and executive and global functioning in individuals who had a therapeutic blood Phe response to sapropterin therapy. The presence of ADHD inattentive symptoms and executive functioning deficits was confirmed in this large cohort of 206 children and adults with PKU, of whom 118 responded to sapropterin therapy. In the 38 individuals with sapropterin-responsive PKU and ADHD symptoms at baseline, sapropterin therapy resulted in a significant improvement in ADHD inattentive symptoms in the first 4 weeks of treatment, and improvements were maintained throughout the 26 weeks of treatment. Sapropterin was well-tolerated with a favorable safety profile. The improvements in ADHD inattentive symptoms and aspects of executive functioning in response to sapropterin therapy noted in a large cohort of individuals with PKU indicates that these symptoms are potentially reversible when blood Phe levels are reduced.
    Full-text · Article · Nov 2014 · Molecular Genetics and Metabolism
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    ABSTRACT: The mainstream of phenylketonuria (PKU) management is lifelong restriction of protein intake; however, this dietary restriction may be accompanied by insufficient dietary intake of long-chain polyunsaturated fatty acids (LCPUFA). The objective of this review was to assess whether significant depletion of LCPUFA can be detected in PKU patients on low-protein diet and whether LCPUFA supplementation is an effective way to increase the availability of LCPUFA in PKU patients. The method included structured search strategy on Ovid MEDLINE, Scopus, LILACS, and the Cochrane Library CENTRAL databases, with formal inclusion/exclusion criteria, data extraction procedure, and meta-analysis. We evaluated 9 case-control studies and 6 randomized controlled trials, dated from the inception of the databases to 2012. The meta-analysis of the case-control studies showed significantly lower values of both eicosapentaenoic acid and docosahexaenoic acid (DHA) in all biomarkers investigated and that of arachidonic acid in total plasma lipids in PKU patients as compared with healthy controls. There were sufficient data to demonstrate that dietary DHA supplementation of patients with PKU significantly increases the contribution of DHA to total plasma lipids. In summary, suboptimal LCPUFA status, especially that of n-3 LCPUFA, can be detected in PKU patients. Supplementing DHA to the diet of PKU patients may improve their LCPUFA status; however, further research is needed to determine the optimal supplementation dosage and to establish beneficial functional outcomes.
    Full-text · Article · Jul 2013 · Nutrition research