A generic emergency protocol for patients with inborn errors of metabolism causing fasting intolerance: A retrospective, single-center study and the generation of www.emergencyprotocol.net.

Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking. This is a retrospective, observational, single-center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders (FAOD). Data on hospital admissions, initial laboratory results, and serious adverse events were collected. Subsequently, the website www.emergencyprotocol.net was generated in the context of the CONNECT MetabERN eHealth project following multiple meetings, protocol revisions, and translations. Representing 470 emergency protocol years, 127 hospital admissions were documented in 54/128 (42%) patients who made use of emergency letters generated based on the generic emergency protocol. Hypoglycemia (here defined as glucose concentration < 3.9 mmol/L) was reported in only 15% of hospital admissions and was uncommon in patients with ketotic GSD and patients with FAOD aged >5 years. Convulsions, coma, or death was not documented. By providing basic information, emergency letters for individual patients with hepatic GSD or the main FAOD can be generated at www.emergencyprotocol.net, in nine different languages. Generic emergency protocols are safe and easy for home management by the caregivers and the first hour in-hospital management to prevent metabolic emergencies in patients with hepatic GSD and medium-chain Acyl CoA dehydrogenase deficiency. The website www.emergencyprotocol.net is designed to support families and healthcare providers to generate personalized emergency letters for patients with hepatic GSD and the main FAOD.

A retrospective in-depth analysis of continuous glucose monitoring datasets for patients with hepatic glycogen storage disease: Recommended outcome parameters for glucose management.

Continuous glucose monitoring (CGM) systems have great potential for real-time assessment of glycemic variation in patients with hepatic glycogen storage disease (GSD). However, detailed descriptions and in-depth analysis of CGM data from hepatic GSD patients during interventions are scarce. This is a retrospective in-depth analysis of CGM parameters, acquired in a continuous, real-time fashion describing glucose management in 15 individual GSD patients. CGM subsets are obtained both in-hospital and at home, upon nocturnal dietary intervention (n = 1), starch loads (n = 11) and treatment of GSD Ib patients with empagliflozin (n = 3). Descriptive CGM parameters, and parameters reflecting glycemic variation and glycemic control are considered useful CGM outcome parameters. Furthermore, the combination of first and second order derivatives, cumulative sum and Fourier analysis identified both subtle and sudden changes in glucose management; hence, aiding assessment of dietary and medical interventions. CGM data interpolation for nocturnal intervals reduced confounding by physical activity and diet. Based on these analyses, we conclude that in-depth CGM analysis can be a powerful tool to assess glucose management and optimize treatment in individual hepatic GSD patients.

Effects of acute nutritional ketosis during exercise in adults with glycogen storage disease type IIIa are phenotype-specific: An investigator-initiated, randomized, crossover study.

Glycogen storage disease type IIIa (GSDIIIa) is an inborn error of carbohydrate metabolism caused by a debranching enzyme deficiency. A subgroup of GSDIIIa patients develops severe myopathy. The purpose of this study was to investigate whether acute nutritional ketosis (ANK) in response to ketone-ester (KE) ingestion is effective to deliver oxidative substrate to exercising muscle in GSDIIIa patients. This was an investigator-initiated, researcher-blinded, randomized, crossover study in six adult GSDIIIa patients. Prior to exercise subjects ingested a carbohydrate drink (~66 g, CHO) or a ketone-ester (395 mg/kg, KE) + carbohydrate drink (30 g, KE + CHO). Subjects performed 15-minute cycling exercise on an upright ergometer followed by 10-minute supine cycling in a magnetic resonance (MR) scanner at two submaximal workloads (30% and 60% of individual maximum, respectively). Blood metabolites, indirect calorimetry data, and in vivo 31 P-MR spectra from quadriceps muscle were collected during exercise. KE + CHO induced ANK in all six subjects with median peak ßHB concentration of 2.6 mmol/L (range: 1.6-3.1). Subjects remained normoglycemic in both study arms, but delta glucose concentration was 2-fold lower in the KE + CHO arm. The respiratory exchange ratio did not increase in the KE + CHO arm when workload was doubled in subjects with overt myopathy. In vivo 31 P MR spectra showed a favorable change in quadriceps energetic state during exercise in the KE + CHO arm compared to CHO in subjects with overt myopathy. Effects of ANK during exercise are phenotype-specific in adult GSDIIIa patients. ANK presents a promising therapy in GSDIIIa patients with a severe myopathic phenotype. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03011203.

Dietary lipids in glycogen storage disease type III: A systematic literature study, case studies, and future recommendations.

A potential role of dietary lipids in the management of hepatic glycogen storage diseases (GSDs) has been proposed, but no consensus on management guidelines exists. The aim of this study was to describe current experiences with dietary lipid manipulations in hepatic GSD patients. An international study was set up to identify published and unpublished cases describing hepatic GSD patients with a dietary lipid manipulation. A literature search was performed according to the Cochrane Collaboration methodology through PubMed and EMBASE (up to December 2018). All delegates who attended the dietetics session at the IGSD2017, Groningen were invited to share unpublished cases. Due to multiple biases, only data on GSDIII were presented. A total of 28 cases with GSDIII and a dietary lipid manipulation were identified. Main indications were cardiomyopathy and/or myopathy. A high fat diet was the most common dietary lipid manipulation. A decline in creatine kinase concentrations (n = 19, P < .001) and a decrease in cardiac hypertrophy in paediatric GSDIIIa patients (n = 7, P < .01) were observed after the introduction with a high fat diet. This study presents an international cohort of GSDIII patients with different dietary lipid manipulations. High fat diet may be beneficial in paediatric GSDIIIa patients with cardiac hypertrophy, but careful long-term monitoring for potential complications is warranted, such as growth restriction, liver inflammation, and hepatocellular carcinoma development.

Safety issues associated with dietary management in patients with hepatic glycogen storage disease.

INTRODUCTION: Hepatic glycogen storage diseases (GSDs) are a group of inherited disorders of carbohydrate metabolism for which dietary management is the cornerstone. Safety and acute complications associated with dietary management have been poorly documented. We hypothesized that safety issues and complications associated with dietary management are prevalent amongst patients with these ultra-rare disorders. METHODS: A questionnaire was developed consisting of 40 questions and was distributed via eight GSD patient organizations from multiple countries. Respondents were (caregivers of) patients with self-reported hepatic GSD. RESULTS: 249 GSD patients from 26 countries responded with a median age of 14.8 years (range: 0.5-66.1). Although management was considered safe by 71% of patients, 51% reported at least one acute complication associated with dietary management, with a total number of 425 reported complications. Most frequently reported causes were: not waking up by an alarm clock (n = 70), forgetting a meal (n = 57) and infections (n = 43). Most frequently reported complications were: hypoglycemia (n = 112), hospital admissions (n = 79) and drowsiness (n = 74). Most complications occurred before the age of 12 years (82%; 637/774 total number of reported events) and during night time (63%; 340/536). Only 61% (152/249) of the GSD patients reported using a written emergency protocol. CONCLUSIONS: Safety issues and complications associated with dietary management are prevalently reported by (caregivers of) 249 GSD patients. A discrepancy has been observed between the patient's perspective on safety of dietary management and occurrence of complications as a result of dietary management.

A preliminary study of telemedicine for patients with hepatic glycogen storage disease and their healthcare providers: from bedside to home site monitoring.

BACKGROUND: The purpose of this project was to develop a telemedicine platform that supports home site monitoring and integrates biochemical, physiological, and dietary parameters for individual patients with hepatic glycogen storage disease (GSD). METHODS AND RESULTS: The GSD communication platform (GCP) was designed with input from software developers, GSD patients, researchers, and healthcare providers. In phase 1, prototyping and software design of the GCP has occurred. The GCP was composed of a GSD App for patients and a GSD clinical dashboard for healthcare providers. In phase 2, the GCP was tested by retrospective patient data entry. The following software functionalities were included (a) dietary registration and prescription module, (b) emergency protocol module, and (c) data import functions for continuous glucose monitor devices and activity wearables. In phase 3, the GSD App was implemented in a pilot study of eight patients with GSD Ia (n = 3), GSD IIIa (n = 1), and GSD IX (n = 4). Usability was measured by the system usability scale (SUS). The mean SUS score was 64/100 [range: 38-93]. CONCLUSIONS: This report describes the design, development, and validation process of a telemedicine platform for patients with hepatic GSD. The GCP can facilitate home site monitoring and data exchange between patients with hepatic GSD and healthcare providers under varying circumstances. In the future, the GCP may support cross-border healthcare, second opinion processes and clinical trials, and could possibly also be adapted for other diseases for which a medical diet is the cornerstone.

Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome.

Glycogen storage disease type III (GSDIII) is a rare disorder of glycogenolysis due to AGL gene mutations, causing glycogen debranching enzyme deficiency and storage of limited dextrin. Patients with GSDIIIa show involvement of liver and cardiac/skeletal muscle, whereas GSDIIIb patients display only liver symptoms and signs. The International Study on Glycogen Storage Disease (ISGSDIII) is a descriptive retrospective, international, multi-centre cohort study of diagnosis, genotype, management, clinical course and outcome of 175 patients from 147 families (86 % GSDIIIa; 14 % GSDIIIb), with follow-up into adulthood in 91 patients. In total 58 AGL mutations (non-missense mutations were overrepresented and 21 novel mutations were observed) were identified in 76 families. GSDIII patients first presented before the age of 1.5 years, hepatomegaly was the most common presenting clinical sign. Dietary management was very diverse and included frequent meals, uncooked cornstarch and continuous gastric drip feeding. Chronic complications involved the liver (hepatic cirrhosis, adenoma(s), and/or hepatocellular carcinoma in 11 %), heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood), and muscle (pain in 34 %). Type 2 diabetes mellitus was diagnosed in eight out of 91 adult patients (9 %). In adult patients no significant correlation was detected between (non-) missense AGL genotypes and hepatic, cardiac or muscular complications. This study demonstrates heterogeneity in a large cohort of ageing GSDIII patients. An international GSD patient registry is warranted to prospectively define the clinical course, heterogeneity and the effect of different dietary interventions in patients with GSDIII.

Normoglycemic Ketonemia as Biochemical Presentation in Ketotic Glycogen Storage Disease.

BACKGROUND: According to the textbooks, the ketotic glycogen storage disease (GSD) types 0, III, VI, IX, and XI are associated with fasting ketotic hypoglycemia and considered milder as gluconeogenesis is intact. METHODS: A retrospective cohort study of biochemical profiles from supervised clinical fasting studies is performed in ketotic GSD patients in our metabolic center. For data analysis, hypoglycemia was defined as plasma glucose concentration <2.6 mmol/L. Total KB was defined as the sum of blood acetoacetate and ß-hydroxybutyrate concentrations. If the product of glucose and KB concentrations was greater than 10, a ketolysis defect was suspected. RESULTS: Data could be collected from 13 fasting studies in 12 patients with GSD III (n = 4), GSD VI (n = 3), and GSD IX (n = 5). Six patients remained normoglycemic with median glucose concentration of 3.9 mmol/L (range, 2.8-4.6 mmol/L) and median total KB concentration of 1.9 mmol/L (range, 0.6-5.1 mmol/L). The normoglycemic patients included type VI (3 out of 3) and type IX (3 out of 5) patients. All type III patients developed ketotic hypoglycemia. Interestingly, in five patients (one GSD III, one GSD VI, and three GSD IX), the biochemical profile suggested a ketolysis defect. CONCLUSION: Normoglycemic ketonemia is a common biochemical presentation in patients with GSD types VI and IX, and ketonemia can precede hypoglycemia in all studied GSD types. Therefore, GSD VI and GSD IX should be added to the differential diagnosis of ketotic normoglycemia, and KB concentrations should be routinely measured in ketotic GSD patients.