BACKGROUND:Apulia and neighbouring Southern Italian regions present a complex genetic stratification shaped by historical migrations. Phenylketonuria (PKU), caused by PAH mutations, serves as an excellent model for molecular epidemiology. This study maps the geographical distribution of PAH variants in a large Southern Italian cohort, evaluating their correlation with clinical phenotypes and long-term Body Mass Index (BMI). METHODS:A retrospective cohort study was conducted on 344 patients followed for at least 10 years. Genetic characterization evolved from Sanger to Next-Generation Sequencing, and patients were stratified into micro-geographic clusters. RESULTS:The genetic landscape was dominated by three ancestral variants (c.1208C>T, c.1066-11G>A, c.898G>T), accounting for 58% of the allelic pool. Significant micro-geographic polarization was observed: c.1222C>T clustered in Central-Northern Apulia, mirroring historical Norman-Swabian migration, whereas c.441+5G>T enriched in Southern Apulia. At final follow-up, classic PKU adult patients exhibited a four-fold increased risk of obesity (p < 0.05), driven by severe null alleles that necessitate a lifelong dependency on engineered low-protein foods. CONCLUSIONS:PAH mutational stratification serves as a contemporary reflection of historical migratory maps. Incorporating regional and genotypic mapping provides a precision medicine framework to anticipate phenotype severity, optimize therapeutic management, and tailor long-term obesity risk monitoring.

Introduction: The psychosocial impact of living with an Inherited Metabolic Disorder (IMD) is becoming increasingly relevant and can have a significant impact on planning the future, conditioning the reproductive decisions made during adolescence and young adulthood. The aim of this paper is to explore thoughts about partner choices, parenthood and pregnancy among adolescents and young adults affected by IMDs. Methods: A cross-sectional study was performed. A sample of 23 patients affected by a range of IMDs were interviewed. Twenty-two questions were provided, distinguished into four main themes: partners, parenthood, pregnancy and need for information. Results: More than half of participants (57%) reported insecurities about relationships and declared that they were single for this reason, with most (70%) having a hope of having children in the future, although with the awareness and fear that they could also be affected. Almost all females (90%) consider themselves able to carry a pregnancy in a way similar to other women. There was the common need for more information about their potential fertility and parenthood linked to their condition. Conclusion: Being diagnosed with an IMD can influence personal decisions regarding relationships and reproduction. The early identification of issues in these domains may enhance referrals for personalized interventions and build more focused support programmes.

BACKGROUND:Patients affected by inherited metabolic diseases (IMDs), through effective newborn screening and better clinical management, are living longer and have a lower burden of disease; this rises the challenge of properly taking life-long care of them as they age. This study aims to assess the Italian experience with the transition of patients affected by IMDs from pediatrician to adult care, focusing on the dietetic approach as well. For this purpose, a survey was created on REDCap® and distributed via email to the members of the "Dietetics and Nutrition Working Group" and "Inherited Metabolic Diseases in Adults Working Group" of "Italian IMD and Newborn Screening Society" (SIMMESN); dissemination was possible with the collaboration of MetabERN. RESULTS:A total of 49 complete responses were collected-28 from medical doctors (MDs) and 21 from dietitians-from 35 different centers. Considering the MDs, 13 take care of pediatric patients; the remaining 15, with heterogeneous specialization, of adults with IMDs. Considering the dietitians, only 6 deal with IMDs patients as their full-time activity. Out of the 35 centers, 19 do not have a transition program (while 10/19 are already trying to implement it); the main barrier identified to the implementation voted by 42% of participants is represented by the lack of identification of a suitable facility. Considering the 16 centers that already have a transition program, the 2 main difficulties reported by 43% of participants were the lack of a psychologist for adult centers and the lack of specific training in IMDs on the adult service team; this last option was also the most voted by the dietitians (44%). CONCLUSIONS:The administered survey allows us to capture the state of transition programs in Italy, the lack of homogeneity in those centers that already have one, and the obstacles to developing a new program. What unequivocally emerged is the need for standardization of the transition program and for delineating a path to train MDs specialized in treating adult patients with IMDs, as well as dedicated dietitians.

Background: To achieve a normal nutritional status, patients suffering from phenylketonuria (PKU) are typically prescribed amino acid (AA) supplements with low or no phenylalanine (Phe) content. Studies evaluating patient preferences regarding the intake modalities of AA supplements are limited. This study aimed to collect real-world data regarding prescription adherence and intake modalities of AA supplements reported by PKU patients while monitoring metabolic control. Methods: This cross-sectional study included 33 PKU patients (16 female and 17 male) with a mean age of 27.2 years. Questionnaires were provided to assess information on AA supplement intake, such as prescription adherence rate, frequency and timing of administration, supplement formulation, and combination with food or drinks. Plasma phenylalanine levels were monitored during the study period. Results: 51.5% (n = 17) of patients reported to lay within an adherence range of 75–100%. The majority of patients consumed AA supplements twice daily, with breakfast (87.9%) and afternoon snacks (51.5%). Powder supplements were most commonly used (72.7%) and often combined with milk and/or fruit juices (45.4%). Conclusions: Despite the known concerns related to treatment compliance among PKU adolescents and adults, most of the study participants reported a high level of adherence to AA supplement prescription. The personalized dietary regimens followed by the patients included in the current study represent a treatment approach that might be worth trying in non-compliant patients.

Background: One of the main objectives of Phenylketonuria (PKU) management is represented by optimising the growth trend under restricted protein diet regimen. The data on long-term growth in PKU children are limited and mostly based on earlier studies. Methods: The data for this twelve-year longitudinal study were collected from 34 PKU children and 37 healthy peers, whose auxological parameters were taken at 7 time-points over the follow-up. The weight-for-length ratio (WLR) z-score and body mass index (BMI) z-score were considered according to age. Prevalence of overweight/obesity was evaluated at last assessment. Results: The median BMI z-score of PKU children was normal and not statistically different from that of controls on all the seven time-point assessments. Their distributions tended to be wider than those of peers, with the upper limit exceeding the normal range since 12 months old, with a peak specifically at 3 years of age. In controls, there was a tendency to approach the BMI z-score values of overweight in later childhood. The prevalence of overweight was comparable (29% vs. 25%, p: 0.78) between the two groups at last assessment, and obese subjects (3/37) were only detected in the control group. Conclusions: In this study, we report data from a long-term follow-up on growth, highlighting that the median BMI z-score of PKU children was normal and not statistically different from that of controls. Also, the prevalence of obesity at 12 years of age was overlapping. However, the high prevalence of overweight children in the general population may explain the lack of difference and does not reassure about patients’ nutritional risk.

Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion of certain macronutrients, putting one at risk of a reduced intake of micronutrients. In this review, we aim to provide available evidence on the most common micronutrient deficits related to specific dietary approaches and on the management of their deficiency, in the meanwhile discussing the main critical points of each nutritional supplementation. The emerging concepts are that a great heterogeneity in clinical practice exists, as well as no univocal evidence on the most common micronutrient abnormalities. In phenylketonuria, for example, micronutrients are recommended to be supplemented through protein substitutes; however, not all formulas are equally supplemented and some of them are not added with micronutrients. Data on pyridoxine and riboflavin status in these patients are particularly scarce. In long-chain fatty acid oxidation disorders, no specific recommendations on micronutrient supplementation are available. Regarding carbohydrate metabolism disorders, the difficult-to-ascertain sugar content in supplementation formulas is still a matter of concern. A ketogenic diet may predispose one to both oligoelement deficits and their overload, and therefore deserves specific formulations. In conclusion, our overview points out the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of high-quality studies, particularly for some under-investigated deficits.

Studies on Hyperphenylalaninemia (HPA) patients are scarce and primarily focused on neurocognitive outcomes compared to PKU patients. In this study, we characterized the food habits and lifestyle of HPA patients compared with healthy peers. We performed a cross-sectional survey of a cohort of 30 patients (13 males, median age/range: 7.9; 2.2–16.7 years) and 28 controls (8 males, median age/range: 7.9; 2.1–16.7 years). Anthropometric parameters, food and nutrient intakes, and level of physical activity were assessed. Food neophobia, eating disorders, and body image perception was investigated by specific tests. Patients showed greater selectivity in the choice of foods than controls, preferring products with lower protein content (p-value: 0.03) and avoiding associating multiple protein and carbohydrate sources. A comparable tendency to distrust new foods emerged without elements suggestive of eating disorders. Patients had higher image dissatisfaction than peers (p-value: 0.01). This group of patients manifested more selective eating habits and worse body image acceptance. A regular evaluation of these aspects in these patients may result in a more effective follow-up of this disorder. More studies are needed to confirm these findings.

Background: Vaccines for COVID-19 have had a significant impact on the spread of COVID-19 infection, reducing the incidence and mortality of the infection in several countries. However, hesitancy toward this vaccine is a global health issue for the general population The Vaccine acceptance rate among patients affected with inherited metabolic disorders (IMD), as well as safety profile, has not been described. Methods: We conducted a cross-sectional study, based on a telephone survey, investigating the COVID-19 vaccination rate, the incidence and type of adverse effects (AEs), the reasons for vaccine refusal and the effects on the underlying disease in a cohort of IMD patients followed at a single center and invited directly to vaccination by specialistic team. Results: Seventy-four patients were included in the study, the median age was 23.4 years (min 12.1–max 61.7), 47% (n = 85) were females and 61% (107) were affected from impaired metabolism of phenylalanine. By October 2021, 94% (n = 163) of them had received at least one dose of the vaccine, which was, in 98% of cases, mRNA-based vaccine, given at the referral hospital in 65% of cases. Overall, 72% of patients with IMD reported AE to the vaccine: 60% after the first dose, 81% after the second. The highest rate of adverse events at the first dose was reported in patients with amino acids related disorders other than impaired phenylalanine metabolism (PKU/HPA) (88%). For the second dose, the PKU/HPA group reported the highest rate of AEs (89% of cases). There was no effect on the underlying disease or acute decompensation after the vaccine. Eleven patients (6%) were not vaccinated because they considered it dangerous. Conclusion: Among individuals with IMD, the vaccination rate was high, the incidence and severity of AEs were comparable to those in the general population with no effects on the disease. Direct contact with the specialist medical team, has proven to reassure patients and effectively contrast hesitancy.

There is a lack of evidence on the impact on body composition of high protein intake and types of protein substitutes in PKU patients—particularly in adolescents, who are more inclined to dietary transgressions. In this observational, cross-sectional study, PKU patients were observed during prepubertal age (p) or after the pubertal spurt (P), assessing body composition and bone quality and correlating these parameters with dietary compliance and types of protein substitutes. Anthropometric and dietary data were evaluated together with bioelectrical impedance analysis (BIA), quantitative ultrasound (QUS) and branched-chain amino acids (BCAAs). A total of 36 patients (16 males, 17 prepubertal and 19 post-pubertal; mean ± SD age 11.4 ± 3.9 years) were included. A higher BMI was observed in adolescents (p-value: 0.018). The BIA revealed a significant increase in total body water (TBW) and muscle mass (MM) in P subjects either compliant (p-value: 0.001) or non-compliant with the diet (p-value: 0.001). MM content correlated with increased Phe intake (r = 0.63; p < 0.001). In the subgroup of five patients taking L-AAs and glycomacropeptides (GMPs), BCAA values tended to be lower than those taking only L-AA mixtures, with a significant trend for valine. Maintenance of body composition parameters within the normal range—for both fat and muscle mass—and levels of BCAAs can be helpful in reducing the risk of becoming overweight in adulthood. Further studies are needed to confirm these findings.

Mitochondrial diseases (MDs) may result from mutations affecting nuclear or mitochondrial genes, encoding mitochondrial proteins, or non-protein-coding mitochondrial RNA. Despite the great variability of affected genes, in the most severe cases, a neuromuscular and neurodegenerative phenotype is observed, and no specific therapy exists for a complete recovery from the disease. The most used treatments are symptomatic and based on the administration of antioxidant cocktails combined with antiepileptic/antipsychotic drugs and supportive therapy for multiorgan involvement. Nevertheless, the real utility of antioxidant cocktail treatments for patients affected by MDs still needs to be scientifically demonstrated. Unfortunately, clinical trials for antioxidant therapies using α-tocopherol, ascorbate, glutathione, riboflavin, niacin, acetyl-carnitine and coenzyme Q have met a limited success. Indeed, it would be expected that the employed antioxidants can only be effective if they are able to target the specific mechanism, i.e., involving the central and peripheral nervous system, responsible for the clinical manifestations of the disease. Noteworthily, very often the phenotypes characterizing MD patients are associated with mutations in proteins whose function does not depend on specific cofactors. Conversely, the administration of the antioxidant cocktails might determine the suppression of endogenous oxidants resulting in deleterious effects on cell viability and/or toxicity for patients. In order to avoid toxicity effects and before administering the antioxidant therapy, it might be useful to ascertain the blood serum levels of antioxidants and cofactors to be administered in MD patients. It would be also worthwhile to check the localization of mutations affecting proteins whose function should depend (less or more directly) on the cofactors to be administered, for estimating the real need and predicting the success of the proposed cofactor/antioxidant-based therapy.

Understanding the potential risks of patients with inherited metabolic disorder (IMD) exposed to the COVID-19 pandemic is an unmet need for those involved in their management. Here, we report on the incidence of COVID-19 in a cohort of patients with IMD treated at a children’s hospital and compare them with a matched control group. Among the total number of 272 patients actively followed at a referral center, 19 (7%) tested positive for SARS-CoV-2 between March 2020 and March 2021. Their median age was 16.2 years (range 1.4–32.8 years). In two-thirds of the cases, the source of infection was a family member; 12/19 patients (63%) were asymptomatic, only one required hospitalization, and none of them died. In our single-center experience, COVID-19 had a moderate impact on a relatively large cohort of patients with IMD, including children and young adults. The clinical course was very mild in all but one case. The proportion of symptomatic cases and the clinical course were comparable in patients with IMD and in a group of matched, non-IMD COVID-19 controls from the general population.