Continuous glucose monitoring in patients with inherited metabolic disorders at risk for Hypoglycemia and Nutritional implications.

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.

High-protein goat's milk diet identified through newborn screening: clinical warning of a potentially dangerous dietetic practice.

OBJECTIVE: Breast-feeding is an unequalled way of providing optimal food for infants' healthy growth and development and the WHO recommends that infants should be exclusively breast-fed for the first 6 months of life. For mothers who are unable to breast-feed or who decide not to, infant formulas are the safest alternative. Despite recommendations, it is possible that parents make potentially harmful nutritional choices for their children because of cultural beliefs or misinformation on infant nutrition. We describe a possible health risk of not breast-feeding, highlighting a potentially dangerous dietetic practice. Design/Setting/Subjects We report the case of a newborn who was fed with undiluted goat's milk because her mother could not breast-feed and was not aware of infant formulas. RESULTS: The dietary mistake was detected because of a positive expanded newborn screening result, characterized by severe hypertyrosinaemia with high methionine and phenylalanine levels, a pattern suggestive of severe liver impairment. The pattern of plasma amino acids was related to a goat's milk diet, because of its very different composition compared with human milk and infant formula. CONCLUSIONS: Our experience demonstrates that, when breast-feeding is not possible or is not exclusive, infants may be at risk of dangerous nutritional practices, including diets with very high protein content, such as a goat's milk diet. Families of not breast-fed infants may need appropriate advice on safe alternatives for infant nutrition to avoid the risks of inappropriate diets.

Renal Replacement Therapy in Methylmalonic Aciduria-Related Metabolic Failure: Case Report and Literature Review.

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.

Gastrointestinal Manifestations and Low-FODMAP Protocol in a Cohort of Fabry Disease Adult Patients.

Fabry disease (FD) is an X-linked lysosomal disorder caused by α-galactosidase A enzyme deficiency. Gastrointestinal (GI) manifestations are reported in FD with a prevalence of about 50%, usually treated by Enzymatic Replacement Therapy (ERT) or oral treatment. Since FODMAPs (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) can be involved in GI manifestations and dysbiosis in FD patients, a low-FODMAP diet could represent an alternative adjunctive treatment in FD subjects, as well as being useful for reducing symptoms in Irritable Bowel Syndrome (IBS). We retrospectively assessed data from 36 adult FD patients followed at the Inherited Metabolic Rare Diseases Adult Centre of the University Hospital of Padova (mean age 47.6 ± 16.2 years). Patients were screened for GI symptoms by IBS severity score and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires. In symptomatic patients, the low-FODMAP diet was proposed in order to improve GI manifestations; it consists of a phase of elimination of fermentable saccharides, succeeded by a gradual reintegration of the same. Severe or moderate GI symptoms were found in 61.1% of patients, with no correlation to the therapy in use, and significantly more severe in the classical form of FD. The protocol was completed by seven patients affected by severe GI manifestations, significantly higher than the others. The low-FODMAP diet significantly improved indigestion, diarrhoea, and constipation. This dietetic protocol seemed to have a positive impact on intestinal symptoms, by identifying and reducing the intake of the foods most related to the onset of disorders and improving the clinical manifestations. A low-FODMAP diet may be an effective alternative approach to improve intestinal manifestations and quality of life, and nutrition can play an important role in the multidisciplinary care of patients with FD.

Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation.

The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications. A recent revision questioned the impact of high doses of coenzyme Q10 on cardiac function in patients with cardiomyopathy (CM). Liver transplantation is a therapeutic option for several patients since it may stabilize or reverse CM. Both the patients waiting for liver transplantation and, even more, the ones not eligible for transplant programs urgently need therapies to improve cardiac function. To this aim, the identification of the pathogenetic mechanisms represents a key point. Aims: This review summarizes: (1) the current knowledge of the pathogenetic mechanisms underlying cardiac complications in PA and (2) the available and potential pharmacological options for the prevention or the treatment of cardiac complications in PA. To select articles, we searched the electronic database PubMed using the Mesh terms "propionic acidemia" OR "propionate" AND "cardiomyopathy" OR "Long QT syndrome". We selected 77 studies, enlightening 12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation-contraction coupling alteration, genetics, epigenetics, microRNAs, micronutrients deficiencies, renin-angiotensin-aldosterone system activation, and increased sympathetic activation. We provide a critical discussion of the related therapeutic options. Current literature supports the involvement of multiple cellular pathways in cardiac complications of PA, indicating the growing complexity of their pathophysiology. Elucidating the mechanisms responsible for such abnormalities is essential to identify therapeutic strategies going beyond the correction of the enzymatic defect rather than engaging the dysregulated mechanisms. Although these approaches are not expected to be resolutive, they may improve the quality of life and slow the disease progression. Available pharmacological options are limited and tested in small cohorts. Indeed, a multicenter approach is mandatory to strengthen the efficacy of therapeutic options.

Increased Soluble Interleukin 6 Receptors in Fabry Disease.

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.

Anthropometrics, Dietary Intake and Body Composition in Urea Cycle Disorders and Branched Chain Organic Acidemias: A Case Study of 18 Adults on Low-Protein Diets.

Low-protein diets (LPDs) are the mainstream treatment for inborn errors of intermediary protein metabolism (IEIPM), but dietary management differs worldwide. Most studies have investigated pediatric populations and their goals such as growth and metabolic balance, showing a tendency toward increasing overweight and obesity. Only a few studies have examined nutritional status and dietary intake of adult IEIPM patients on LPDs. We assessed nutritional parameters (dietary intake using a 7-day food diary record, body composition by bioimpedance analysis, and biochemical serum values) in a group of 18 adult patients with urea cycle disorders (UCDs) and branched chain organic acidemia (BCOA). Mean total protein intake was 0.61 ± 0.2 g/kg/day (73.5% of WHO Safe Levels) and mean natural protein (PN) intake was 0.54 ± 0.2 g/kg/day; 33.3% of patients consumed amino acid (AA) supplements. A totally of 39% of individuals presented a body mass index (BMI) > 25 kg/m2 and patients on AA supplements had a mean BMI indicative of overweight. All patients reported low physical activity levels. Total energy intake was 24.2 ± 5 kcal/kg/day, representing 72.1% of mean total energy expenditure estimated by predictive formulas. The protein energy ratio (P:E) was, on average, 2.22 g/100 kcal/day. Plasmatic levels of albumin, amino acids, and lipid profiles exhibited normal ranges. Phase angle (PA) was, on average, 6.0° ± 0.9°. Fat mass percentage (FM%) was 22% ± 9% in men and 36% ± 4% in women. FM% was inversely and significantly related to total and natural protein intake. Data from IEIPM adults on LPDs confirmed the pediatric trend of increasing overweight and obesity despite a low energy intake. A low protein intake may contribute to an increased fat mass. Nutritional parameters and a healthy lifestyle should be routinely assessed in order to optimize nutritional status and possibly reduce risk of cardiovascular degenerative diseases in adult UCD and BCOA patients on LPDs.

High prolactin levels in dihydropteridine reductase deficiency: A sign of therapy failure or additional pathology?

We report the case of a 22-year-old man with a diagnosis of dihydropteridine reductase (DHPR) deficiency who progressively developed movement disorders and epilepsy. Despite L-Dopa supplementation the patient continued to show high prolactin levels, with a discrepancy between the neurological clinical picture and the hormonal biochemical levels. For this reason, other potential causes were ruled out by performing a cerebral magnetic resonance imaging, which demonstrated a solid lesion in the pituitary gland strongly suggestive of a prolactinoma. As the association between metabolic disorders affecting biogenic amine synthesis and prolactinoma has not been previously reported in humans, this report suggests that a critical evaluation of the use of prolactin as a guide for therapy dosage should be made in patients with DHPR deficiency disorders.

Nutrient Intake and Nutritional Status in Adult Patients with Inherited Metabolic Diseases Treated with Low-Protein Diets: A Review on Urea Cycle Disorders and Branched Chain Organic Acidemias.

Low-protein diets (LPDs) are the main treatment for urea cycle disorders (UCDs) and organic acidemias (OAs). In most cases, LPDs start in childhood and must be continued into adulthood. The improved life expectancy of patients with UCDs and OAs raises the question of their consequences on nutritional status in adult subjects. As this topic has so far received little attention, we conducted a review of scientific studies that investigated the nutrient intake and nutritional status in adult patients with UCDs and branched chain organic acidemias (BCOAs) on LPD. METHODS: The literature search was conducted in PubMed/MEDLINE, Scopus, EMBASE and Google Scholar from 1 January 2000 to 31 May 2020, focusing on nutrient intake and nutritional status in UCD and OA adult patients. RESULTS: Despite protein restriction is recommended as the main treatment for UCDs and OAs, in these patients, protein intake ranges widely, with many patients who do not reach safety levels. When evaluated, micronutrient intake resulted below recommended values in some patients. Lean body mass resulted in most cases lower than normal range while fat body mass (FM) was often found normal or higher than the controls or reference values. Protein intake correlated inversely with FM both in adult and pediatric UCD patients. CONCLUSIONS: The clinical management of adult patients with UCDs and BCOAs should include an accurate assessment of the nutritional status and body composition. However, as little data is still available on this topic, further studies are needed to better clarify the effects of LPDs on nutritional status in adult UCD and BCOA patients.