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Background Lysosomal storage diseases (LSDs) are inborn errors of metabolism resulting from 50 different inherited disorders. The increasing availability of treatments and the importance of early intervention have stimulated newborn screening (NBS) to diagnose LSDs and permit early intervention to prevent irreversible impairment or severe disability. We present our experience screening newborns in North East Italy to identify neonates with Mucopolysaccharidosis type I (MPS I) and Pompe, Fabry, and Gaucher diseases. Methods Activities of acid β-glucocerebrosidase (ABG; Gaucher), acid α-glucosidase (GAA; Pompe), acid α-galactosidase (GLA; Fabry), and acid α-L-iduronidase (IDUA; MPS-I) in dried blood spots (DBS) from all newborns during a 17-month period were determined by multiplexed tandem mass spectrometry (MS/MS) using the NeoLSD ® assay system. Enzymatic activity cutoff values were determined from 3500 anonymous newborn DBS. In the screening study, samples were retested if the value was below cutoff and a second spot was requested, with referral for confirmatory testing and medical evaluation if a low value was obtained. Results From September 2015 to January 2017, 44,411 newborns were screened for the four LSDs. We recalled 40 neonates (0.09%) for collection of a second DBS. Low activity was confirmed in 20, who had confirmatory testing. Ten of 20 had pathogenic mutations: two Pompe, two Gaucher, five Fabry, and one MPS-I. The incidences of Pompe and Gaucher diseases were similar (1/22,205), with Fabry disease the most frequent (1/8882) and MPS-I the rarest (1/44411). The combined incidence of the four disorders was 1/4411 births. Conclusions Simultaneously determining multiple enzyme activities by MS/MS, with a focus on specific biochemical markers, successfully detected newborns with LSDs. The high incidence of these disorders supports this screening program.

Background: Lysosomal storage disorders (LSDs) are rare inherited metabolic diseases characterized by defects in lysosomal enzyme function or membrane transport. These defects lead to substrate accumulation and multisystemic manifestations. This review focuses on gastrointestinal (GI) involvement in LSDs, which is a significant but often overlooked aspect of these disorders. Methods: A comprehensive literature review was conducted to examine the pathophysiology, clinical presentation, diagnosis and management of GI manifestations in several LSDs, including Fabry disease, Gaucher disease, Pompe disease, Niemann–Pick disease type C, mucopolysaccharidoses and Wolman disease. Results: The pathogenesis of GI involvement in LSDs varies and encompasses substrate accumulation in enterocytes, mesenteric lymphadenopathy, mass effects, smooth muscle dysfunction, vasculopathy, neuropathy, inflammation and alterations to the microbiota. Clinical presentations range from non-specific symptoms, such as abdominal pain, diarrhea and malabsorption, to more severe complications, such as protein-losing enteropathy and inflammatory bowel disease. Diagnosis often requires a high level of suspicion, as GI symptoms may precede the diagnosis of the underlying LSD or be misattributed to more common conditions. Management strategies include disease-specific treatments, such as enzyme replacement therapy or substrate reduction therapy, as well as supportive care and targeted interventions for specific GI complications. Conclusions: This review highlights the importance of recognizing and properly managing GI manifestations in LSDs to improve patient outcomes and quality of life. It also emphasizes the need for further research to develop more effective treatments for life-threatening GI complications associated with these rare genetic disorders.

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.

3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is a metabolic disorder with a wide clinical spectrum ranging from asymptomatic individuals to severe metabolic decompensation. Following the introduction of expanded newborn screening, a high number of asymptomatic individuals with 3-MCCD were identified, prompting debates about its inclusion in screening panels. In order to inform policy and healthcare decisions regarding the inclusion of 3-MCCD in newborn screening programs, we evaluated the long-term outcomes for newborns with positive results over a decade of screening experience in North-East Italy, as well as the psychological impact on their parents. Of the 336,668 newborns screened between 2014 and 2025, 9 were confirmed to be affected. These infants underwent annual clinical and biochemical assessments, including dried blood spot acylcarnitine profile, plasma free carnitine, and urinary organic acids assays. An emergency protocol was provided to all affected children to manage intercurrent illnesses. An ad hoc survey was developed to assess the psychological impact of the disease on parents. During follow-up (mean age at last visit: 4.2 years), one patient experienced metabolic decompensation during an intercurrent illness, which was promptly treated. One patient presented with growth retardation and another with transient psychomotor delay. Five patients developed carnitine deficiency, requiring supplementation. Psychological assessments revealed an initial high level of parental psychological impact, which decreased over time. All parents strongly supported the screening program. Newborn screening for 3-MCCD enabled the early identification and management of affected individuals, thereby avoiding severe metabolic decompensation. Although there is an initial psychological burden on parents, it significantly decreases over time. Therefore, the long-term benefits of newborn screening for 3-MCCD seem to outweigh the psychological drawbacks.

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.

Background: Phenylketonuria (PKU) is a rare metabolic disorder requiring lifelong dietary treatment. Adolescents and young adults face unique challenges in managing the condition, often compromising adherence and psychological well-being. This study aimed to explore coping strategies used by patients to manage their condition and their associations with dietary adherence, PKU-related symptoms, and quality of life (QoL) in young individuals with PKU. Methods: A cross-sectional study was conducted with 21 adolescents and young adults (13–25 years) with classical PKU, followed at the Unit of Inherited Metabolic Diseases in Padua, Italy. Participants completed questionnaires assessing dietary adherence, QoL, and coping. Biochemical data were collected from medical records. Results: Only 57.1% fully adhered to the diet; social barriers like embarrassment and school/work environments hindered adherence. Adolescents reported more irritability and concentration difficulties, while young adults reported greater fatigue. QoL was moderately impacted. Avoidance coping was more frequent in young adults and correlated with irritability and lower QoL. Transcendence-oriented coping was linked to fewer insomnia symptoms. Conclusions: Coping strategies influence symptom experience and QoL in PKU. Integrating psychological support and personalized care into routine treatment is essential to improve adherence and support patients through the transition to adulthood.

Background Phenylketonuria (PKU) is a rare inborn error of metabolism affecting the catabolism of phenylalanine (Phe). To date, findings regarding health-related quality of life (HRQoL) in adults with early-treated classical PKU are discrepant. Moreover, little is known about metabolic, demographic, and cognitive factors associated with HRQoL. Hence, we aimed to investigate HRQoL and its association with demographic, metabolic, and cognitive characteristics in a large European sample of adults with early-treated classical PKU. Results This cross-sectional study included 124 adults with early-treated classical PKU from Hungary, Italy, Spain, Switzerland, and Turkey. All participants prospectively completed the PKU quality of life questionnaire (PKU-QoL), a questionnaire specifically designed to evaluate the impact of PKU and its treatment on HRQoL in individuals with PKU. In addition, information about Phe levels (concurrent and past year), demographic (age and sex), and cognitive variables (intelligence quotient, IQ) were collected. Most domains revealed little or no impact of PKU on HRQoL and more than three-quarters of the patients rated their health status as good, very good, or excellent. Nevertheless, some areas of concern for patients were identified. Patients were worried about the guilt that they experience if they do not adhere to the dietary protein restriction and they were most concerned about high Phe levels during pregnancy. Further, tiredness was the most affected symptom, and the supplements’ taste was considered a main issue for individuals with PKU. The overall impact of PKU on HRQoL was higher in women ( U  = 1315.5, p  = .012) and in adults with a lower IQ ( r s  = − 0.448, p  = .005). The overall impact of dietary protein restriction was higher in adults with higher concurrent Phe levels ( r s = 0.272, p  = .007) and higher Phe levels during the past year ( r s = 0.280, p  = .009). Conclusion The impact of PKU on most domains assessed in the PKU-QoL was considered to be low. These results likely reflect the successful implementation of the newborn screening resulting in the prevention of severe adverse long-term outcomes. However, a particular clinical focus should be given to patients with lower IQ, higher Phe levels, and women, as these variables were associated with a lower HRQoL.

Fabry disease (FD) is a progressive multisystemic lysosomal storage disease. Early diagnosis by newborn screening (NBS) may allow for timely treatment, thus preventing future irreversible organ damage. We present the results of 5.5 years of NBS for FD by α-galactosidase A activity and globotriaosylsphingosine (lyso-Gb3) assays in dried blood spot through a multiplexed MS/MS assay. Furthermore, we report our experience with long-term follow-up of positive subjects. We screened more than 170,000 newborns and 22 males were confirmed to have a GLA gene variant, with an incidence of 1:7879 newborns. All patients were diagnosed with a variant previously associated with the later-onset phenotype of FD or carried an unclassified variant (four patients) or the likely benign p.Ala143Thr variant. All were asymptomatic at the last visit. Although lyso-Gb3 is not considered a reliable second tier test for newborn screening, it can simplify the screening algorithm when its levels are elevated at birth. After birth, plasma lyso-Gb3 is a useful marker for non-invasive monitoring of all positive patients. Our study is the largest reported to date in Europe, and presents data from long-term NBS for FD that reveals the current incidence of FD in northeastern Italy. Our follow-up data describe the early disease course and the trend of plasma lyso-Gb3 during early childhood.

Background Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD) are inherited metabolic diseases characterized by dysfunction of peroxisomes, that are essential for lipid metabolism and redox balance. Oxidative stress has been reported to have a significant role in the pathogenesis of neurodegenerative diseases such as peroxisomal disorders, but little is known on the intracellular activation of Mitogen-activated protein kinases (MAPKs). Strictly related to oxidative stress, a correct autophagic machinery is essential to eliminated oxidized proteins and damaged organelles. The aims of the current study are to investigate a possible implication of MAPK pathways and autophagy impairment as markers and putative therapeutic targets in X-ALD and ZSDs. Methods Three patients with ZSD (2 M, 1 F; age range 8–17 years) and five patients with X-ALD (5 M; age range 5- 22 years) were enrolled. A control group included 6 healthy volunteers. To evaluate MAPKs pathway, p-p38 and p-JNK were assessed by western blot analysis on peripheral blood mononuclear cells. LC3II/LC3I ratio was evaluated ad marker of autophagy. Results X-ALD and ZSD patients showed elevated p-p38 values on average 2- fold (range 1.21- 2.84) and 3.30-fold (range 1.56- 4.26) higher when compared with controls, respectively. p-JNK expression was on average 12-fold (range 2.20–19.92) and 2.90-fold (range 1.43–4.24) higher in ZSD and X-ALD patients than in controls. All patients had altered autophagic flux as concluded from the reduced LC3II/I ratio. Conclusions In our study X-ALD and ZSD patients present an overactivation of MAPK pathways and an inhibition of autophagy. Considering the absence of successful therapies and the growing interest towards new therapies with antioxidants and autophagy inducers, the identification and validation of biomarkers to monitor optimal dosing and biological efficacy of the treatments is of prime interest.