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

Psychosomatics 2012:53:517–523

© 2012 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Review Articles A Neuropsychiatric Perspective of Phenylketonuria I: Overview of Phenylketonuria and Its Neuropsychiatric Sequelae Ashley Bone, M.D., Angela K. Kuehl, Pharm.D., M.S., Andrew F. Angelino, M.D., D.F.A.P.A.

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 se-

quelae 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. (Psychosomatics 2012; 53:517–523)

P

600 ␮mol/L at 8 weeks of gestation gave birth to 78 (92%) of 85 infants born with microcephaly in the overall study group of 251 births, underscoring the need for dietary control in pregnant women.5 Behavior disturbances affecting those children with PKU will be discussed later in the paper. Despite the high rates of cognitive impairment associated with elevated levels of Phe in the bloodstream even in patients treated with diet early in life, the PKU clinical treating community has not developed a comprehensive approach to screening and referring patients to mental healthcare providers for assessment and treatment of their mental impairments. The goal of this paper is to focus attention on the opportunity to improve care of patients with PKU. This review provides a general orientation to the issues involved in the psychosomatic problems that

henylketonuria (PKU) is an autosomal recessive metabolic genetic disorder that is associated with neuropsychiatric sequelae of varying severity. PKU is characterized by a mutation in the gene coding for the hepatic enzyme phenylalanine hydroxylase (PAH), which is necessary for the conversion of the amino acid phenylalanine (Phe) to tyrosine (Tyr). The resulting reduction in PAH activity and accumulation of Phe in the blood lead to significant cognitive, psychiatric, and intellectual impairment if the patient is not treated early in life. In fact, PKU is the most common biochemical cause of what was historically diagnosed as mental retardation.1 Even among those who receive treatment, deficits in these areas are frequently evident later in life. Excessive Phe is thought to interfere with brain growth, myelination, and neurotransmitter synthesis. Mental impairment worsens during myelination in early childhood in the presence of increased Phe exposure. In addition to mental retardation, patients with untreated PKU may develop epilepsy, motor deficits, microcephaly, and behavioral disturbances.2,3 For example, generalized seizures occur in 25% of patients with PKU.4 Also, in a study of maternal PKU comparing Phe levels above and below 600 ␮mol/L, women with blood Phe levels greater than Psychosomatics 53:6, November-December 2012

Received March 5, 2012; revised April 20, 2012; accepted April 23, 2012. From Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD (AB, AFA); Symbiotix, Inc., Lexington, KY (AKK). Send correspondence and reprint requests to Andrew F. Angelino, M.D., D.F.A.P.A., Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 4940 Eastern Ave., A4Center-457, Baltimore, MD 21224; e-mail: aangelino@ jhmi.edu © 2012 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

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A Neuropsychiatric Perspective of Phenylketonuria I affect persons with PKU, with the primary goal of orienting practitioners to the topic of cognitive and behavioral impairment experienced by children and adults with PKU. BACKGROUND INFORMATION ON PKU The incidence of PKU in the United States is approximately 1 in 15,000 live births.6 The disorder was discovered in 1934 by the Norwegian physician Ivar Asbjørn Følling, when he identified phenylketones in the urine of two mentally retarded siblings.7 In 1953, the defect in PAH was identified and a diet low in Phe was shown to improve mental development in individuals with PKU.8,9 In 1962, Guthrie and Susi developed a bacterial inhibition assay to detect elevated Phe levels in dried blood spots on filter paper.10 This became the basis for newborn screening in the industrialized world and led to widespread early dietary treatment of PKU, resulting in the avoidance of the most severe neurologic sequelae associated with the disorder. The mainstays of treatment are adherence to a nutritionally balanced diet that severely restricts Phe and supplementation with medical foods, consisting of Phe-free protein substitutes that contain ⱕ 1 g protein per serving and supply approximately 75%–90% of protein requirements.11 Foods high in protein such as meat, fish, poultry, dairy products, eggs, nuts, standard breads and pastas, and legumes should be eliminated or drastically limited. The overall goal of dietary management is to lower blood Phe levels and replace Tyr to avoid de novo synthesis of Phe; however, diet must be adequate to support normal growth and development. Initially, the low protein diet was discontinued when patients with PKU reached 6 years of age, when the majority of brain growth was thought to be complete. These patients are often referred to as “early-treated” patients. Later, the age for stopping a low-Phe diet was raised to 12 years. However, results of the National Collaborative Study for PKU, conducted from 1967 through 1983, indicated a correlation between early discontinuation of diet and a decline in school performance and an increase in behavioral problems.12–14 This formed the basis for the “diet for life” recommendation, which encouraged patients with PKU to follow the diet indefinitely.6,15,16 These patients, if adherent, are referred to as “continuously-treated” patients. Successful long-term adherence to the diet is influenced by various cognitive, emotional, physiological, and cultural factors, and is complicated by the poor palatability 518

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of protein substitutes. Patients and their caregivers vary in their willingness and ability to adhere to dietary treatment and are often inconsistent in their degree of compliance.17 Dietary adherence is particularly challenging among adolescents and adults.18,19 The National Institutes of Health recommends a multidisciplinary approach to overcoming barriers to dietary adherence, including ongoing monitoring of metabolic control as reflected by blood Phe levels and clinical outcomes, coordinated patient education and support, and assurance that medical foods and low-protein products are readily accessible.6 The first nondietary treatment proven effective at lowering blood Phe in some patients with PKU is sapropterin (Kuvan).20 Oral sapropterin is a synthetic formulation of the active 6R-isomer of tetrahydrobiopterin (BH4; a naturally occurring cofactor of PAH) and is approved in the United States for use in patients with BH4-responsive PKU. Supplementation with large neutral amino acids (LNAAs), such as arginine, histidine, isoleucine, leucine, lysine, methionine, threonine, tryptophan, tyrosine, and valine, is another treatment aimed at reducing Phe levels in the blood and consequently in cerebral tissue. LNAAs tyrosine and tryptophan are necessary for the synthesis of neurotransmitters, such as dopamine and serotonin. Increased levels of Phe (also a LNAA) competitively inhibit transport of other crucial LNAAs across the blood-brain barrier; therefore, LNAA supplementation may reverse this inhibition and reduce the transport of Phe into the brain.21–23 Other treatment options are being actively pursued, including enzyme substitution with phenylalanine ammonia-lyase to relax dietary restrictions24 and gene therapy (presently in a murine model).25 COGNITIVE AND PSYCHIATRIC SYMPTOMS OF PKU Cognitive Although diet-treated children with PKU tend to have IQ scores within the normal range, their scores are, on average, approximately one-half of a standard deviation lower than those of non-PKU controls. They also score slightly lower than their unaffected parents or siblings.26,27 Cognitive outcomes are significantly correlated inversely to blood Phe levels. During a critical developmental period (age 0 –12 years), each 100 ␮mol/L rise in Phe levels predicted a 1.3- to 3.1-point decline in IQ scores among children treated early with dietary therapy. Similar Psychosomatics 53:6, November-December 2012

Bone et al. significant correlations were observed between lifetime Phe levels and IQ scores among early-treated patients.28 After age 10 years, IQ development appears relatively stable.29 More recent research has focused on neuropsychological abilities in patients with PKU. Although strict dietary adherence beginning in infancy prevents profound neurologic impairment, more subtle deficits persist and are detectable across a range of domains in early-treated children and adults. Areas of deficit include executive functioning,30 –36 response speed,37,38 academic abilities,30,39 attention,40 – 42 interhemispheric transfer of information,43,44 and visuo-spatial and visual-motor abilities.31,38,45– 48 Impairment of executive functioning is one of the most consistent findings in individuals with PKU. One meta-analysis spanning over two decades concluded that patients with early-treated PKU had greater deficits in executive abilities, such as planning, working memory, inhibition, and cognitive flexibility, compared with demographically matched controls.49 Findings from behavioral studies verify that processing speed is impaired in individuals with PKU. One 3-year study examined IQ, information processing, and selective and sustained attention among adolescents and young adults with PKU to diabetic individuals matched for gender, age, and socioeconomic status.50 Patients with PKU had significantly poorer test results; this was due to reduced performance speed as opposed to deficits in executive functioning. Processing speed was also inversely correlated with blood Phe levels. Processing-speed deficits may adversely affect individuals across many aspects of life, including home, school, and work environments. A 2004 study by Arnold and colleagues reports that as many as half of the patients with PKU may exhibit attentional deficits, which are significantly correlated with mean Phe levels and can lead to poor academic and work performance.51 Despite IQs in the normal or near-normal range, children with early-treated PKU are more likely than their peers to struggle academically. One study investigated the relationship between school performance, cognitive functions, and dietary control in 26 early- and continuously treated patients with PKU and 21 matched controls.52 Several cognitive functions were assessed, including intelligence, visual and auditory memory, visuospatial skills, fine motor skills, attention, executive functioning, and language skills. Compared with controls, patients with PKU scored significantly lower in fine motor functions (p ⬍ 0.001), intelligence (p ⬍ 0.0001), and attention (p ⫽ Psychosomatics 53:6, November-December 2012

0.02), as well as on tests measuring executive functioning (p ⫽ 0.013). Half of the patients with PKU presented with school problems, compared with one-fourth of controls (p ⫽ 0.028). The school problems frequently required that students repeat classes or obtain special tutoring, and some students did not finish school.52 These findings are likely explained at least in part by deficits in processing speed, common among those with PKU. In fact, among early-treated patients, academic performance appears to worsen with age. This is likely due to a combination of factors, including the tendency toward lower dietary adherence in older children and the demand for increasingly more complex executive functioning abilities during later school years.51,52 Psychiatric Patients with untreated PKU have been shown to demonstrate severe behavioral disturbances, including psychotic, autistic, and aggressive disorders.53 Følling characterized such patients as anxious, shy, angry, prone to temper tantrums, irritated, unsociable, and catatonic.7 The introduction of newborn screening and widespread early initiation of dietary treatment led to elimination of the most severe psychiatric disturbances; however, more subtle psychiatric findings have been identified in diettreated patients. Discontinuation of diet and elevated Phe levels are associated with higher incidences of behavior problems. In one study, for example, behavior deviancy rates of 40% by teacher assessment and 24% by parent assessment were reported in a cohort of 99 children with PKU enrolled in a British PKU registry. In general, children with PKU exhibit mannerisms, hyperactivity, and signs of anxiety; they are less responsive and more aloof than their noninfected peers.54 Other studies also report elevated behavior deviancy rates in children with PKU.55,56 These well-documented psychological and psychiatric problems most commonly fall within the areas of social competence, autonomy, self-esteem, mood, and anxiety.57 Nearly half of the children who discontinued dietary therapy exhibited attentional difficulties, as well as adjustment disorders, encopresis, oppositional defiant disorder, and phobias.58 Adolescents with PKU described themselves as having less autonomy, greater dependency, lower selfregard, and a low frustration threshold.59 In adults, depressive and anxiety-related symptoms are the two most frequently described psychiatric disturbances associated with early-treated PKU.16,60 One study, www.psychosomaticsjournal.org

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A Neuropsychiatric Perspective of Phenylketonuria I noting symptoms of agoraphobia along with depression and anxiety, reported a relationship of symptoms with Phe levels and dietary treatment adherence; resolution of symptoms may occur with reinstated treatment that leads to improvement in metabolic control.61

rotonin in the brain. Although the complex interactions among the neurotransmitter systems are not fully understood, the activity of dopamine, norepinephrine, and serotonin have all individually been shown to be involved in regulating mood, emotion, and cognition.57

COGNITIVE AND PSYCHIATRIC EFFECTS OF PKU: POTENTIAL MECHANISMS

IMPLICATIONS FOR CLINICAL MANAGEMENT OF PKU

Proposed explanations for the cognitive and psychiatric impairments among patients with PKU include abnormalities of white matter and neurotransmitters, as well as disruption of cerebral protein synthesis secondary to compromised transport of amino acids across the blood-brain barrier.62 MRI abnormalities typically include areas of symmetrical prolongation of T2 relaxation time, mainly in the posterior periventricular cerebral white matter.63– 66 This abnormal signal suggests an increase in water content of the myelin, perhaps caused by structural change in the myelin sheath.67 The severity of white matter involvement is closely related to Phe levels at the time of scanning. High Phe concentrations destabilize already-formed myelin, and demyelinated axons revert to an immature state, leading to neuronal dysfunction.67 Processing-speed impairments observed in those with PKU may be related to white matter dysfunction, as well as to prefrontal dysfunction.67,68 Reduced production of neurotransmitters may have a key role in the neuropsychiatric effects seen in patients with PKU. Impaired breakdown of Phe to tyrosine results from insufficient activity of the PAH enzyme. Phe influences the synthesis of two biogenic amines, dopamine and serotonin, which are critical in neurotransmission. An inverse relationship between dopamine plasma concentrations and Phe levels has been documented. High Phe concentrations reduce availability of the amino acids tyrosine and tryptophan, which are precursors of catecholamines and serotonin.69 Furthermore, impaired uptake of tyrosine and tryptophan across the blood-brain barrier may also contribute to the inhibitory effect of Phe on biogenic amine synthesis. Since brain cell membrane surface area is many orders of magnitude greater than that of the blood-brain barrier, the movement of amino acids from plasma to the brain is the rate-limiting step.70 Phe, tyrosine, and tryptophan share the same transport system and compete for a common transport function. Increased concentrations of Phe could limit the transport of amino acids across the blood-brain barrier and, therefore, reduce levels of dopamine and se-

Profound neuropsychiatric impairments associated with PKU have been prevented by widespread screening of newborns for PAH deficiency and initiation of early dietary treatment for those affected. Although evidence suggests that PKU-associated cognitive impairment can be remediated to a certain extent with dietary control of Phe,71 mounting evidence shows that patients with PKU continue to be subject to numerous cognitive and psychiatric challenges in later life. These deficits impact every area of the lives of those with PKU, often resulting in overall poor quality of life and an inability to adequately function in the workplace, home, or school environment. Indeed, patients with PKU are often unaware of the level of impairment posed by these deficits and do not appreciate their impact on the ability to carry out day-to-day responsibilities. Patients often find it difficult or even impossible to maintain adherence to dietary treatment, thus creating a vicious cycle of higher Phe levels and continued impairment. Because patients with PKU may be unaware of the presence of their cognitive impairment, they do not actively seek psychiatric or psychosocial support on their own initiative. Thus, metabolic clinics, i.e., the primary points of care for patients with PKU, bear a difficult burden in ensuring optimal patient management. There has been to date no systematic attempt to determine the standards of practice for integrated mental health care and metabolic care of patients with PKU, and, thus, no widespread recommendations regarding screening and referral to mental health providers can be described. Further, since PKU is a rare condition, many psychiatrists and psychologists do not include PKU in the differential diagnosis of a patient presenting with cognitive or psychiatric symptoms, and the vast majority of mental health providers have little to no experience in treating patients with PKU. Given the detrimental effects of high Phe levels on the brains of patients with PKU, one could propose that management of these patients should ideally be provided by a full complement of mental healthcare professionals (social workers, educational and vocational specialists, psychologists, and psychiatrists) to optimize the care and improve

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Bone et al. the quality of life of those with PKU. Recent research has focused on creating relationships between metabolic clinics and mental healthcare providers to facilitate adequate assessment for impairment, determine appropriate treatment, and ensure access to social services for patients with PKU and mental impairment. One such study evaluated the successful establishment of a formal screening assessment for impairment and incorporation of mental healthcare providers, either within the metabolic clinic or as part of a referral system. Within the framework of the Diversified Approach for PKU Treatment (ADAPT) program implemented at the PKU Clinic at Children’s Memorial Hospital in Chicago, one of three ADAPT centers, 73 patients (32 adults, 41 children) were screened for psychi-

atric issues. Of these, 21 patients (29%) screened positive for psychiatric distress—with adults screening positive more frequently than children (44% vs. 17%; P ⫽ 0.03).72 A companion paper to this review further describes the discontinuity of care between many metabolic clinics and mental healthcare providers and discusses opportunities for integrating care for the betterment of all with PKU. By opening this discussion, it is hoped that healthcare for patients with PKU and psychiatric issues will take a step forward in the foreseeable future. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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