In infants with phenylketonuria (PKU), dietary management is based on lowering and titrating phenylalanine (Phe) intake from breast milk or standard infant formula in combination with a Phe-free infant formula in order to maintain blood Phe levels within target range. Professionals use different methods to feed infants with PKU and our survey aimed to document practices across Europe. We sent a cross sectional, survey monkey® questionnaire to European health professionals working in IMD. It contained 31 open and multiple-choice questions. The results were analysed according to different geographical regions. Ninety-five centres from 21 countries responded. Over 60% of centres commenced diet in infants by age 10 days, with 58% of centres implementing newborn screening by day 3 post birth. At diagnosis, infant hospital admission occurred in 61% of metabolic centres, mainly in Eastern, Western and Southern Europe. Breastfeeding fell sharply following diagnosis with only 30% of women still breast feeding at 6 months.53% of centres gave pre-measured Phe-free infant formula before each breast feed and 23% alternated breast feeds with Phe-free infant formula. With standard infant formula feeds, measured amounts were followed by Phe-free infant formula to satiety in 37% of centres (n = 35/95), whereas 44% (n = 42/95) advised mixing both formulas together. Weaning commenced between 17 and 26 weeks in 85% centres, ≥26 weeks in 12% and < 17 weeks in 3%. This is the largest European survey completed on PKU infant feeding practices. It is evident that practices varied widely across Europe, and the practicalities of infant feeding in PKU received little focus in the PKU European Guidelines (2017). There are few reports comparing different feeding techniques with blood Phe control, Phe fluctuations and growth. Controlled prospective studies are necessary to assess how different infant feeding practices may influence longer term feeding development.

Managing Inherited Metabolic Disorders (IMDs) at risk for hypoglycemia, such as Glycogen Storage Diseases (GSDs), Hereditary Fructose Metabolism Disorders (HFMDs) and Congenital Hyperinsulinism (CH), poses challenges in dietary treatments and blood glucose monitoring. The effectiveness of Continuous Glucose Monitoring (CGM) remains a subject of ongoing debate, with IMD guidelines maintaining caution. Therefore, a systematic evaluation is needed to understand the potential benefits of CGM during dietary interventions. A systematic literature review was conducted in PubMed according to the PICOS model and PRISMA recommendations on studies published from January 01, 2003, up to October 15, 2023 (PROSPERO CRD42024497744). The risk of bias was assessed using NIH Quality Assessment Tools. Twenty-four studies in GSDs (n = 13), CH (n = 10), and HFMDs (n = 1) were analyzed. In GSDs, Real-time CGM (Rt-CGM) was associated with metabolic benefits during nutritional interventions, proving to be an accurate system for hypoglycemia detection although with some concerns about reliability. Rt-CGM in CH, primarily involving children, also showed potential benefits for glycemic control and metabolic stability with acceptable accuracy, although its use during dietary changes was limited. Few experiences on Flash Glucose Monitoring (FGM) were reported, with some concerns about reliability. Overall, the studies analyzed presented different designs, and their quality was predominantly fair or poor. Heterogeneity and limited consensus on reliability and glycemic targets underscore the need for prospective studies and future recommendations for the use of CGM in optimizing nutritional status and providing personalized dietary education in individuals with IMDs prone to hypoglycemia.

Background: Methylmalonic Aciduria (MA) without homocystinuria (or isolated MA) is a group of rare inherited metabolic disorders which leads to the accumulation of methylmalonic acid (MMA), a toxic molecule that accumulates in blood, urine, and cerebrospinal fluid, causing acute and chronic complications including metabolic crises, acute kidney injury (AKI), and chronic kidney disease (CKD). Detailed Case Description: Herein, we report a case of a 39-year-old male with MA and stage IV CKD who experienced acute metabolic decompensation secondary to gastrointestinal infection. The patient underwent a single hemodialysis (HD) session to correct severe metabolic acidosis unresponsive to medical therapy and to rapidly remove MMA. The HD session resulted in prompt clinical improvement and shortening of hospitalization. Discussion: MMA accumulation in MA patients causes acute and life-threatening complications, such as metabolic decompensations, and long-term complications such as CKD, eventually leading to renal replacement therapy (RRT). Data reported in the literature show that, overall, all dialytic treatments (intermittent HD, continuous HD, peritoneal dialysis) are effective in MMA removal. HD, in particular, can be useful in the emergency setting to control metabolic crises, even with GFR > 15 mL/min. Kidney and/or liver transplantations are often needed in MA patients. While a solitary transplanted kidney can be rapidly affected by MMA exposure, with a decline in renal function even in the first year of follow-up, the combined liver–kidney transplantation showed better long-term results due to a combination of reduced MMA production along with increased urinary excretion. Conclusions: Early diagnosis, multidisciplinary management and preventive measures are pivotal in MA patients to avoid recurrent AKI episodes and, consequently, to slow down CKD progression.

Background: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an inborn error affecting fatty acid β-oxidation (FAO). Differently than other FAO deficiencies, LCHADD patients may develop progressive retinopathy and peripheral neuropathy. The pathogenesis of retinopathy is not completely understood, and the role of dietary interventions in preventing the development of retinopathy remains uncertain. We examined the literature to assess the impact of the dietary management of LCHADD patients on retinopathy prevention. Methods: Our systematic search included studies published in the last 20 years according to PRISMA guidelines. The aims of the review were to analyze the correlation between retinopathy and the following: (1) age at first metabolic decompensation and/or at the start of the dietary treatment, (2) chronic dietary treatment, (3) emergency regimens, (4) other nutritional supplements. The protocol was registered in PROSPERO, and evidence was assessed using the GRADE system. Results: Seven full papers were identified according to search criteria, with only four including meaningful data. Early presentation of the disease, acute neonatal symptoms, and a suboptimal chronic treatment control were associated with more aggressive retinopathy and a poorer sight outcome. The number of metabolic decompensations and/or hospitalizations were also positively correlated with vision loss. Chronic fat modulation in the diet had less impact than emergency treatments. The role of other nutritional supplements was not well defined. Conclusions: Newborn screening may improve retinal outcomes. Nevertheless, early treatment adopting the current LCHADD therapeutic regimen can often only delay the onset of retinopathy. Clearly, our current treatment strategies are not adequate and retina-specific treatments are needed. The optimal composition of the diet, the role of fasting limitation, and the benefits of some nutritional supplements deserve further investigations.

Fabry disease (FD) is an X-linked lysosome storage disease that results in the accumulation of globotriaosylceramide (Gb3) throughout the body leading to irreversible target organ damage. As the role of secondary mediators (inflammatory molecules) and their mechanisms has not been fully elucidated, we focused on the interleukin (IL)-6 system in adult FD patients and in matched healthy subjects. To obtain insights into the complex regulation of IL-6 actions, we used a novel approach that integrates information from plasma and exosomes of FD patients (n = 20) and of healthy controls (n = 15). Soluble IL-6 receptor (sIL-6R) levels were measured in plasma with the ELISA method, and membrane-bound IL-6R was quantified in plasma and urinary exosomes using flow cytometry. In FD patients, the levels of soluble IL-6R in plasma were higher than in control subjects (28.0 ± 5.4 ng/mL vs. 18.9 ± 5.4 ng/mL, p < 0.0001); they were also higher in FD subjects with the classical form as compared to those with the late-onset form of the disease (36.0 ± 11.4 ng/mL vs. 26.1 ± 4.5 ng/mL, p < 0.0001). The percentage of urinary exosomes positive for IL-6R was slightly lower in FD (97 ± 1 vs. 100 ± 0% of events positive for IL-6R, p < 0.05); plasma IL-6 levels were not increased. These results suggest a potential role of IL-6 in triggering the inflammatory response in FD. As in FD patients only the levels of sIL-6Rs are consistently higher than in healthy controls, the IL-6 pathogenic signal seems to prevail over the homeostatic one, suggesting a potential mechanism causing multi-systemic damage in FD.

Background: Fabry disease (FD) is a rare, X‐linked lysosomal storage disorder affecting multiple organs, including the musculoskeletal system. The physical status of FD patients remains poorly characterized. This multicentre cross‐sectional study aimed to evaluate physical fitness and function in FD patients and investigate associations with sex, FD phenotype and treatment status. Methods: Adults (aged ≥ 18 years) with genetically confirmed FD were recruited. Demographic and laboratory data were collected. Physical fitness was assessed using cardiopulmonary exercise testing (VO ₂ peak) and body composition parameters (fat‐free mass index [FFMI], fat mass index [FM] and phase angle [PA]) via bioelectrical impedance analysis. Physical function was evaluated with performance tests (6‐min walk test, handgrip strength test, 30‐s chair‐stand test, short physical performance battery), muscle strength tests (isometric and isokinetic knee strength) and self‐report fatigue questionnaires. Statistical analyses were stratified by sex, phenotype (classic vs. late‐onset/Variants of Uncertain Significance [VUS]) and treatment status (enzyme replacement therapy [ERT]/chaperone‐treated versus untreated). Results: Forty‐two FD patients (13 males; mean age 46 ± 13.9 years) were enrolled. VO ₂ < 85% of predicted was more frequent in classic phenotype patients (53.8%) than in late‐onset/VUS (11.5%; p < 0.01). FFMI was lower in classic than late‐onset/VUS (16.8 ± 1.0 vs. 18.6 ± 2.1 kg/m ² ; p = 0.01). Treated males had lower PA than untreated males (4.8° ± 1.0° vs. 7.6° ± 0.9°; p = 0.04), and PA correlated with VO ₂ peak ( r = 0.879; p = 0.01). Among classic phenotype males, 74.3% scored below the 50th percentile in handgrip strength (26.1 ± 7.8 kg), and 60.9% performed below predicted values in the 30‐s chair‐stand test (12.4 ± 4.3 repetitions). Self‐reported fatigue scores were higher in classic versus late‐onset/VUS patients ( p = 0.05) and in treated patients compared to untreated patients ( p = 0.02). Conclusions: Classic FD phenotype, particularly in males, was associated with reduced exercise capacity, muscle mass and physical performance. These findings support the integration of cardiopulmonary exercise testing, physical functional assessments and body composition analysis into the routine evaluation of FD patients.