Expert opinion of an Italian working group on the assessment of cognitive, psychological, and neurological outcomes in pediatric, adolescent, and adult patients with phenylketonuria

Manti et al. Orphanet Journal of Rare Diseases https://doi.org/10.1186/s13023-022-02488-2 (2022) 17:443 Open Access POSITION STATEMENT Expert opinion of an Italian working group on the assessment of cognitive, psychological, and neurological outcomes in pediatric, adolescent, and adult patients with phenylketonuria Filippo Manti1, Stefania Caviglia2, Chiara Cazzorla3, Annamaria Dicintio4, Andrea Pilotto5 and Alessandro P. Burlina6*    Abstract Phenylketonuria (PKU) is an inherited metabolic disease characterized by a defective conversion of phenylalanine (Phe) to tyrosine, potentially leading to Phe accumulation in the brain. Dietary restriction since birth has led to normal cognitive development. However, PKU patients can still develop cognitive or behavioral abnormalities and subtle neurological deficits. Despite the increasing evidence in the field, the assessment of neurocognitive, psychopathological, and neurological follow-up of PKU patients at different ages is still debated. The high interindividual variability in the cognitive outcome of PKU patients makes the specificity of the neurocognitive and behavioral assessment extremely challenging. In the present paper, a multidisciplinary panel of Italian PKU experts discussed different tools available for cognitive, psychopathological, and neurological assessment at different ages based on the existing literature and daily clinical practice. This study aims to provide evidence and a real-life-based framework for a specific clinical assessment of pediatric, adolescent, and adult patients affected by PKU. Keywords: Phenylketonuria, Quality of life, Follow-up, Psychology, Neurology, Brain magnetic resonance imaging, Expert opinion Background 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 *Correspondence: 6 Neurology Unit, St. Bassiano Hospital, Bassano del Grappa, Italy Full list of author information is available at the end of the article 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 [4–7]. 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 © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Manti et al. Orphanet Journal of Rare Diseases (2022) 17:443 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 [20–23], mainly executive functions (CFx) and attention [24–27]. CFx are responsible for goal-directed or futureoriented 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, Page 2 of 9 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’ differ (...truncated)