The relation between dietary polysaccharide intake and urinary excretion of tetraglucoside.

The urinary metabolite tetraglucoside (Glc4) is a potential biomarker for hepatic glycogen storage diseases (GSDs). Glc4 is believed to reflect body glycogen content and/or turnover. However, dietary polysaccharide intake may influence Glc4 excretion, potentially limiting the utility of Glc4 as a monitoring biomarker in hepatic GSDs. We aimed to investigate the association of dietary polysaccharide intake with Glc4 excretion. Urinary Glc4 excretion (mmol/mmol creatinine and mmol/24 h) was analyzed using a validated LC-MS/MS method. Data was analyzed from 65 kidney transplant recipients and 58 healthy kidney donors in the TransplantLines cohort study. Spearman's correlation and multivariable linear regression analyses were performed. In the multivariable analysis, dry lean body mass (DLBM), dietary polysaccharide intake, transplantation status, age, sex, and glycated hemoglobin (HbA1c) served as independent variables. Daily variation was examined in 21 healthy individuals of urinary Glc4 excretion in 2-h collections over a 24-h period. Mixed generalized additive models were built to study the association of prior polysaccharide intake with Glc4 excretion. No (univariate) associations were found between polysaccharide intake and Glc4 excretion. However, a significant interaction between DLBM and polysaccharide on 24 h Glc4 excretion was observed in the multivariate analysis. Glc4 excretion throughout the day exhibited no relationship to prior polysaccharide intake. Our findings suggest an indirect effect of polysaccharide intake on Glc4 excretion, potentially due to changes in muscle glycogen content and/or turnover. We have found no evidence that dietary polysaccharides under normal intakes increase urinary Glc4 directly.

Continuous glucose monitoring metrics in people with liver glycogen storage disease and idiopathic ketotic hypoglycemia: A single-center, retrospective, observational study.

BACKGROUND: Cohort data on continuous glucose monitoring (CGM) metrics are scarce for liver glycogen storage diseases (GSDs) and idiopathic ketotic hypoglycemia (IKH). The aim of this study was to retrospectively describe CGM metrics for people with liver GSDs and IKH. PATIENTS AND METHODS: CGM metrics (descriptive, glycemic variation and glycemic control parameters) were calculated for 47 liver GSD and 14 IKH patients, categorized in cohorts by disease subtype, age and treatment status, and compared to published age-matched CGM metrics from healthy individuals. Glycemic control was assessed as time-in-range (TIR; ≥3.9 - ≤7.8 and ≥3.9 - ≤10.0 mmol/L), time-below-range (TBR; <3.0 mmol/L and ≥3.0 - ≤3.9 mmol/L), and time-above-range (TAR; >7.8 and >10.0 mmol/L). RESULTS: Despite all patients receiving dietary treatment, GSD cohorts displayed significantly different CGM metrics compared to healthy individuals. Decreased TIR together with increased TAR were noted in GSD I, GSD III, and GSD XI (Fanconi-Bickel syndrome) cohorts (all p < 0.05). In addition, all GSD I cohorts showed increased TBR (all p < 0.05). In GSD IV an increased TBR (p < 0.05) and decreased TAR were noted (p < 0.05). In GSD IX only increased TAR was observed (p < 0.05). IKH patient cohorts, both with and without treatment, presented CGM metrics similar to healthy individuals. CONCLUSION: Despite dietary treatment, most liver GSD cohorts do not achieve CGM metrics comparable to healthy individuals. International recommendations on the use of CGM and clinical targets for CGM metrics in liver GSD patients are warranted, both for patient care and clinical trials.

A specific serum lipid signature characterizes patients with glycogen storage disease type Ia.

Glycogen storage disease type Ia (GSDIa) is a rare, inherited glucose-6-phosphatase-α (G6Pase-α) deficiency-induced carbohydrate metabolism disorder. Although hyperlipidemia is a hallmark of GSDI, the extent of lipid metabolism disruption remains incompletely understood. Lipidomic analysis was performed to characterize the serum lipidome in patients with GSDIa, by including age- and sex-matched healthy controls and age-matched hypercholesterolemic controls. Metabolic control and dietary information biochemical markers were obtained from patients with GSDIa. Patients with GSDIa showed higher total serum lysophosphatidylcholine (Fold Change, (FC) 2.2, P < 0.0001), acyl-acyl-phosphatidylcholine (FC 2.1, P < 0.0001), and ceramide (FC 2.4, P < 0.0001) levels and bile acid (FC 0.7, P < 0.001), acylcarnitines (FC 0.7, P < 0.001), and cholesterol esters (FC 1.0, P < 0.001) than those of healthy controls, and higher di- (FC 1.1, P < 0.0001; FC 0.9, P < 0.01) and triacylglycerol (FC 6.3, P < 0.0001; FC 3.9, P < 0.01) levels than those of healthy controls and hypercholesterolemic subjects. Both total cholesterol and triglyceride values correlated with Cer (d16:1/22:0), Cer (d18:1/20:0), Cer (d18:1/20:0(OH)), Cer (d18:1/22:0), Cer (d18:1/23:0), Cer (d18:1/24:1), Cer (d18:2/22:0), Cer (d18:2/24:1). Total cholesterol also correlated with Cer (d18:1/24:0), Cer (d18:2/20:0), HexCer (d16:1/22:0), HexCer (d18:1/18:0), and Hex2Cer (d18:1/20:0). Triglyceridelevels correlated with Cer (d18:0/24:1). Alanine aminotransferase values correlated with Cer (d18:0/22:0), insulin with Cer (d18:1/22:1) and Cer (d18:1/24:1), and HDL with hexosylceramide (HexCer) (d18:2/23:0). These results expand on the currently known involvement of lipid metabolism in GSDIa. Circulating Cer may allow for refined dietary assessment compared with traditional biomarkers. Because specific lipid species are relatively easy to assess, they represent potential novel biomarkers of GSDIa.

Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin.

Renal proximal tubulopathy in Fanconi-Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen. SGLT2 inhibitors act on apical glucose reabsorption of renal proximal tubular cells. The purpose of this study was to retrospectively describe the first experiences with repurposing the SGLT2 inhibitor empagliflozin to treat the generalized tubulopathy in Fanconi-Bickel syndrome. A case series was conducted of seven persons from five families (five males, two females; three children, who were 14y5m, 2y9m, and 1y6m old) with genetically confirmed Fanconi-Bickel syndrome, off-label treated with empagliflozin. Median (range) age at start of empagliflozin was 27 years (1y6m - 61y) and duration of follow-up under empagliflozin treatment was 169 days (57-344). Under empagliflozin (up to 25 mg/d), biochemical parameters of tubular cell integrity (urinary N-acetyl-glucosaminidase) and/or tubular functions (including urinary α1-microglobulin) improved in all persons with Fanconi-Bickel syndrome, albeit to varying degrees. Clinically, supplementations (i.e., phosphate, alkali, carnitine, and alfacalcidol) could be completely discontinued in the three children, whereas results in the four adult patients were more variable and not as significant. Empagliflozin was well-tolerated and no symptomatic hypoglycemia was observed. In conclusion, SGLT2 inhibitors such as empagliflozin shift the metabolic block in Fanconi-Bickel syndrome, that is, they intervene specifically in the underlying pathophysiology and can thus attenuate renal proximal tubulopathy, especially when started in early childhood.

Empagliflozin for treating neutropenia and neutrophil dysfunction in 21 infants with glycogen storage disease 1b.

Empagliflozin has been successfully repurposed for treating neutropenia and neutrophil dysfunction in patients with glycogen storage disease type 1b (GSD 1b), however, data in infants are missing. We report on efficacy and safety of empagliflozin in infants with GSD 1b. This is an international retrospective case series on 21 GSD 1b infants treated with empagliflozin (total treatment time 20.6 years). Before starting empagliflozin (at a median age of 8.1 months with a median dose of 0.3 mg/kg/day) 12 patients had clinical signs and symptoms of neutrophil dysfunction. Six of these previously symptomatic patients had no further neutropenia/neutrophil dysfunction-associated findings on empagliflozin. Eight patients had no signs and symptoms of neutropenia/neutrophil dysfunction before start and during empagliflozin treatment. One previously asymptomatic individual with a horseshoe kidney developed a central line infection with pyelonephritis and urosepsis during empagliflozin treatment. Of the 10 patients who were treated with G-CSF before starting empagliflozin, this was stopped in four and decreased in another four. Eleven individuals were never treated with G-CSF. While in 17 patients glucose homeostasis remained stable on empagliflozin, four showed glucose homeostasis instability in the introductory phase. In 17 patients, no other side effects were reported, while genital (n = 2) or oral (n = 1) candidiasis and skin infection (n = 1) were reported in the remaining four. Empagliflozin had a good effect on neutropenia/neutrophil dysfunction-related signs and symptoms and a favourable safety profile in infants with GSD 1b and therefore qualifies for further exploration as first line treatment.

Endocrine involvement in hepatic glycogen storage diseases: pathophysiology and implications for care.

Hepatic glycogen storage diseases constitute a group of disorders due to defects in the enzymes and transporters involved in glycogen breakdown and synthesis in the liver. Although hypoglycemia and hepatomegaly are the primary manifestations of (most of) hepatic GSDs, involvement of the endocrine system has been reported at multiple levels in individuals with hepatic GSDs. While some endocrine abnormalities (e.g., hypothalamic­pituitary axis dysfunction in GSD I) can be direct consequence of the genetic defect itself, others (e.g., osteopenia in GSD Ib, insulin-resistance in GSD I and GSD III) may be triggered by the (dietary/medical) treatment. Being aware of the endocrine abnormalities occurring in hepatic GSDs is essential (1) to provide optimized medical care to this group of individuals and (2) to drive research aiming at understanding the disease pathophysiology. In this review, a thorough description of the endocrine manifestations in individuals with hepatic GSDs is presented, including pathophysiological and clinical implications.

Idiopathic Pathological Ketotic Hypoglycemia: Finding the Needle in a Haystack.

Sick children often have a decreased appetite and experience vomiting and diarrhea; however, hypoglycemia (plasma glucose concentration ≤50 mg/dL or 2.8 mmol/L) is rare. Ketotic hypoglycemia (KH) is the most common cause of hypoglycemia presenting to an Emergency Department in a previously healthy child between 6 months and 6 years of age. Ketosis and hypoglycemia are now well understood to be normal physiologic responses of young children to prolonged fasting.There is now substantial evidence that the term KH describes a variety of conditions including both the lower end of the normal distribution of fasting tolerance in young children as well as numerous rare disorders that impair fasting adaptation. Recent advances in molecular genetic testing have led to the discovery of these rare disorders. Idiopathic pathological KH is a diagnosis of exclusion that describes rare children who have abnormally limited fasting tolerance, experience recurrent episodes of KH, or develop symptoms of hypoglycemia despite elevated ketone levels, and in whom an explanation cannot be found despite extensive investigation. This review provides an approach to distinguishing between physiological KH and pathological KH and includes recommendations for management.

Repurposing empagliflozin in individuals with glycogen storage disease Ib: A value-based healthcare approach and systematic benefit-risk assessment.

Off-label repurposing of empagliflozin allows pathomechanism-based treatment of neutropenia/neutrophil-dysfunction in glycogen storage disease type Ib (GSDIb). From a value-based healthcare (VBHC) perspective, we here retrospectively studied patient-reported, clinical and pharmacoeconomic outcomes in 11 GSDIb individuals before and under empagliflozin at two centers (the Netherlands [NL], Austria [AT]), including a budget impact analysis, sensitivity-analysis, and systematic benefit-risk assessment. Under empagliflozin, all GSDIb individuals reported improved quality-of-life-scores. Neutrophil dysfunction related symptoms allowed either granulocyte colony-stimulating factor cessation or tapering. Calculated cost savings per patient per year ranged between € 6482-14 190 (NL) and € 1281-41 231 (AT). The budget impact analysis estimated annual total cost savings ranging between € 75 062-225 716 (NL) and € 37 697-231 790 (AT), based on conservative assumptions. The systematic benefit-risk assessment was favorable. From a VBHC perspective, empagliflozin treatment in GSDIb improved personal and clinical outcomes while saving costs, thereby creating value at multiple pillars. We emphasize the importance to reimburse empagliflozin for GSDIb individuals, further supported by the favorable systematic benefit-risk assessment. These observations in similar directions in two countries/health care systems strongly suggest that our findings can be extrapolated to other geographical areas and health care systems.

Treatment recommendations for glycogen storage disease type IB- associated neutropenia and neutrophil dysfunction with empagliflozin: Consensus from an international workshop.

Glycogen storage disease type Ib (GSD Ib, biallelic variants in SLC37A4) is a rare disorder of glycogen metabolism complicated by neutropenia/neutrophil dysfunction. Since 2019, the SGLT2-inhibitor empagliflozin has provided a mechanism-based treatment option for the symptoms caused by neutropenia/neutrophil dysfunction (e.g. mucosal lesions, inflammatory bowel disease). Because of the rarity of GSD Ib, the published evidence on safety and efficacy of empagliflozin is still limited and does not allow to develop evidence-based guidelines. Here, an international group of experts provides 14 best practice consensus treatment recommendations based on expert practice and review of the published evidence. We recommend to start empagliflozin in all GSD Ib individuals with clinical or laboratory signs related to neutropenia/neutrophil dysfunction with a dose of 0.3-0.4 mg/kg/d given as a single dose in the morning. Treatment can be started in an outpatient setting. The dose should be adapted to the weight and in case of inadequate clinical treatment response or side effects. We strongly recommend to pause empagliflozin immediately in case of threatening dehydration and before planned longer surgeries. Discontinuation of G-CSF therapy should be attempted in all individuals. If available, 1,5-AG should be monitored. Individuals who have previously not tolerated starches should be encouraged to make a new attempt to introduce starch in their diet after initiation of empagliflozin treatment. We advise to monitor certain safety and efficacy parameters and recommend continuous, alternatively frequent glucose measurements during the introduction of empagliflozin. We provide specific recommendations for special circumstances like pregnancy and liver transplantation.

Endogenous Glucose Production in Patients With Glycogen Storage Disease Type Ia Estimated by Oral D-[6,6-2H2]-glucose.

CONTEXT: Glycogen storage disease type Ia (GSDIa) is an inborn metabolic disorder characterized by impaired endogenous glucose production (EGP). Monitoring of patients with GSDIa is prioritized because of ongoing treatment developments. Stable isotope tracers may enable reliable EGP monitoring. OBJECTIVE: The aim of this study was to prospectively assess the rate of appearance of endogenous glucose into the bloodstream (Ra) in patients with GSDIa after a single oral D-[6,6-2H2]-glucose dose. METHODS: Ten adult patients with GSDIa and 10 age-, sex-, and body mass index-matched healthy volunteers (HVs) were enrolled. For each participant, 3 oral glucose tracer tests were performed: (1) preprandial/fasted, (2) postprandial, and (3) randomly fed states. Dried blood spots were collected before D-[6,6-2H2]-glucose administration and 10, 20, 30, 40, 50, 60, 75, 90, and 120 minutes thereafter. RESULTS: Glucose Ra in fasted HVs was consistent with previously reported data. The time-averaged glucose Ra was significantly higher in (1) preprandial/fasted patients with GSDIa than HV and (2) postprandial HV compared with fasted HV(P < .05). A progressive decrease in glucose Ra was observed in preprandial/fasted patients with GSDIa; the change in glucose Ra time-course was directly correlated with the change in capillary glucose (P < .05). CONCLUSION: This is the first study to quantify glucose Ra in patients with GSDIa using oral D-[6,6-2H2] glucose. The test can reliably estimate EGP under conditions in which fasting tolerance is unaffected but does not discriminate between relative contributions of EGP (eg, liver, kidney) and exogenous sources (eg, dietary cornstarch). Future application is warranted for longitudinal monitoring after novel genome based treatments in patients with GSDIa in whom nocturnal dietary management can be discontinued.

A Delphi Survey Study to Formulate Statements on the Treatability of Inherited Metabolic Disorders to Decide on Eligibility for Newborn Screening.

The Wilson and Jungner (W&J) and Andermann criteria are meant to help select diseases eligible for population-based screening. With the introduction of next-generation sequencing (NGS) methods for newborn screening (NBS), more inherited metabolic diseases (IMDs) can technically be included, and a revision of the criteria was attempted. This study aimed to formulate statements and investigate whether those statements could elaborate on the criterion of treatability for IMDs to decide on eligibility for NBS. An online Delphi study was started among a panel of Dutch IMD experts (EPs). EPs evaluated, amended, and approved statements on treatability that were subsequently applied to 10 IMDs. After two rounds of Delphi, consensus was reached on 10 statements. Application of these statements selected 5 out of 10 IMDs proposed for this study as eligible for NBS, including 3 IMDs in the current Dutch NBS. The statement: 'The expected benefit/burden ratio of early treatment is positive and results in a significant health outcome' contributed most to decision-making. Our Delphi study resulted in 10 statements that can help to decide on eligibility for inclusion in NBS based on treatability, also showing that other criteria could be handled in a comparable way. Validation of the statements is required before these can be applied as guidance to authorities.

Personalised modelling of clinical heterogeneity between medium-chain acyl-CoA dehydrogenase patients.

BACKGROUND: Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients-if untreated-are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients. RESULTS: We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients. CONCLUSIONS: We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.

Glycogen storage diseases.

Glycogen storage diseases (GSDs) are a group of rare, monogenic disorders that share a defect in the synthesis or breakdown of glycogen. This Primer describes the multi-organ clinical features of hepatic GSDs and muscle GSDs, in addition to their epidemiology, biochemistry and mechanisms of disease, diagnosis, management, quality of life and future research directions. Some GSDs have available guidelines for diagnosis and management. Diagnostic considerations include phenotypic characterization, biomarkers, imaging, genetic testing, enzyme activity analysis and histology. Management includes surveillance for development of characteristic disease sequelae, avoidance of fasting in several hepatic GSDs, medically prescribed diets, appropriate exercise regimens and emergency letters. Specific therapeutic interventions are available for some diseases, such as enzyme replacement therapy to correct enzyme deficiency in Pompe disease and SGLT2 inhibitors for neutropenia and neutrophil dysfunction in GSD Ib. Progress in diagnosis, management and definitive therapies affects the natural course and hence morbidity and mortality. The natural history of GSDs is still being described. The quality of life of patients with these conditions varies, and standard sets of patient-centred outcomes have not yet been developed. The landscape of novel therapeutics and GSD clinical trials is vast, and emerging research is discussed herein.

Abnormal glucose homeostasis and fasting intolerance in patients with congenital porto-systemic shunts.

In physiological glucose homeostasis, the liver plays a crucial role in the extraction of glucose from the portal circulation and storage as glycogen to enable release through glycogenolysis upon fasting. In addition, insulin secreted by the pancreas is partly eliminated from the systemic circulation by hepatic first-pass. Therefore, patients with a congenital porto-systemic shunt present a unique combination of (a) postabsorptive hyperinsulinemic hypoglycaemia (HH) because of decreased insulin elimination and (b) fasting (ketotic) hypoglycaemia because of decreased glycogenolysis. Patients with porto-systemic shunts therefore provide important insight into the role of the portal circulation and hepatic function in different phases of glucose homeostasis.

Important Lessons on Long-Term Stability of Amino Acids in Stored Dried Blood Spots.

Residual heel prick Dried Blood Spots (DBS) are valuable samples for retrospective investigation of inborn metabolic diseases (IMD) and biomarker analyses. Because many metabolites suffer time-dependent decay, we investigated the five-year stability of amino acids (AA) in residual heel prick DBS. In 2019/2020, we analyzed 23 AAs in 2170 residual heel prick DBS from the Dutch neonatal screening program, stored from 2013-2017 (one year at +4 °C and four years at room temperature), using liquid chromatography mass-spectrometry. Stability was assessed by AA changes over the five years. Hydroxyproline could not be measured accurately and was not further assessed. Concentrations of 19 out of the remaining 22 AAs degraded significantly, ranked from most to least stable: aspartate, isoleucine, proline, valine, leucine, tyrosine, alanine, phenylalanine, threonine, citrulline, glutamate, serine, ornithine, glycine, asparagine, lysine, taurine, tryptophan and glutamine. Arginine, histidine and methionine concentrations were below the limit of detection and were likely to have been degraded within the first year of storage. AAs in residual heel prick DBS stored at room temperature are subject to substantial degradation, which may cause incorrect interpretation of test results for retrospective biomarker studies and IMD diagnostics. Therefore, retrospective analysis of heel prick blood should be done in comparison to similarly stored heel prick blood from controls.

Patient-reported outcomes on empagliflozin treatment in glycogen storage disease type Ib: An international questionnaire study.

In patients with glycogen storage disease type Ib (GSD Ib), quality of life is severely hampered by neutropenia and neutropenia-associated symptoms. SGLT2 inhibitors are a new treatment option and have shown improved medical outcomes in more than 120 patients so far. The aim of this international questionnaire study was to assess patient-reported outcomes of this new treatment in GSD Ib patients. Patients and caregivers of pediatric patients were invited to complete a web-based questionnaire. This was designed to evaluate treatment effects of the SGLT2 inhibitor empagliflozin on clinical symptoms and important aspects of daily life including physical performance, sleep, social and work life, traveling, socioeconomic aspects, and quality of life. The questionnaire was completed by 73 respondents from 17 different countries. The mean duration of treatment was 15 months, the cumulative treatment time was 94.8 years. More than 80% of patients reported an improved quality of life. The number of hospitalizations was reduced (66% of patients), as well as the number of days absent from school or work. Granulocyte colony-stimulating factor (G-CSF) treatment could be stopped in 49% of patients and reduced in another 42%. Clear improvement of neutropenia and all neutropenia-associated symptoms was reported by the majority of patients. Additionally, patients or caregivers reported positive effects on appetite (63%), level of activity (75%), overall well-being (96%), and sleep (63%). Empagliflozin positively impacts many aspects of daily life including work and social life and thereby significantly improves quality of life of patients and caregivers.

Continuous glucose monitoring for children with hypoglycaemia: Evidence in 2023.

In 2023, childhood hypoglycaemia remains a major public health problem and significant risk factor for consequent adverse neurodevelopment. Irrespective of the underlying cause, key elements of clinical management include the detection, prediction and prevention of episodes of hypoglycaemia. These tasks are increasingly served by Continuous Glucose Monitoring (CGM) devices that measure subcutaneous glucose at near-continuous frequency. While the use of CGM in type 1 diabetes is well established, the evidence for widespread use in rare hypoglycaemia disorders is less than convincing. However, in the few years since our last review there have been multiple developments and increased user feedback, requiring a review of clinical application. Despite advances in device technology, point accuracy of CGM remains low for children with non-diabetes hypoglycaemia. Simple provision of CGM devices has not replicated the efficacy seen in those with diabetes and is yet to show benefit. Machine learning techniques for hypoglycaemia prevention have so far failed to demonstrate sufficient prediction accuracy for real world use even in those with diabetes. Furthermore, access to CGM globally is restricted by costs kept high by the commercially-driven speed of technical innovation. Nonetheless, the ability of CGM to digitally phenotype disease groups has led to a better understanding of natural history of disease, facilitated diagnoses and informed changes in clinical management. Large CGM datasets have prompted re-evaluation of hypoglycaemia incidence and facilitated improved trial design. Importantly, an individualised approach and focus on the behavioural determinants of hypoglycaemia has led to real world reduction in hypoglycaemia. In this state of the art review, we critically analyse the updated evidence for use of CGM in non-diabetic childhood hypoglycaemia disorders since 2020 and provide suggestions for qualified use.

Towards values-based healthcare for inherited metabolic disorders: An overview of current practices for persons with liver glycogen storage disease and fatty acid oxidation disorders.

Value-based healthcare (VBHC) intends to achieve better outcomes for patients, to improve quality of patient care, with reduced costs. Four dimensions define a model of intimately related value-pillars: personal value, allocative value, technical value, and societal value. VBHC is mostly applied in common diseases, and there are fundamental challenges in applying VBHC strategies to low volume, high complex healthcare situations, such as rare diseases, including inherited metabolic disorders. This article summarizes current practices at various academical domains (i.e., research, healthcare, education, and training) that (aim to) increase values at various value-pillars for persons with liver glycogen storage diseases or fatty acid oxidation disorders and their families. Future perspectives may include facilitating virtual networks to function as integrated practice units, improving measurement of outcomes, and creating information technology platforms to overcome the ethical, legal, societal, and technical challenges of data sharing for healthcare and research purposes.

Neonatal Long-Chain 3-Ketoacyl-CoA Thiolase deficiency: Clinical-biochemical phenotype, sodium-D,L-3-hydroxybutyrate treatment experience and cardiac evaluation using speckle echocardiography.

Isolated long-chain 3-keto-acyl CoA thiolase (LCKAT) deficiency is a rare long-chain fatty acid oxidation disorder caused by mutations in HADHB. LCKAT is part of a multi-enzyme complex called the mitochondrial trifunctional protein (MTP) which catalyzes the last three steps in the long-chain fatty acid oxidation. Until now, only three cases of isolated LCKAT deficiency have been described. All patients developed a severe cardiomyopathy and died before the age of 7 weeks. Here, we describe a newborn with isolated LCKAT deficiency, presenting with neonatal-onset cardiomyopathy, rhabdomyolysis, hypoglycemia and lactic acidosis. Bi-allelic 185G > A (p.Arg62His) and c1292T > C (p.Phe431Ser) mutations were found in HADHB. Enzymatic analysis in both lymphocytes and cultured fibroblasts revealed LCKAT deficiency with a normal long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD, also part of MTP) enzyme activity. Clinically, the patient showed recurrent cardiomyopathy, which was monitored by speckle tracking echocardiography. Subsequent treatment with special low-fat formula, low in long chain triglycerides (LCT) and supplemented with medium chain triglycerides (MCT) and ketone body therapy in (sodium-D,L-3-hydroxybutyrate) was well tolerated and resulted in improved carnitine profiles and cardiac function. Resveratrol, a natural polyphenol that has been shown to increase fatty acid oxidation, was also considered as a potential treatment option but showed no in vitro benefits in the patient's fibroblasts. Even though our patient deceased at the age of 13 months, early diagnosis and prompt initiation of dietary management with addition of sodium-D,L-3-hydroxybutyrate may have contributed to improved cardiac function and a much longer survival when compared to the previously reported cases of isolated LCKAT-deficiency.

Dynamic Methods for Childhood Hypoglycemia Phenotyping: A Narrative Review.

Hypoglycemia results from an imbalance between glucose entering the blood compartment and glucose demand, caused by a defect in the mechanisms regulating postprandial glucose homeostasis. Hypoglycemia represents one of the most common metabolic emergencies in childhood, potentially leading to serious neurologic sequelae, including death. Therefore, appropriate investigation of its specific etiology is paramount to provide adequate diagnosis, specific therapy and prevent its recurrence. In the absence of critical samples for biochemical studies, etiological assessment of children with hypoglycemia may include dynamic methods, such as in vivo functional tests, and continuous glucose monitoring. By providing detailed information on actual glucose fluxes in vivo, proof-of-concept studies have illustrated the potential (clinical) application of dynamic stable isotope techniques to define biochemical and clinical phenotypes of inherited metabolic diseases associated with hypoglycemia. According to the textbooks, individuals with glycogen storage disease type I (GSD I) display the most severe hypoglycemia/fasting intolerance. In this review, three dynamic methods are discussed which may be considered during both diagnostic work-up and monitoring of children with hypoglycemia: 1) functional in vivo tests; 2) in vivo metabolic profiling by continuous glucose monitoring (CGM); 3) stable isotope techniques. Future applications and benefits of dynamic methods in children with hypoglycemia are also discussed.