Are Phe-Free Protein Substitutes Available in Italy for Infants with PKU All the Same?

Breastfeeding or standard infant formulas, alongside phenylalanine (Phe)-free protein substitutes, constitute the dietary management for infants with PKU to guarantee protein requirements are met in compliance with metabolic tolerance. This work aims to analyse the nutritional composition of Phe-free infant protein substitutes, in terms of macronutrients, micronutrients and functional components, available for PKU dietary management in Italy. A total of seven infant Phe-free protein substitutes were included in this review, six powder and one liquid. A second analysis was conducted to compare them to the composition of formulas intended for healthy infants, taking into consideration the Commission Delegated Regulation (EU) 2016/127 and Commission Delegated Regulation (EU) 2016/128 for micronutrients. The analysis revealed heterogeneity among protein substitutes suitable for infants with PKU. The energy and protein equivalents (P.Eq.) content are different; all of the substitutes contain docosahexaenoic acid (DHA) and arachidonic acid (ARA), while eicosapentaenoic acid (EPA), fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), human milk oligosaccharides (HMOs) and nucleotides are not present in all the substitutes. More attention should be paid to these infant products to ensure metabolic control of PKU, and also promote proper growth, cognitive neurodevelopment, favourable gut microbiota composition, and immune system health, while reducing the risk for non-communicable diseases (NCDs).

Quality of life aspects of a low protein diet using GMP in patients with phenylketonuria.

OBJECTIVE: To assess some quality of life (QOL) aspects of a low protein diet, using glycomacropeptide (GMP) as a protein substitute in patients with phenylketonuria (PKU). METHODS: This was a multicentre, prospective observational cohort, study. Metabolic control, nutritional parameters, and dietary adherence were assessed in patients with PKU before (T0), and six months after (T6) starting a low protein diet using GMP. Selected items from the PKU-QOL questionnaire were used to assess patients' acceptance of their modified diet. RESULTS: 18 patients from three Italian Centres, completed the study. With the exception of LDL-cholesterol and vitamin 25OH-D concentrations, there were no differences between T0 and T6 in metabolic or nutritional parameters. Data suggested that patients have a good acceptance of protein substitutes containing GMP, probably because of their improved palatability. CONCLUSIONS: According to our patients' responses to items related to dietary regimen, GMP based protein substitutes do not appear to significantly affect QOL.

Expanded Newborn Screening in Italy Using Tandem Mass Spectrometry: Two Years of National Experience.

Newborn screening (NBS) for inborn errors of metabolism is one of the most advanced tools for secondary prevention in medicine, as it allows early diagnosis and prompt treatment initiation. The expanded newborn screening was introduced in Italy between 2016 and 2017 (Law 167/2016; DM 13 October 2016; DPCM 12-1-2017). A total of 1,586,578 infants born in Italy were screened between January 2017 and December 2020. For this survey, we collected data from 15 Italian screening laboratories, focusing on the metabolic disorders identified by tandem mass spectrometry (MS/MS) based analysis between January 2019 and December 2020. Aminoacidemias were the most common inborn errors in Italy, and an equal percentage was observed in detecting organic acidemias and mitochondrial fatty acids beta-oxidation defects. Second-tier tests are widely used in most laboratories to reduce false positives. For example, second-tier tests for methylmalonic acid and homocysteine considerably improved the screening of CblC without increasing unnecessary recalls. Finally, the newborn screening allowed us to identify conditions that are mainly secondary to a maternal deficiency. We describe the goals reached since the introduction of the screening in Italy by exchanging knowledge and experiences among the laboratories.

Italian national consensus statement on management and pharmacological treatment of phenylketonuria.

BACKGROUND: Phenylketonuria (PKU) is a rare inherited metabolic disorder caused by defects in the phenylalanine-hydroxylase gene (PAH), the enzyme catalyzing the conversion of phenylalanine to tyrosine. PAH impairment causes phenylalanine accumulation in the blood and brain, with a broad spectrum of pathophysiological and neurological consequences for patients. Prevalence of disease varies, with peaks in some regions and countries, including Italy. A recent expert survey described the real-life of clinical practice for PKU in Italy, revealing inhomogeneities in disease management, particularly concerning approach to pharmacotherapy with sapropterin hydrochloride, analogous of the natural PAH co-factor, allowing disease control in a subset of patients. Therefore, the purpose of this paper is to continue the work initiated with the expert survey paper, to provide national guidances aiming to harmonize and optimize patient care at a national level. PARTICIPANTS: The Consensus Group, convened by 10 Steering Committee members, consisted of a multidisciplinary crowd of 46 experts in the management of PKU in Italy. CONSENSUS PROCESS: The Steering Committee met in a series of virtual meeting in order to discuss on clinical focuses to be developed and analyzed in guidance statements, on the basis of expert practice based evidence, large systematic literature review previously performed in the expert survey paper, and evidence based consensus published. Statements were re-discussed and refined during consensus conferences in the widest audience of experts, and finally submitted to the whole consensus group for a modified-Delphi voting. RESULTS: Seventy three statements, divided in two main clinical areas, PKU management and Pharmacotherapy, achieved large consensus in a multidisciplinary group of expert in different aspects of disease. Importantly, these statements involve guidances for the use of sapropterin dihydrochloride, still not sufficiently implemented in Italy, and a set of good practice to approach the use of novel enzyme replacement treatment pegvaliase. CONCLUSIONS: This evidence-based consensus provides a minimum set of guidances for disease management to be implemented in all PKU centers. Moreover, these guidances represent the first statement for sapropterin dihydrochloride use, implementation and standardization in Italy, and a guide for approaching pegvaliase treatment at a national level on a consistent basis.

Dysbiosis, Host Metabolism, and Non-communicable Diseases: Trialogue in the Inborn Errors of Metabolism.

Inborn errors of metabolism (IEMs) represent a complex system model, in need of a shift of approach exploring the main factors mediating the regulation of the system, internal or external and overcoming the traditional concept of biochemical and genetic defects. In this context, among the established factors influencing the metabolic flux, i.e., diet, lifestyle, antibiotics, xenobiotics, infectious agents, also the individual gut microbiota should be considered. A healthy gut microbiota contributes in maintaining human health by providing unique metabolic functions to the human host. Many patients with IEMs are on special diets, the main treatment for these diseases. Hence, IEMs represent a good model to evaluate how specific dietary patterns, in terms of macronutrients composition and quality of nutrients, can be related to a characteristic microbiota associated with a specific clinical phenotype ("enterophenotype"). In the present review, we aim at reporting the possible links existing between dysbiosis, a condition reported in IEMs patients, and a pro-inflammatory status, through an altered "gut-liver" cross-talk network and a major oxidative stress, with a repercussion on the health status of the patient, increasing the risk of non-communicable diseases (NCDs). On this basis, more attention should be paid to the nutritional status assessment and the clinical and biochemical signs of possible onset of comorbidities, with the goal of improving the long-term wellbeing in IEMs. A balanced intestinal ecosystem has been shown to positively contribute to patient health and its perturbation may influence the clinical spectrum of individuals with IEMs. For this, reaching eubiosis through the improvement of the quality of dietary products and mixtures, the use of pre-, pro- and postbiotics, could represent both a preventive and therapeutic strategy in these complex diseases.

Creatine Levels in Patients with Phenylketonuria and Mild Hyperphenylalaninemia: A Pilot Study.

BACKGROUND: Creatine (Cr) levels are strongly dependent on diets, including animal-derived proteins. Cr is an important metabolite as it represents a source of stored energy to support physical performance and potentially sustain positive effects such as improving memory or intelligence. This study was planned to assess Cr levels in PKU children adhering to a diet low in phenylalanine (Phe) content and compared with those of children with mild hyperphenylalaninemia (MHP) on a free diet. METHODS: This retrospective pilot study analyzed Cr levels from Guthrie cards in 25 PKU and 35 MHP subjects. Anthropomorphic and nutritional data of the study populations were assessed, compared and correlated. RESULTS: Cr levels of PKU subjects were significantly lower than those of MHP subjects and correlated to the low intake of animal proteins. Although no deficiencies in PKU subjects were identified, PKU subjects were found to have a 26-fold higher risk of displaying Cr levels <25° percentile than MHP counterparts. CONCLUSIONS: This pilot study suggests that Cr levels might be concerningly low in PKU children adhering to a low-Phe diet. Confirmatory studies are needed in PKU patients of different age groups to assess Cr levels and the potential benefits on physical and intellectual performance of Cr supplementation.

The management of phenylketonuria in adult patients in Italy: a survey of six specialist metabolic centers.

INTRODUCTION: Phenylketonuria (PKU) is a rare autosomal recessive disorder caused by a deficiency of phenylalanine hydroxylase (PAH). Its prevalence is estimated to be 1:10,000 in Europe. PKU is the commonest congenital inborn error of metabolism. The aim of our study was to investigate the characteristics of clinical practice in relation to PKU in Italy, in order to raise awareness about the current management and therapeutic approaches adopted. METHODS: Six Italian experts conducted a systematic literature review as well as an internal survey to investigate the relevant clinical aspects. Collectively, the expert panel managed a total of 678 PKU patients treated in the early stages of the condition over a 16-year period across six centers. RESULTS: The management of PKU varied markedly between centers, with differences in the composition of the multidisciplinary team, dietary treatments, compliance and adherence to management, tetrahydrobiopterin use, and patient follow-up. Patients were mostly managed by a pediatric reference center from the initial PKU diagnosis during newborn screening until adulthood, without transition to a specialized adult clinician. Fogginess, concentration reduction, low attention, anxiety, irritability, memory deficit, headache, and unstable mood were common features in patients with uncontrolled blood phenylalanine levels (generally above 600 µmol/L). CONCLUSION: A homogeneous and shared approach to the management of PKU patients is important. Our survey demonstrates the current management of PKU in Italy, with the aim of promoting the implementation of therapeutic strategies and follow-up, increased patient compliance and adherence, and the achievement of the phenylalanine level targets recommended by European Union guidelines. Emerging therapies are likely to become a standard treatment for patients unable to comply with diet therapy and maintain their phenylalanine levels below the threshold values.Supplemental data for this article is available online at https://doi.org/10.1080/03007995.2020.1847717.

Children with special health care needs attending emergency department in Italy: analysis of 3479 cases.

BACKGROUND: Although children with special health care needs (CSHCN) represent a minority of the population, they go through more hospitalizations, more admissions to the Emergency Department (ED), and receive a major number of medical prescriptions, in comparison to general pediatric population. Objectives of the study were to determine the reasons for admission to the ED in Italian CSHCN, and to describe the association between patient's demographic data, clinical history, and health services requirements. METHODS: Ad hoc web site was created to collect retrospective data of 3479 visits of CSHCN to the ED in 58 Italian Hospitals. RESULTS: Seventy-two percent of patients admitted to ED were affected by a previously defined medical condition. Most of the ED admissions were children with syndromic conditions (54%). 44.2% of the ED admissions were registered during the night-time and/or at the weekends. The hospitalization rate was of 45.6% among patients admitted to the ED. The most common reason for admission to the ED was the presence of respiratory symptoms (26.6%), followed by gastrointestinal problems (21.3%) and neurological disorders (18.2%). 51.4% of the access were classified as 'urgent', with a red/yellow triage code. Considering the type of ED, 61.9% of the visits were conducted at the Pediatric EDs (PedEDs), 33.5% at the Functional EDs (FunEDs) and 4.6% at the Dedicated EDs (DedEDs). Patients with more complex clinical presentation were more likely to be evaluated at the PedEDs. CSHCN underwent to a higher number of medical procedures at the PedEDs, more in comparison to other EDs. Children with medical devices were directed to a PedED quite exclusively when in need for medical attention. Subjects under multiple anti-epileptic drug therapy attended to PedEDs or FunEDs generally. Patients affected by metabolic diseases were more likely to look for medical attention at FunEDs. Syndromic patients mostly required medical attention at the DedEDs. CONCLUSIONS: Access of CSHCN to an ED is not infrequent. For this reason, it is fundamental for pediatricians working in any kind of ED to increase their general knowledge about CHSCN and to gain expertise in the management of such patients and their related medical complexity.

Nutrition, Microbiota and Role of Gut-Brain Axis in Subjects with Phenylketonuria (PKU): A Review.

The composition and functioning of the gut microbiota, the complex population of microorganisms residing in the intestine, is strongly affected by endogenous and exogenous factors, among which diet is key. Important perturbations of the microbiota have been observed to contribute to disease risk, as in the case of neurological disorders, inflammatory bowel disease, obesity, diabetes, cardiovascular disease, among others. Although mechanisms are not fully clarified, nutrients interacting with the microbiota are thought to affect host metabolism, immune response or disrupt the protective functions of the intestinal barrier. Similarly, key intermediaries, whose presence may be strongly influenced by dietary habits, sustain the communication along the gut-brain-axis, influencing brain functions in the same way as the brain influences gut activity. Due to the role of diet in the modulation of the microbiota, its composition is of high interest in inherited errors of metabolism (IEMs) and may reveal an appealing therapeutic target. In IEMs, for example in phenylketonuria (PKU), since part of the therapeutic intervention is based on chronic or life-long tailored dietetic regimens, important variations of the microbial diversity or relative abundance have been observed. A holistic approach, including a healthy composition of the microbiota, is recommended to modulate host metabolism and affected neurological functions.

Neonatal malpractice claims in Italy: how big is the problem and which are the causes?

Medical errors are topics of increasing importance in neonatology. Very few data are available on neonatal malpractice claims. We report the first data obtained in Italy on neonatology regarding a wide population study during a 6-year survey. Data concerning 191 claims regarding delivery room (n = 77; 38.74%), nursery (n = 72; 37,69%), NICU (n = 42; 21,98%) and the transport system (n = 3; 1.57%) are presented and discussed. On data allow an analysis of main causes and suggest how to face the problem.