The Effects of Phenylketonuria on Physical, Cognitive, and Behavioral Development


This paper examines the genetic disorder Phenylketonuria (PKU), in which there is an inability to metabolize the amino acid phenylalanine into the amino acid tyrosine, which is necessary for proper brain development. Elevated levels of phenylalanine are damaging to many parts of the brain and body. Physical effects of the disorder involve a short stature in childhood, a tendency to be overweight—primarily in treated individuals, and a decreased head circumference. Mental retardation can occur in untreated individuals with PKU, but even treated individuals can have deficits in specific cognitive constructs, especially processing speed.

Components of executive functioning can also be impaired. In society, people with PKU experience a struggle to choose between their health and a normal social life. Behavioral abnormalities for children in middle childhood with phenylketonuria include easy distraction, lower persistence, decreased responsive energy, and unpredictable actions. The behavior for individuals with PKU is also strayed from normalcy by their increased susceptibility to psychiatric disorders, even in treated people.

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In prenatal maternal PKU, the escalated levels of phenylalanine are extremely damaging to the overall health of the fetus.

Keywords: Phenylketonuria, developmental effects, maternal PKU


Phenylketonuria (PKU) is a genetic disorder characterized by the inability to convert the amino acid phenylalanine into the amino acid tyrosine, leading to hyperphenalaninemia, escalated levels of phenylalanine in the blood; it affects approximately one livebirth for every 15,000 in the USA (Blau, 2010). Phenylalanine enters the body through dietary proteins, so the treatment involves a strict diet to limit the intake of the amino acid (Kalat, 2016).

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Generally, people with PKU cannot handle more than 250 mg of phenylalanine per day; however, the variable tolerance is often used to classify the severity of the disorder (Blau, 2010). Differences in blood phenylalanine levels before treatment divide the disorder into three groups: mild hyperphenylalaninemia (120-600 μmol/L), mild phenylketonuria (600-1200 μmol/L), and classic phenylketonuria (higher than 1200 μmol/L), while the normal individual has a blood phenylalanine level between 50-110 μmol/L (Blau, 2010). Even with treatment, the rare genetic disorder phenylketonuria is linked to a variety of cognitive deficits, physical abnormalities, and unusual social behaviors, including psychiatric disorders.

Physical Effects

Individuals with untreated phenylketonuria often exemplify physical symptoms of the disorder including a short stature, decreased head size, and abnormal weight. Many of the studies linking physical abnormalities to PKU are decades old since these effects are easier to measure compared to mental ones and have remained consistent over time. Additionally, treatment options were extremely limited or stopped early, so results of phenylketonuria were visual and unavoidable.

A study conducted in the late 1960s measured heights and head circumferences for both children who were treated for phenylketonuria and for those who were not (Holm & Knox, 1979). For untreated and treated children with PKU, there were statistically significant depressions in head circumference and short statures (Holm & Knox, 1979). Additionally, there is a statistically significant difference in both physical effects between untreated and treated children, demonstrating the effectiveness of PKU treatment (Holm & Knox, 1979). For example, when measuring head circumference, of the 37 treated children with phenylketonuria, only one was in the range of microcephaly, while eleven of the 47 untreated individuals where in the range (Holm & Knox, 1979). Because of the time period, much of the research was collected while the individuals with phenylketonuria were institutionalized (Holm & Knox, 1979). Unfortunately, some of the data may have been skewed due to the detrimental environment in which the children with PKU were tested.

In order to attribute findings to the correct variable, Holm, Kronmal, Williamson, and Roche conducted more research pertaining to not only height and head circumference, but also weight (1979). Results of the study indicate that individuals with PKU generally have a shorter stature for the first few years of life, but height at the end of the growth period is consistent with the normal population and dependent on environment (Holm et. al., 1979).

Additionally, individuals with phenylketonuria tend to be in a higher percentile for weight compared to their age and sex, which can be explained by the necessary abnormal food behaviors and possible parental pressure to ensure a child has received the proper food intake (Holm et. al., 1979). In relation to head size, girls who were treated for PKU had statistically significant depressions in head circumference (Holm et. al., 1979). Without a doubt, there are physical effects that phenylketonuria has on individuals. They often will exhibit smaller head circumferences—more prominent in females, an initially short stature which will eventually develop into normal height, and a slight tendency to be overweight in individuals who are treated for PKU. Fortunately, many physical symptoms are lessened through treatment, allowing individuals with phenylketonuria to experience a normalcy in physicality.

Cognitive Effects

Phenylketonuria is associated with a variety of cognitive deficits and disorders. The most worrisome cognitive damage for parents of children with PKU is the possibility of mental retardation. Mental retardation occurs in people with phenylketonuria because extremely high levels of phenylalanine become toxic to the brain causing irreparable brain damage (Widaman, 2009). The decline is so extreme that being untreated with phenylketonuria for the first two years of life can potentially lead to severe mental retardation with a mean IQ of 50 (Widaman, 2009). However, the damage to the brain is not immediate; if the blood phenylalanine levels remain high (> 600 μmol/L) for a certain period of time, generally around a few weeks, no more than a month, serious cognitive deficits can occur (St. Germain, 2018). Unfortunately, even chronic moderately high levels (240-360 μmol/L) can lead to less severe cognitive damage, such as learning disabilities and slightly lower IQs (St. Germain, 2018). A variety of cognitive constructs have been negatively associated with phenylketonuria, possibly due to memory insufficiencies.

According to Romani, MacDonald, De Felice, and Palermo, the cognitive components most often linked to phenylketonuria when treated are executive functioning tasks and processing speed (2018). In studies conducted comparing adults with PKU (AwPKU) to a control group, over and over again, research demonstrates that people with PKU have slower processing speeds, measured through response times (Romani et. al., 2018). Slower processing speeds are also present in adolescents who stopped treatment recently, but had been continuously treated from birth (Moyle, Fix, Bynevelt, Arthur, Burnett, 2007). Romani et. al.’s research hypothesized that AwPKU may suffer from an overarching speed deficit, meaning slower processes in any component of cognition (2018). However, the study found that not all language tasks had the same delays in response time; processing speed decreased as the verbal tasks became more linguistic, from picture naming, to word naming, and then to non-word naming (Romani et. al., 2018).

Although, visuo-spatial attention was determined to be related early-in-life blood phenylalanine levels (Romani et. al., 2018). This research established the important difference between visuo-spatial processing speed and language processing speed; of which, only visuo-spatial tasks were associated with hyperphenylalaninemia. Additionally, the studies indicated that cognitive deficits associated with phenylketonuria are not uniform—they exhibit a property of specificity in which individual components of cognition are adversely affected by the disorder. Moyle et. al. established a possible reasoning behind the slower processing speed: increased concentrations of phenylalanine affect the process of myelination (2007). Because the fatty myelin sheath surrounding the axon allows impulses to travel faster to the presynaptic terminals of the neuron, the reduction of myelin production could be at fault, since messages within the central nervous system would be sent slower.

Many studies have focused on specific cognitive constructs in order to establish a link between them and phenylketonuria. A study conducted by Jahja et. al. established a connection between daily life executive functions and blood phenylalanine levels (2017). Additionally, research exemplified a reduction of efficiency on tests involved with perception and intelligence, specifically the Perceptual Organization Index (POI) and the Wechsler Adult Intelligence Scale Third Edition (WAIS-III) (Moyle et. al., 2007). The majority of these cognitive deficits is either due to a slower processing speed or contributes to a slower processing speed. Because of this, some tests of intelligence and cognitive abilities are less accurate when comparing people with PKU to the general population because they consist of a time component, unless response time is considered to be a measure of intelligence (Romani et. al., 2018). In addition to processing speed, cognitive deficits associated with phenylketonuria include struggles of planning, decision-making, cognitive flexibility, intelligence, and the integration of perception into the brain.

While many cognitive constructs may be damaged by the effect hyperphenylalaninemia has on dopamine availability and white matter deterioration, there is new research which may place blame onto new systems in the body (Romani et. al., 2018). Current studies investigate the excitatory neurotransmitter glutamate and its two main ionotropic receptors in the central nervous system, which are involved in learning and memory (Kalat, 2016). Glutamate receptor NMDA allows for calcium ions to enter the neuron which sets off a chain of events releasing a particular protein involved in regulating gene expression at the nucleus (Kalat, 2016). This process demonstrates the necessity of the glutamate NMDA receptor in the memory system; this series of reactions is the biological mechanism for learning.

In order to study the reasoning behind the development of mental retardation in people with phenylketonuria, researchers found a connection between NMDA receptors and elevated levels of phenylalanine (Glushakov et. al., 2002). Glycine-binding sites can regulate the functioning of NMDA receptors through various amino acids; phenylalanine is known to be an amino acid which suppresses the current of NMDA receptors (Glushakov et. al., 2002). Since individuals with phenylketonuria have escalated levels of phenylalanine, when the amino acid competes for the glycine-binding site, it wins more often (Glushakov et. al., 2002). Therefore, research done by Glushakov et. al. establishes a strong connection between mental retardation in PKU and the NMDA glutamate receptor (2002). This specific study only emphasizes mental retardation in association with phenylketonuria; however, further research could connect the NMDA receptor to other cognitive deficits in PKU.

Behavioral Effects

Because each and every construct in life is viewed and analyzed most accurately through a biopsychosocial perspective indicating the inclusion of biology, psychology, and social interactions, phenylketonuria is not only associated with physical and cognitive abnormalities, but also behavioral differences. These behaviors include the perception of fitting into a personal society by individuals with PKU, and components of temperament. One study conducted by the University of Milan interviewed 47 individuals with phenylketonuria emphasizing an interest in the emotional response to the disorder, the personal understanding of the disorder, the significance of the disorder in social situations, and the perception of the future with the disorder (Vegni, Fiori, Riva, Giovannini, Moja, 2010). Research suggests that one of the most frustrating results of the disorder is deciding between health and social acceptance (Vegni et. al., 2010). Psychologists have identified humans as “the social animal,” so it is no wonder the threat of being ostracized in society is extremely difficult to manage for individuals suffering from phenylketonuria.

Another study conducted in the mid-80s by David P. Schor involved parental ratings relating to behavioral elements of temperament (1986). Parents of children with PKU completed the Middle Childhood Temperament questionnaire, which consisted of 99 questions pertaining to various temperament factors for which the parent could rate his or her child’s behavior as “almost never” (equivalent to a zero) through “almost always” (equivalent to a six) (Schor, 1986). The most prevalent differences, in comparison to children aged 8 through 12 without phenylketonuria, included easy distraction, unpredictable behavior, lower perseverance, and decreased responsive energy for children in the same age range with PKU (Schor, 1986). The chart below demonstrates the contrast and operationally defines the tested temperament constructs.

Psychiatric Disorders

At the blood-brain barrier (BBB), phenylalanine competes with serotonin and other bodily chemicals to enter the central nervous system (Kalat, 2016). Serotonin is a neurotransmitter involved in mood regulation, and a lack of this transmitter is linked to anxiety and depression (Kalat, 2016). Therefore, individuals with phenylketonuria are at an increased risk for psychiatric disorders, since phenylalanine, at such high levels, becomes no match for serotonin at the BBB (Kalat, 2016). One study separated individuals with PKU into three groups and compared their symptoms of psychological disorders: untreated individuals, early-treated individuals in childhood or adolescence, early-treated individuals in adulthood (Brumm, 2009).

Untreated individuals exemplified behaviors as severe as psychotic symptoms and autistic symptoms (Brumm, 2009). Additionally, they demonstrated an increased aggression, which is strengthened by the fact that serotonin turnover is negatively correlated with aggression (Brumm, 2009; Kalat, 2016). However, all three groups exhibited a few overlapping symptoms of psychiatric disorders including a depressed mood, anxiety, low self-esteem, and impaired social skills (Brumm, 2009). Unfortunately, this research concludes that even individuals who are treated for phenylketonuria are more susceptible to psychiatric disorders relative to the general population, unless treatment allows for phenylalanine levels to return to normal. However, the symptoms for treated individuals will likely be much less intense than in untreated individuals.


If an individual with phenylketonuria becomes pregnant, not only does she risk passing on the gene for PKU, but also, the high blood phenylalanine levels can negatively impact the fetus. In the mid-80s, research was conducted under the Maternal PKU Collaborative (MPKUC) study which involved monitoring the blood phenylalanine levels in mothers with phenylketonuria and promoting strict PKU-friendly diets during pregnancy (Widaman, 2009). Because some mothers found it difficult to maintain the diet and the researchers tracked blood phenylalanine levels at each prenatal appointment, the study was able to assess the intelligence of the offspring through various tests and compare the results to the maternal phenylalanine levels (Widaman, 2009). The David Wechsler’s intelligence test for children (WISC) exemplified a negative correlation between offspring intelligence and average maternal phenylalanine levels during pregnancy (Widaman, 2009). It is also necessary to mention the adverse way in which intelligence changes in these offspring.

Apparently, the negative correlation becomes stronger as the children grow older, explained through the comparison of intelligence tests for the same children at ages one and seven (Widaman, 2009). The phenylalanine acts similarly to any other teratogen in the prenatal environment, which is supported by the nearly identical appearance and cognitive profile in babies born from maternal PKU and babies born with fetal alcohol syndrome (FAS) (Waisbren, 1999). Research demonstrates the most prominent effect of all teratogens on newborns involves an impairment of memory and language processing (Waisbren, 1999). However, treatment during pregnancy can greatly reduce the risk of negative outcomes for the fetus, but many women struggle to follow through on the diet or fail to begin at conception (Waisbren, 1999). The chart below provides a visual for the neonatal abnormalities associated with maternal phenylketonuria.


Phenylketonuria is associated with a wide variety of developmental delays including physical, cognitive, and behavioral factors. Although there are a large variety of possible negative side effects of phenylketonuria, continuous treatment greatly minimizes the risk of developing them, allowing these individuals to live a relatively normal life. Because untreated PKU yields severe negative consequences but it is easily treated, phenylketonuria was the reason behind the initiation of neonatal screening (St. Germain, 2018). Modern treatments include a combination of strict dieting, medical foods altered to reduce protein, gene therapy, and the medication Kuvan designed to stimulate an enzyme to reduce blood phenylalanine levels (PKU Medical Guidelines, 2017).

Generally, each individual with PKU must tailor his or her own treatment plan to himself or herself in order to keep blood phenylalanine levels within the recommended range of 120-360 μmol/L (Vegni et. al., 2010; PKU Medical Guidelines, 2017). As recently as thirty years ago, most treatment for PKU was terminated once an individual had turned one year old, because it was thought that he or she would grow out of phenylketonuria; however, in the modern world, PKU is recognized as a lifetime disorder (St. Germain, 2018). While this may appear overwhelming for individuals with the diagnosis, phenylketonuria is becoming much more manageable as the modern world is rapidly developing new technology and conducting medical research.

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The Effects of Phenylketonuria on Physical, Cognitive, and Behavioral Development. (2022, May 05). Retrieved from

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