Italian national consensus statement on management and pharmacological treatment of phenylketonuria

Abstract

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.

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

“…Visits are scheduled according to the age and needs of the patient. Neurological examinations should be performed repeatedly in children and adolescent, whereas, for adults, the guidelines suggest at least once a year in the absence of complications [ 3 ]. The frequency of the neurocognitive follow-up is increased according to the patient’s clinical and life conditions (causing clinical worsening/poor therapeutic compliance/comorbidity).…”

“…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 ].…”

Real-world use of orphan medicinal products (OMPs) in rare disease (RD) patients: A population-based registry study

“…The therapeutic landscape for this disease has dramatically changed in recent years and now includes different therapeutic options, to be used in a variety of combinations, according to the patient's clinical profile. Besides medical foods, these include two approved OMPs, sapropterin and, more recently, pegvaliase (Burlina et al, 2021). Another example is spinal muscular atrophy, the most common genetic cause of death in infancy.…”

From PKU Online Lessons for Dietetics Students to the PKU Sandwiches Album

“…A PKU diet might also constitute a major obstacle in patients' establishment of meaningful social relationships [20]. However, certain patients with PKU (mainly with a mild form of PKU) are responsive to treated with cofactor tetrahydrobiopterin (BH4) [16,21,22], but till now not refunded in Poland. Since the majority of Polish PKU patients suffer from a classic type of PKU characterized by a very low Phe tolerance, i.e., 200-250 mg Phe/day, a monitored intake of Phe-sourced from fruits and vegetables-is advisable.…”