Phenylketonuria (PKU) is a rare inherited metabolic disorder (IMD) caused by a deficiency in the phenylalanine (Phe) hydroxylase (PAH) enzyme, impairing the conversion of the amino acid Phe to tyrosine. The incidence of PKU in Europe is around 1/10,000–1/15,000 births, but it is higher in some countries, including Italy, where it reaches 1/4500 [1]. Deficiency of the hepatic PAH leads to a broad spectrum of hyperphenylalaninemia (HPA). HPAs are classified according to the treatment options: non-PKU HPA (Phe concentration ranging from 120 to 360 μmol/L) and PKU HPA (blood Phe concentration > 360 μmol/L) [2, 3]. The consequent accumulation of Phe to toxic concentrations in the brain results in severe clinical, neuropsychological, neurophysiologic, biochemical, and imaging alterations in untreated patients [4,5,6,7]. In particular, high Phe levels (> 600 μmol/L) could be associated with different neurotransmitters deficits and white matter alterations [8]. Thanks to the neonatal screening for PKU, patients can be treated in their early days while growing up, thus avoiding severe neurological deficits. However, a relevant percentage of patients treated early in their childhood still exhibit subtle cognitive deficits and psychosocial alterations in adulthood [9, 10]. In PKU patients treated early, prolonged high levels of Phe, particularly in adolescence, could negatively impact the individual’s cognitive functions [7, 11]. Unfortunately, nowadays, the chance of a pre-screening patient with a severe cognitive deficit arriving at the center is still possible.
There is a large consensus about the importance of analyzing the impact of neurocognitive deficits in PKU patients; however, it seems difficult to define a standardized and systematic neurocognitive patient assessment, as this strictly depends on age and severity of deficits [12].
The first-line treatment of PKU is based on a low Phe diet in combination with a protein substitute (mixtures of amino acids Phefree). Adherence to diet commonly decreases from childhood to adulthood; this event should be avoided, as hyperphenylalaninemia also impacts the adult brain [13, 14].
Until 2018, the only pharmacological therapy approved for PKU was the supplementation of tetrahydrobiopterin (BH4), an enzymatic co-factor of PAH. The tetrahydrobiopterin drug (Kuvan®) is the oral form of sapropterin dihydrochloride [15]. BH4 is not available worldwide, and only a proportion (estimated 30%) of PKU patients can respond to this treatment [16]. In 2018 and 2019, the US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) approved pegvaliase (Palynziq®, BioMarin Pharmaceutical), respectively; pegvaliase is a pegylated recombinant Anabaena variabilis-derived Phe ammonia lyase able to reduce blood Phe concentration by substituting for Phe hydroxylase and converting Phe to ammonia and trans-cinnamic acid [17]. With pegvaliase, approved for patients ˃ 16 years old and with Phe levels > 600 μmol/L, patients can follow a diet with an amount of protein intake meeting the recommended dietary intake for the general population and even liberalize their diet [18, 19].
Outcomes in PKU and available tools for the assessment
Cognitive functions
Several single and multicenter studies showed that children, adolescents, and adults with PKU, even if treated from birth, may exhibit deficits in several domains [20,21,22,23], mainly executive functions (CFx) and attention [24,25,26,27]. CFx are responsible for goal-directed or future-oriented behavior, including initiating activity, impulse control, self-regulation, working memory, mental flexibility, planning, and organization ability [28]. The most consistent impairments of CFx in PKU patients have been observed in working memory, sustained attention, and inhibitory control [10, 29]. However, the degree of deficits and impairments broadly vary among different studies [10, 30]. This may be due to researchers' different ways of conceptualizing CFx and employing various CFx assessment tasks [31].
Several neuropsychological tests are available to assess cognitive performance in PKU patients but finding the best tool for the specific patient and impairment is not trivial, as no standard method for PKU patients exists. On the one hand, intellectual quotient (IQ) evaluation usually provides a reliable assessment of general cognitive functioning; on the other, it is not sensitive enough to detect minor neurocognitive dysfunctions [32]. As neuropsychological and behavioral alterations in PKU are heterogeneous in terms of degree and domains impaired, it is essential to identify the right tool for the right patient (according to the phenotype and age). Moreover, identifying a tool/pool of tools able to assess the overall burden of illness of PKU patients is crucial [33].
The central issue in assessing CFx in PKU populations is the lack of consistent use of valid and sensitive tests suitable for both children and adults [29]. Moreover, many traditional CFx tasks depend on multiple cognitive processes and show significant variability in the results. In the future, it will be essential to define a specific set of neuropsychological tasks to be used across international PKU centers [10, 14].
Quality of life, emotional and behavioral symptoms in PKU
PKU is associated with an increased incidence of emotional and behavioral problems [34,35,36] that could impair the Quality of Life (QoL) of patients [11]. Children and adults with PKU show emotional troubles such as low self-esteem, lower achievement motivation, decreased autonomy and reduced social competence. In contrast, adolescents and adults tend to have mood and anxiety disorders and social isolation [11, 37,38,39]. Patients with PKU often avoid meeting with friends, traveling, and performing sports, and recreational activities, with a significant impact on their QoL [40]. The management of a PKU patient should include an emotional and behavioral assessment and be aimed at identifying psychiatric disorders to allow for early treatment. The presence of emotional and behavioral troubles in PKU patients is possibly the consequence of growing up and living with a chronic disease [39].
Despite the evidence mentioned above, studies assessing the QoL of PKU patients provided conflicting results; in some cases, the results were similar to those of the general population [41,42,43]. In others, the studies showed a worsening of this parameter [44, 45]. Future studies, as recommended by European (EU) guidelines [14], should use the recently developed PKU-QoL questionnaire that is specifically designed to detect the impact of PKU on all aspects of a patient's life [46, 47].
Neurological outcome
Neurological signs (i.e., tremor, spastic paraparesis, and ataxia) are described in approximately 90% of untreated PKU patients and in a high proportion of late-treated PKU patients [48]. However, also in early treated PKU patients, some neurological signs, such as brisk tendon reflexes, clumsy motor coordination, and tremor, are frequently reported [47,48,49]. More recently, in a cohort of French adult PKU patients, the incidence of neurological complications has accounted for 5.1% [50].
Neuroimaging studies revealed that early-treated PKU adults exhibit a wide range of brain abnormalities, mostly related to white matter involvement [9]. Most patients exhibit mild to moderate white matter hyperintensities with no cortical atrophy or gray matter lesions [8, 9]. The degree of white matter alterations has been associated with mean Phe levels, but there are contradicting data addressing the relationship between dietary adherence and the severity of brain abnormalities [9]. No studies show a strict correlation between the degree of burden of white matter hyperintensities and the severity of cognitive or behavioral abnormalities, making magnetic resonance imaging (MRI) assessment questionable, except in a research setting. Nevertheless, the paper by Jaulent and colleagues recently showed that in a limited number of patients, who resumed or initiated a low-Phe diet, there was a partial/total regression of white matter abnormalities [50].
Indeed, the conventional brain MRI [(FLAIR/T2-weighted imaging and diffusion-weighted imaging (DWI)] is a powerful, readily available, noninvasive tool for detecting brain changes in PKU patients [9]. In line with this, EU guidelines and the Italian national consensus statement on management and pharmacological treatment of PKU suggest that neuroimaging examinations should be reserved only for those patients presenting with an atypical clinical course and/or unexpected neurological deficits, or for research purposes [3, 14].
Aim
Available scientific literature highlights the importance of a specific neurocognitive, psychopathological, and neurological assessment in PKU [9].
The different degrees of neurological and behavioral abnormalities of early-treated PKU patients (especially adults) are still debated, and the choice of the “best” neurocognitive test, sensitive to high levels of Phe, remains a challenge. To make things more complicated, a remarkable interindividual variability in the cognitive outcome and an inconsistent correlation between cognitive performances and biochemical control have been observed, suggesting the presence of an individual resilience or vulnerability to Phe in young early-treated adults [51].
Therefore, there is a significant need to reach an agreement on an appropriate set of tests according to the age of patients. The tasks should be suitable for use in everyday clinical practice. To fill this gap, a multidisciplinary group of Italian experts in the PKU field has assembled to propose a more comprehensive neurocognitive, psychopathological, and neurological assessment of PKU patients based on the existing literature and their clinical experience.
