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Visuo-motor coordination Grooved Pegboard and Digit Symbol was reduced in comparison to controls but was thought to reflect general cognitive slowing rather than a specific difficulty with motor coordination or peripheral motor speed. Reading speed was slower than controls but was accurate.
Spelling was intact, as was picture naming. Hofman et al. Across studies, the most consistent findings were deficits in motor skills, working memory, and vigilance. However, impairments in other cognitive domains were less consistently observed. The relationship between Phe levels and cognition across the lifespan was variable, with no definitive linear pattern of association found. This was thought to reflect a number of core challenges in studying cognition in PKU.
These included high heterogeneity in the nature of study samples, resulting in large variability in phenylalanine levels, as well as wide variation in the type and sensitivity of neuropsychological measures used to assess cognitive functioning. Study samples were often small, with cohorts exhibiting different levels of disease severity, age ranges, and socioeconomic status. No standard PKU core neuropsychological battery had been uniformly used. Weglage et al. PKU participants and controls were assessed on IQ, attention, and information-processing abilities.
Magnetic resonance imaging MRI of the brain was performed in all patients. Neuropsychological assessments and MRI were repeated at a 5-year follow-up. In the 5-year interval, there was no change in processing speed or attentional measures. At both assessment times, IQ scores were significantly lower in PKU individuals as compared to controls.
Intellectual quotients, attention, and information processing showed no correlation to imaging results; however, they were significantly correlated to blood phenylalanine Phe levels throughout childhood and adolescence. Phe levels had also been higher in the adolescent years of older adult patients, suggestive of an early relaxation of diet recommended when the older patients were adolescents. Untreated PKU is characterized by motor deficits, intellectual disability, microcephaly, autism, seizures, developmental problems, behavioral issues, and a range of psychiatric symptoms Failure to implement treatment in the neonatal period causes substantial lifelong disability through the toxic effects of excess Phe exposure to the brain, in particular to myelin and dendritic projections during critical postnatal periods of neuronal development Brain MRI and histopathology of individuals with late- or never-treated PKU demonstrate diffuse cortical atrophy, hypomyelination, white matter vacuolization, and astrocytic gliosis 47 , Gonzalez et al.
The aim was to investigate the relationship between neurological complications and behavioral problems, age at diagnosis and dietary control among a follow-up group There were Eighty-eight percent of patients were treated with a protein-restricted diet, and the remainder with BH4.
Almost all In early-diagnosed patients, there was a significantly negative correlation between IQ and the index of dietary control during the first 6 years of life and that of the immediately preceding year.
The proportion of patients with late diagnosis and neurological and behavioral problems was significantly higher than that of those diagnosed early. In addition, the proportion of early-diagnosed patients with behavioral and neurological problems who had good, intermediate, or poor dietary control during the first 6 years of life and the immediate-past year also differed significantly The severe cognitive impairments seen in untreated PKU can be partially reversed with dietary treatment in many individuals, and the prompt initiation of treatment following newborn metabolic screening remains essential for the prevention of disability and optimal neurodevelopment.
PKU results, in untreated patients, a profound intellectual disability and more subtle cognitive deficits in individuals who were treated early and continuously. The assessment of intellectual functioning in PKU has been an important target outcome variable since the implementation of neonatal PKU screening programs in the s , Research on intellectual functioning in individuals with PKU has played a significant role in guiding treatment recommendations and mproving outcomes Brumm and Grant conducted a literature review examining the relationship between intellectual outcome and treatment parameters including initiation of treatment, duration of treatment, and blood phenylalanine Phe levels from infancy through adulthood.
While current PKU treatment practices have eliminated severe neurological and cognitive impairment, evidence suggests that intellectual functioning, although typically within the average range when PKU is treated early and continuously, may not be maximized under the current definition of well-controlled PKU, which is based on blood Phe levels Two prior meta-analyses examining blood Phe concentrations and intellectual functioning in pediatric populations found a strong inverse relationship between historical blood Phe measurements and IQ , Future research assessing intellectual and neurocognitive outcome in PKU should enhance the development of new treatment strategies.
Executive function is an umbrella term that refers to cognitive processes that are necessary for purposeful, future orientated behavior.
These processes are necessary to plan and complete tasks in spite of potential distracting or irrelevant information Executive functions include cognitive processes such as regulation of attention, inhibition of inappropriate responses, coordination of information in working memory, and cognitive flexibility.
Higher-order executive functions require the simultaneous use of multiple basic executive functions and include planning, reasoning, and problem-solving Reviews of executive functions have found that the most consistent phenylalanine-related impairments have been observed in working memory, sustained attention, and inhibitory control 65 , , There have been several investigations to try and establish a theoretical model of executive functioning deficit in individuals with PKU, which has resulted in detailed analysis of various aspects of executive functioning Part of the difficulty in the assessment of executive functioning in PKU populations has been the lack of consistent use of valid and sensitive tools that are suitable for both children and adults As an example, an executive test such as Trails B indexes both speed and mental switching Studies have demonstrated significant variability in their findings, in part due to the methodological challenges in conducting research in rare and diverse PKU populations.
In the future, it will be important for a consistent and sensitive core neuropsychological battery to be implemented across international PKU centers, to try and standardize consensus regarding cognitive treatment outcomes 17 , High Phe blood levels during pregnancy have a known teratogenic effect on the developing fetus, resulting in growth retardation, microcephaly, intellectual disability, and birth defects There have been several studies that have assessed the cognitive outcomes of children born to mothers with PKU - A summary of the literature suggests that children who are born to mothers with PKU who have attained metabolic control before or very early in pregnancy seem to have a normal developmental trajectory.
However, a delay in attainment of maternal metabolic control is associated with declines in offspring developmental outcome, including lower IQ and higher rates of externalizing behavioral difficulties Waisbren and Azen conducted a prospective longitudinal study that assessed cognitive and behavioral outcomes in treated mPKU offspring Two hundred and twenty-eight children who were born to mothers with treated PKU or untreated mild hyperphenylalaninemia were compared with 70 control subjects at 7 years of age.
There was an increased risk of low IQ in PKU offspring if the mother came from a lower SES background and was also unable to provide a stimulating early home environment The postnatal environment also significantly affected outcome.
Interventions to improve dietary compliance before and throughout pregnancy may reduce the risks associated with mPKU Social cognition is a domain of cognition involving all mental processes that underlie social interactions, and encompasses the ability to perceive, interpret, and then respond appropriately to social cues. While there has been comprehensive investigation into the role of executive functions in PKU, there has only been one study to date that has assessed social-cognitive abilities Deficits in social cognitive abilities are consistently reported in individuals with executive dysfunction, because of shared underlying neurobiology and neuroanatomy — In other disorders affecting the CNS, impairments in executive function have been correlated with deficits in communication skills and social relationships High Phe levels may in some cases result in irritability, impacting on adaptive social skills.
Ninety-five PKU patients mean age Early treated AwPKU performed worse than controls on all four tasks included; however, when age was controlled for, impairments were only observed on two tasks. PKU patients demonstrated poorer social cognition and had poorer social skills than controls, regardless of general cognitive abilities. The quality of social skills was also inversely related to lifetime phenylalanine levels in adult patients, and more specifically to Phe levels up to 12 years of age.
No differences with respect to social outcome measures were observed between the BH4 and non-BH4 groups. Jahja and colleagues concluded that PKU patients have difficulties with social cognition and social skills that appear to be strongly related to Phe levels. Impairments in functioning seem to be more evident among adolescents and adults with PKU, with high Phe levels during childhood and early adolescence presumably during critical periods of development of frontal circuits subserving social cognitive functioning seem to be of greater influence than current and recent Phe levels in PKU individuals Two theories have been postulated regarding the mechanism of action of the disrupted Phe metabolism in individuals with PKU.
The first theory suggests that because Phe competes with other LNAAs tryptophan and tyrosine for transport across the blood—brain barrier, high levels of Phe saturate the LNAA transporters. This leads to PKU individuals presenting with lower brain concentrations of other LNAA and important neurotransmitters such as dopamine, norepinephrine, and serotonin , which are known to be important in cognitive functioning The second theory suggests that high brain Phe concentrations cause neurotoxicity.
This interferes with cerebral protein synthesis, increases myelin turnover, and inhibits neurotransmitter synthesis One of the primary cognitive changes that is consistently seen in the AwPKU literature is a reduction in speed of processing. This is reflective of cognitive slowing, rather than a peripheral reduction in motor speed Information processing speed relies on the speed with which action potentials are able to travel along the long myelinated axons.
If myelination of these axons was damaged or incomplete, there would be a reduction in processing speed. There is currently no consensus regarding a standardized PKU neuropsychological battery for children or adults. This correlates with changes in treatment targets for blood Phe and life changes including school transitions, living situation, and transfer to adult clinics and brain development see Table 2.
When conducting a neuropsychological assessment in individuals with PKU, it is important for clinicians to conduct a comprehensive examination encompassing all cognitive domains.
If time is limited, the domains most likely to be susceptible to high Phe levels are attention, working memory, motor control, complex speed of processing, and executive functioning 17 , , Intellectual functioning as a stand-alone outcome measure has been found to be less sensitive than the above-mentioned cognitive abilities While memory retention is often sound, attentional difficulties can affect registration and encoding of new information and should be assessed.
A thorough clinical history should be obtained prior to an assessment being conducted, to help guide test selection, with a particular focus on cognitive strengths and weaknesses, social cognition, psychiatric symptoms, psychosocial adjustment, quality of life, and behavioral difficulties 17 , As there is emerging evidence that social cognition skills facial and emotional recognition and theory of mind and emotional and behavioral regulation are affected in individuals with PKU, it is important to consider assessment of these domains as part of a comprehensive neuropsychological examination A brief psychiatric history should also be obtained, as conditions such as depression and anxiety can negatively impact on cognitive test performance, particularly on measures of attention and speed.
Mood and anxiety symptoms can be treated, which may lead to an improvement in cognitive functioning. By conducting a comprehensive neuropsychological examination, cognitive, psychological, and social cognition interventions can be individually tailored to best assist individuals with PKU to achieve their highest potential and enhance quality of life. Ms T was a year-old single woman who was not diagnosed with PKU until after 12 months of age and only started dietary treatment at 18 months of age.
Prior to this period, she had significant irritability, childhood anxiety, delayed milestones, and failure to thrive and progress Figure 2. She continued dietary treatment until the age of 9, at which time the family was told to stop dietary management. She did not resume diet until 30 years of age. She presented with attentional deficits, hyperactivity, and social cognition issues throughout childhood, and then developed a psychotic illness in her late teens.
When dietary control was good Phe — , psychotic symptoms were significantly attenuated, anxiety was minimal, and impulse control returned to normal. Figure 2 Timeline in years of proposed neural development, onset of neuropsychiatric disorder green and dietary coverage orange for Case Vignette 1. This case highlights the importance of neuronal development across the lifespan, with insult during the early neurodevelopmental NDT stages resulting in intellectual disability ID , autism spectrum disorder ASD , and attention deficit hyperactivity disorder ADHD ; while insult during the later stages of neurodevelopment, during adolescence with disruption of synaptic pruning leading to disorders such as bipolar disorder and in this instance, schizophrenia , Mr C was a year-old married engineer and father of two, who was diagnosed at birth on bloodspot screening.
His anxiety was generalized, with occasional panic episodes and periods of low mood with mild neurovegetative disturbance. After 12 months of dietary control, anxiety levels had improved markedly, and his mood was persistently euthymic. Mr C underwent comprehensive neuropsychological assessment prior to commencing a low Phe diet baseline and after 12 months of good dietary control. He performed in keeping with these estimates on all tasks, with the exception of verbal new learning and memory, where he was in the Borderline Impaired range.
Mr C reported that he found it challenging to attend to the verbal information being presented. After 18 months on diet, Mr C demonstrated statistically significant improvements in the domains of processing speed from 34 percentile at baseline to 77 percentile on-diet and new learning and memory from 7 percentile at baseline to 50 percentile on diet. A number of executive functioning measures also improved, although the improvements were mild and not statistically significant.
He reported being able to think more clearly and quickly, with improved concentration. Ms N was a 36 year-old married lady who was diagnosed at birth on bloodspot screening. She adhered to a low Phe diet for the first 7 years of her life then ceased dietary control. She recommenced on diet at age 35 due to symptomatic PKU affecting her cognitive functioning and mental health. Ms N had a long history of mental health difficulties starting in childhood. She had difficulties regulating her mood and had episodes of depression.
She had her first panic attack in her mid-teens, along with generalized anxiety symptoms and infrequent self-harming behaviors. She had been under psychiatric care since her teenage years and had several psychiatric admissions. She had worked in a variety of semi-skilled roles in a part-time capacity, but had found it difficult to maintain employment due to fluctuating mental health. She saw a psychologist on a regular basis and had been on pharmacological treatment with SSRIs since her early 30s, with some improvement.
She reported significant cognitive limitations, including difficulties with attention and concentration, memory, planning, and organization and slowed mental processing. These difficulties had affected her ability to maintain productive employment, leading to feelings of inferiority and low self-esteem.
Baseline neuropsychological assessment prior to resuming a low Phe diet revealed that Ms N was of average intelligence. However, she demonstrated moderate impairments on tasks of divided attention and psychomotor speed and severe impairments on task of planning, organization, and self-monitoring. She also showed a significant regression in white matter lesions Figure 3. Her depression and anxiety symptoms also improved; however, they did not fully resolve and she benefitted from the introduction of escitalopram, initially at 20 mg but ultimately required a dose escalation to 40 mg.
Figure 3 T2-weighted magnetic resonance imaging showing i baseline: prior to the recommencing diet, and ii 12 months after recommencing diet, showing reduction in white matter hyperintensity, particularly in the posterior regions, as indicated by the white arrows. Though rare, PKU is an important cause of preventable neurodevelopmental disability that requires lifelong commitment to Phe restriction.
The literature supports treatment being initiated as early as possible, even before 10 days, in order to minimize neurological damage.
Every 4-week delay in starting treatment has been shown to cause a decline of IQ score by approximately 4 points 1. The most reliable literature suggests they should be treated during the first 12 years of age to prevent cognitive function impairment in PKU Dietary treatment is comprised of three aspects: natural protein restriction, Phe-free- L-amino acid supplements, and low protein food Though central to the treatment, dietary modification remains very challenging for patients and their families, due to cost and impact on quality of life, and despite optimal dietary treatment, outcomes remain suboptimal, hence the ongoing exploration into alternate treatments.
Striking a balance between adequate protein intake and maintaining acceptable Phe levels needs to be individualized to each patient Phe is an essential amino acid for protein synthesis both in childhood and adulthood and is gained through dietary protein intake Traditional treatment of PKU has been to restrict overall dietary protein intake However, as the understanding of PKU neuropathophysiology has unfolded, it has become clear that just keeping Phe levels low does not constitute optimal treatment.
A mainstay of dietary treatment is supplementation with Phe-free L-amino acid supplements. The van Wegberg et al. European Guidelines on Phenylketonuria Diagnosis and Treatment state that supplementation should be evenly administered throughout the day in at least three equal portions to minimize losses of L-amino acids due to oxidation, and to help minimize fluctuations in blood Phe concentrations over a h period 17 , Oral supplementation with LNAAs has been proven to be helpful in reducing brain Phe concentrations via competitive binding at LAT1, which improves neuropsychological functioning , LNAA supplementation either alone or in combination with a low-Phe diet has been shown to improve health outcome for individuals unable to follow the low-Phe diet.
However, long-term outcome studies assessing efficacy and safety of LNAA supplementation are needed Promising developments include van Vliet et al. Additionally, Tyr and Trp in conjunction serve to optimally ameliorate brain monoaminergic neurotransmitter concentrations Dietary modification has continued to evolve to ensure that foods are affordable, palatable, and supplemented with micronutrients otherwise lacking in a low-Phe diet. One such advancement is the utility of glycomacropeptide GMP , an intact protein source derived from cheese whey that improves Phe utilization and protein retention Compliance has been shown to be improved with GMP as compared with traditional amino acid foods due to greater acceptability and fewer gastrointestinal side effects Other supplementation changes include improved caloric content, addition of taurine and other micronutrients, and addition of long-chain polyunsaturated fats LCPUFAs LCPUFAs have been found to be decreased in systematic review and meta-analysis of studies in PKU, likely secondary to dietary restriction and possibly metabolic changes, though the latter is only partially understood , The addition of omega-3 docosahexaenoic acid DHA to the diet of children with PKU has been shown to increase central nervous system processing speed as measured by visual evoked potentials as well as motor and coordination skills, suggesting DHA is an essential part of the treatment of PKU Tetrahydropterin acts as a molecular chaperone in PKU patients and promotes correct folding and stability of the PAH enzyme, thus acting as a critical co-factor in a normal PAH system A subset of patients with PKU benefit from adjunctive treatment with pharmacological doses of tetrahydropterin BH4 or sapropterin hydrochloride Long-term treatment with sapropterin of such responsive patients with PKU also appears to improve Phe tolerance and may allow patients to discontinue highly restrictive diets Patients with high residual activity of the PAH enzyme have a greater probability of BH4 response, but a minority of patients with classical PKU have been shown to benefit from BH4 treatment , Understandably, BH4 responsive patients have been shown to have a higher natural protein tolerance , There is ongoing research required to establish if other molecules in addition to tetrahydrobiopterin may act as chaperones to assist in the folding of PAH; however, there are some promising studies including one by Pey et al, which performed a high-throughput ligand screening of over 1, pharmacological agents, identifying four compounds that enhanced the stability of PAH activity As per Thomas et al.
These studies have evaluated over adults with PKU being treated with Pegvaliase. The PRISM clinical program exemplified that with a manageable self-administration program, patients with PKU were able to achieve sustained reductions in blood Phe concentration, that were associated with sustained improvements in associated neuropsychiatric symptoms Evidence from Vockley et al. Interestingly, studies indicate that while there are patients with PKU suffering from all the sequelae of non-treatment, or poor adherence to treatment, so too there is likely a subset of patients who are over-restricting their protein consumption.
Blood levels of Phe do not necessarily fluctuate with small changes in dietary intake , For those with either late diagnosis or no previous treatment, there is a growing body of evidence that introduction of the low Phe diet and adjunctive treatments will benefit patients and can reverse some of the IQ loss in reported cases, particularly in the younger age group 4 to 6 years old Concerningly, there are high rates of attrition from services, with some services reporting that a majority of adults with PKU were lost to follow-up and, without the support of specialist services, are likely to have suboptimal metabolic control , Accumulating evidence increasingly indicates that improving quality of sleep is an important target for intervention in optimizing the cognitive and psychiatric state of those with PKU.
Bruinenberg et al. Additionally they identified an increased fragmentation and a shift in diurnality, in PKU mice Previously, results of the study by DeGiorgis et al. Surendran et al. Elevated rates of psychiatric illness and cognitive impairment occur in PKU, and their nature and prevalence vary in accordance with the severity of the deficit in PAH function, the degree of dietary treatment, and—perhaps most crucially—the timing of attempts to attenuate the hyperPhe that defines the illness.
Although some of the effects of hyperPhe on monoaminergic function and myelination appear reversible, persistent and prolonged hyperPhe across key neurodevelopmental periods appears to cause permanent alterations to the trajectory of brain development. When this occurs across early periods of neurodevelopment, gross intellectual and behavioral changes occur. While the emerging data show consistent elevations in rates of these disorders, very little data exist on treatment of psychiatric illness, in particular in the setting of PKU.
For some off-diet patients, a return to diet may afford significant improvement in common psychiatric symptoms. It is not known, however, how likely diet alone is to effect a full remission in psychiatric illness; nor is evidence available to guide clinicians on the use of commonly utilized treatments for these disorders—such as antidepressants in mood and anxiety disorders, and stimulants in attentional disorders.
Further evaluation of specific agents in these patient populations is warranted. Early treated individuals with PKU that maintain a strict low Phe diet throughout life are more likely to fulfil their academic potential, without compromise to intellectual functioning.
As a significant number of PKU individuals with cognitive inefficiencies have co-morbid mood and anxiety symptoms, future research should consider looking at the contribution of depression and anxiety on the neuropsychological profile in PKU. It is possible that enhanced psychological and pharmacological treatment of psychiatric symptoms may alleviate subtle cognitive deficits, particularly in the areas of complex attention and speed of information processing. Further research is required to look at the relationship between social cognition, psychological adjustment, and quality of life with optimal illness control.
The evidence available suggests that dietary adherence attenuates, but does not completely eliminate, the elevated risk for psychiatric illness and cognitive impairment in PKU. This may be in part because reductions in Phe down to the levels seen in non-PKU individuals are very difficult to achieve by diet alone; furthermore, the degree of protein restriction required may have other downstream effects on brain structure and function that are not yet clearly understood.
This, along with diet adherence itself, is onerous and often difficult to maintain. Treatment modalities, such as pegvaliase, that do not involve significant dietary restriction may allow PKU patients to have the best of both worlds: a relatively normal diet, free of restriction and stigma, alongside stable mental health and optimal cognitive functioning. MW conceived and provided the methodological framework for the review and completed the manuscript.
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You may opt-out of email communications at any time by clicking on the unsubscribe link in the e-mail. Your in-depth digestive health guide will be in your inbox shortly. You will also receive emails from Mayo Clinic on the latest health news, research, and care. To have an autosomal recessive disorder, you inherit two mutated genes, one from each parent. These disorders are usually passed on by two carriers. Their health is rarely affected, but they have one mutated gene recessive gene and one normal gene dominant gene for the condition.
A defective gene genetic mutation causes PKU, which can be mild, moderate or severe. In a person with PKU, this defective gene causes a lack of or deficiency of the enzyme that's needed to process phenylalanine, an amino acid. These infants may also have a low birth weight and grow more slowly than other children.
Other characteristic medical problems include heart defects or other heart problems, an abnormally small head size microcephaly , and behavioral problems. Women with PKU and uncontrolled phenylalanine levels also have an increased risk of pregnancy loss. The occurrence of PKU varies among ethnic groups and geographic regions worldwide. Most cases of PKU are detected shortly after birth by newborn screening, and treatment is started promptly. As a result, the severe signs and symptoms of classic PKU are rarely seen.
Mutations in the PAH gene cause phenylketonuria. The PAH gene provides instructions for making an enzyme called phenylalanine hydroxylase. This enzyme converts the amino acid phenylalanine to other important compounds in the body. If gene mutations reduce the activity of phenylalanine hydroxylase, phenylalanine from the diet is not processed effectively.
As a result, this amino acid can build up to toxic levels in the blood and other tissues. Because nerve cells in the brain are particularly sensitive to phenylalanine levels, excessive amounts of this substance can cause brain damage.
Classic PKU, the most severe form of the disorder, occurs when phenylalanine hydroxylase activity is severely reduced or absent. People with untreated classic PKU have levels of phenylalanine high enough to cause severe brain damage and other serious health problems. Mutations in the PAH gene that allow the enzyme to retain some activity result in milder versions of this condition, such as variant PKU or non-PKU hyperphenylalaninemia.
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