Glycogen Storage Disease Type Research Articles

Pediatric Considerations in Pompe Disease: A Comprehensive Review

Pompe disease, also known as glycogen storage disease type II, is a rare inherited disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA), leading to the accumulation of glycogen in various tissues, particularly muscles. While Pompe disease can affect individuals of all ages, its presentation and management in pediatric patients present unique challenges. This review aims to provide a comprehensive overview of the clinical manifestations, diagnosis, and management of Pompe disease in pediatric populations. Special considerations in the areas of respiratory support, nutrition, physical therapy, and long-term outcomes will be discussed. Understanding these aspects is crucial for optimizing the care and quality of life for children with Pompe disease

Clinical spectrum, over 12-year follow-up and experience of SGLT2 inhibitors treatment on patients with glycogen storage disease type Ib: a single-center retrospective study

BackgroundGlycogen storage disease type Ib (GSD Ib) is a rare disorder characterized by impaired glucose homeostasis caused by mutations in the SLC37A4 gene. It is a severe inherited metabolic disease associated with hypoglycemia, hyperlipidemia, lactic acidosis, hepatomegaly, and neutropenia. Traditional treatment consists of feeding raw cornstarch which can help to adjust energy metabolism but has no positive effect on neutropenia, which is fatal for these patients. Recently, the pathophysiologic mechanism of the neutrophil dysfunction and neutropenia in GSD Ib has been found, and the treatment with the SGLT2 inhibitor empaglifozin is now well established. In 2020, SGLT2 inhibitor empagliflozin started to be used as a promising efficient remover of 1,5AG6P in neutrophil of GSD Ib patients worldwide. However, it is necessary to consider long-term utility and safety of a novel treatment.ResultsIn this study, we retrospectively examined the clinical manifestations, biochemical examination results, genotypes, long-term outcomes and follow-up of thirty-five GSD Ib children who visited our department since 2009. Fourteen patients among them underwent empagliflozin treatment since 2020. This study is the largest cohort of pediatric GSD Ib patients in China as well as the largest cohort of pediatric GSD Ib patients treated with empagliflozin in a single center to date. The study also discussed the experience of long-term management on pediatric GSD Ib patients.ConclusionEmpagliflozin treatment for pediatric GSD Ib patients is efficient and safe. Increase of urine glucose is a signal for pharmaceutical effect, however attention to urinary infection and hypoglycemia is suggested.

Genotypic and phenotypic features of 39 Chinese patients with glycogen storage diseases type I, VI, and IX.

Glycogen storage diseases (GSDs) are abnormally inherited glycogen metabolism mainly affecting the liver, muscles, and heart. Deficiency of proteins involved in glycogen metabolism caused by genetic mutations are responsible for different subtype of GSDs. However, there are still some challenges in diagnosing GSD. This study includes 39 suspected GSDs patients from unrelated families in China. Next-generation sequencing (NGS) was used to investigate the reason for their diseases at the genetic level. Finally, all 39 patients were diagnosed with GSDs, including 20 GSD-Ia, 4 GSD-VI, and 15 GSD IX (12 GSD-IXa patients and 3 GSD-IXb patients). Thirty-two mutations in G6PC1, PYGL, PHKA2, and PHKB genes were identified, with 14 of them being novel variants. The pathogenicity of novel variants was classified according to ACMG guildlines and predicted by in slico algorithms. Mutations p.L216L and p.R83H in G6PC1 gene may be the hot spot mutation in Chinese. Hearing impairment is a rare clinical feature of GSD Ia, which has also been observed in our cohort. The severity of GSD VI and IX was indicated by our patients. Close follow-up should be applied to GSD VI and IX patients. Our findings provided evidence for building the phenotype-genotype of GSDs and expanded the mutation spectrum of related genes.

Medium-Chain Triglyceride Oil and Dietary Intervention Improved Body Composition and Metabolic Parameters in Children with Glycogen Storage Disease Type 1 in Jordan: A Clinical Trial.

Glycogen storage diseases (GSDs) are a group of carbohydrate metabolism disorders, most of which are inherited in autosomal recessive patterns. GSDs are of two types: those that have to do with liver and hypoglycaemia (hepatic GSDs) and those that are linked to neuromuscular presentation. This study aims to assess the impact of dietary intervention, including medium-chain triglyceride (MCT) oil, on anthropometric measurements, body composition analysis and metabolic parameters among Jordanian children and is expected to be the first in the country. A sample of 38 children with glycogen storage disease type 1 (GSD-1) (median age = 6.4 years) were on a diet that included uncooked cornstarch therapy and a fructose-, sucrose- and lactose-restricted diet. Patients started to take MCT oil along with the prescribed diet after the first body composition test. Patients' nutritional status was re-evaluated three months later. The study results show that the percentage of patients who suffered from hypoglycaemia at the beginning of the study decreased significantly from 94.7% to 7.9% (p < 0.0001). The serum levels of triglycerides, cholesterol, uric acid and lactate decreased significantly after three months of intervention (100-71.1%, 73.7-21.1%, 97.4-52.6% and 94.7-18.4%, respectively). In contrast, there was no statistical difference in neutrophil count. Regarding clinical parameters, liver span was significantly reduced from (16.01 ± 2.65 cm) to (14.85 ± 2.26 cm) (p < 0.0001). There were significant improvements in growth parameters, including height-for-age and BMI-for-age for children aged ≥2 years (p = 0.034 and p = 0.074, respectively). Significant improvements in skeletal muscle mass and bone mineral content were also noticed at the end of the trial (p ≤ 0.05). In conclusion, medium-chain triglyceride therapy is found to improve biochemical and growth parameters in children with GSD-1 in Jordan.

Genome editing for glycogen storage disease type 1A

Genome editing for glycogen storage disease type 1A

Trial interviews to explore glycogen storage disease type Ia patient experiences of gene therapy

Trial interviews to explore glycogen storage disease type Ia patient experiences of gene therapy

A Phase 1/2 first-in-human study to evaluate the safety, tolerability, and pharmacokinetics of UX053 in patients with glycogen storage disease type III

A Phase 1/2 first-in-human study to evaluate the safety, tolerability, and pharmacokinetics of UX053 in patients with glycogen storage disease type III

Effects of DTX401 gene therapy administration on endocrine dysregulation in glycogen storage disease type Ia

Effects of DTX401 gene therapy administration on endocrine dysregulation in glycogen storage disease type Ia

Neutrophil functions in patients with neutropenia due to glycogen storage disease type 1b treated with empagliflozin

AbstractNeutropenia and neutrophil dysfunction in glycogen storage disease type 1b (GSD1b) are caused by the accumulation of 1,5-anhydroglucitol-6-phosphate in granulocytes. The antidiabetic drug empagliflozin reduces the concentration of 1,5-anhydroglucitol (1,5-AG), thus restoring neutrophil counts and functions, leading to promising results in previous case reports. Here, we present a comprehensive analysis of neutrophil function in 7 patients with GSD1b and 11 healthy donors, aiming to evaluate the immediate (after 3 months) and long-term (after 12 months) efficacy of empagliflozin compared with the reference treatment with granulocyte-colony stimulating factor (G-CSF). We found that most patients receiving G-CSF remained neutropenic with dysfunctional granulocytes, whereas treatment with empagliflozin increased neutrophil counts and improved functionality by inhibiting apoptosis, restoring phagocytosis and the chemotactic response, normalizing the oxidative burst, and stabilizing cellular and plasma levels of defensins and lactotransferrin. These improvements correlated with the decrease in serum 1,5-AG levels. However, neither G-CSF nor empagliflozin overcame deficiencies in the production of cathelicidin/LL-37 and neutrophil extracellular traps. Given the general improvement promoted by empagliflozin treatment, patients were less susceptible to severe infections. G-CSF injections were therefore discontinued in 6 patients (and the dose was reduced in the seventh) without adverse effects. Our systematic analysis, the most extensive reported thus far, has demonstrated the superior efficacy of empagliflozin compared with G-CSF, restoring the neutrophil population and normal immune functions. This trial was registered as EudraCT 2021-000580-78.

Essential dextrin structure as donor substrate for 4-α-glucanotransferase in glycogen debranching enzyme.

Glycogen debranching enzyme is a single polypeptide with distinct catalytic sites for 4-α-glucanotransferase and amylo-α-1,6-glucosidase. To allow phosphorylase to degrade the inner tiers of highly branched glycogen, 4-α-glucanotransferase converts the phosphorylase-limit biantennary branch G-G-G-G-(G-G-G-G↔)G-G- (G: d-glucose, hyphens: α-1,4-linkages; double-headed arrow: α-1,6-linkage) into the G-G-G-G-(G↔)G-G- residue, which is then subjected to amylo-α-1,6-glucosidase to release the remaining G↔ residue. However, while the essential side-chain structure of the 4-α-glucanotransferase donor substrate has been determined to be the G-G-G-G↔ residue (Watanabe, Y., etal. (2008) J. Biochem.143, 435-440), its essential main-chain structure remains to be investigated. In this study, we probed the 4-α-glucanotransferase donor-binding region using novel fluorogenic dextrins Gm-(G4↔)G-Gn-F (F: 1-deoxy-1-[(2-pyridyl)amino]-d-glucitol) and maltohexaose (G6) as the donor and acceptor substrates, respectively. 4-α-Glucanotransferase exhibited maximum activity towards G4-(G4↔)G-F and G4-(G4↔)G-G-F, indicating that recognition of the G4-(G4↔)G-moiety was essential for full enzyme function. Notably, when the 4-α-glucanotransferase activity towards G4-(G4↔)G-G-F was taken as unity, those towards nonbranching dextrins were < 0.001. This indicated that the disproportionation activities towards maltooligosaccharides (Gm) are abnormal behaviours of 4-α-glucanotransferase. Notably, however, these activities have been traditionally measured to identify the 4-α-glucanotransferase mutations causing glycogen storage disease type III. This study provides a basis for more accurate identification.

Infantile-onset pompe disease: a case report emphasizing the role of genetic counseling and prenatal testing

BackgroundPompe disease, classified as glycogen storage disease type II, arises from a deficiency in the acid alpha-glucosidase (GAA) enzyme, leading to glycogen accumulation in multiple tissues. The unique correlation between genotype and enzyme activity is a key feature. This case highlights an infantile-onset form, emphasizing genetic counseling and prenatal testing importance.Case PresentationAn 18-week-old infant with respiratory distress, cyanosis, and fever was admitted. Born healthy, her sibling died from Pompe disease. She presented with cardiomegaly, hypotonia, and absent reflexes. Diagnosis was confirmed by significantly reduced GAA activity. Despite treatment initiation, the patient succumbed to cardiac arrest.ConclusionsThe case underscores genetic counseling’s role, offering insights into prenatal testing advancements, antenatal diagnosis through echocardiography, and the significance of early intervention, particularly in infantile-onset Pompe disease.SynopsisGenetic risk assessment and prenatal testing are crucial for families with a history of Pompe disease to improve early diagnosis and management outcomes.

A simple, non-invasive method for the diagnosis of glycogen storage disease type III in two patients with a similar facial appearance

A simple, non-invasive method for the diagnosis of glycogen storage disease type III in two patients with a similar facial appearance

Report of an Iranian child with chronic abdominal pain and constipation diagnosed as glycogen storage disease type IX: a case report

BackgroundGlycogen storage disease type IX is a rare disorder that can cause a wide variety of symptoms depending on the specific deficiency of the phosphorylase kinase enzyme and the organs it affects.Case presentationA 4-and-a-half-year-old Caucasian girl was referred to our clinic with a liver biopsy report indicating a diagnosis of glycogen storage disease. Prior to being referred to our clinic, the patient had been under the care of pediatric gastroenterologists. The patient’s initial symptoms included chronic abdominal pain, constipation, and elevated liver transaminase. With the help of the pediatric gastroenterologists, cholestasis, Wilson disease, and autoimmune hepatitis were ruled out. Given that glycogen storage diseases type I and type III are the most common, we initially managed the patient with frequent feedings and a diet that included complex carbohydrates such as a corn starch supplement and a lactose restriction. Following an unfavorable growth velocity and hepatomegaly during the follow-up period, genetic analysis was conducted, which revealed a novel mutation of the phosphorylase kinase regulatory subunit beta gene— a c.C412T (P.Q138x) mutation. As the diagnosis of glycogen storage disease type IX was confirmed, the treatment regimen was altered to a high protein diet (more than 2 g/kg/day) and a low fat diet.ConclusionGiven the mild and varied clinical manifestations of glycogen storage disease type IX, it is possible for the diagnosis to be overlooked. It is important to consider glycogen storage disease type IX in children who present with unexplained hepatomegaly and elevated transaminase levels. Furthermore, due to the distinct management of glycogen storage disease type IX compared with glycogen storage disease type I and glycogen storage disease type III, genetic analysis is essential for an accurate diagnosis.

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.

Toward an Understanding of GSD5 (McArdle disease): How Do Individuals Learn to Live with the Metabolic Defect in Daily Life.

Glycogen storage disease type 5 (GSD) is an autosomal recessive inherited metabolic myopathy caused by a deficiency of the enzyme muscle glycogen phosphorylase. Individuals with GSD5 experience physical activity intolerance. This patient-led study aimed to capture the daily life experiences of GSD5, with a focus on adapting to and coping with their physical activity intolerance. An online survey was composed in close collaboration with patient organizations. It consisted of customized and validated questionnaires on demographics, general health and comorbidities, physical activity, psychosocial well-being and functioning, pain, fatigue and adapting to and coping with GSD5. One hundred sixty-two participants (16 countries) participated. The majority, n = 86 (69%) were from the Netherlands, USA or UK. We observed a high rate of misdiagnosis prior to GSD5 diagnosis (49%), surprisingly a relatively high proportion had not been diagnosed by DNA testing which is the gold standard. Being diagnosed had a strong impact on emotional status, daily life activities and important life choices. A large proportion had not received any rehabilitation (41%) nor medical treatment (57%) before diagnosis. Engagement in vigorous and moderate physical activity was reduced. Health related quality of life was low, most likely related to low physical health. The median Fatigue Severity Score was 4.3, indicating moderate to severe fatigue. Participants themselves had found various ways to adapt to and cope with their disability. The adaptations concerned all aspect of their life, including household chores, social and physical activities, and work. In addition to lack of support, participants reported limited availability of information sources. Participants have provided guidance for newly diagnosed people, including the advice to accept one's limited abilities and maintain an active lifestyle. We conclude that adequate counseling on ways of adapting and coping is expected to increase both health-related quality of life and physical activity.

Diagnosing glycogen storage disease type 1b in adulthood: A case with multiple hepatocellular adenomas

Diagnosing glycogen storage disease type 1b in adulthood: A case with multiple hepatocellular adenomas

Glycogen storage disease type 1 (GSD1a) and the liver adenoma/ hepatocellular carcinoma (HCC) sequence: insights from whole genome sequencing (WGS)

Glycogen storage disease type 1 (GSD1a) and the liver adenoma/ hepatocellular carcinoma (HCC) sequence: insights from whole genome sequencing (WGS)

“A Complex Conundrum”- Fanconi-Bickel Syndrome

Fanconi-Bickel Syndrome (FBS) is a rare form of Glycogen Storage Disease (GSD) type 11 characterised by massive hepatomegaly due to the buildup of glycogen and severe hypophosphatemic rickets due to a proximal renal tubular dysfunction. Since 1940, it has been initially known as hepatorenal glycogenesis with proximal renal tubular dysfunction. It is due to a pathogenic mutation of the GLUT-2 (glucose transporter) gene. Herein, present case report a young toddler who is the firstborn of 3rd-degree consanguinity, presented with rickets, recurrent respiratory tract infections, and hepatomegaly, and was subsequently diagnosed with FBS with the help of genetic studies, showing a mutation in the GLUT-2 gene. With less than 200 cases reported so far, this child represents a unique case with recurrent respiratory infections and developmental delay as presentations along with rachitic features.

Anesthetic management of glycogen storage disease type 1b during liver transplantation: a case report

The glycogen storage disease type 1b is a rare metabolic disease caused by the glucose 6-phosphate transporter disorder. This study presents a 10-year-old female patient with growth retardation, neutropenia and inflammatory bowel disease, severe hypoglycemia attacks before and during the surgery, and hepatocellular carcinoma who underwent liver transplantation. A multidisciplinary approach from the preoperative preparation stage is essential in addition to intraoperative intervention for hypoglycemia and lactic acidosis in the anesthetic management of these patients.

Glycogen storage disease type III: a mixed-methods study to assess the burden of disease.

Glycogen storage disease type III (GSD III) is a rare inherited disorder that results from a glycogen debranching enzyme deficiency. The purpose of this research was to collect data on the signs, symptoms, and impacts of GSD III from the perspective of adult patients and caregivers of individuals with GSD III. Online survey and qualitative interviews. Following institutional review board approval, adult patients and caregivers of children with GSD III were recruited through advocacy networks and clinical sites. If eligible, participants were consented, screened, and sent a survey and/or participated in a 60-min interview. The survey and interview included questions about family history, diagnosis, signs and symptoms, impacts, and management of GSD III. Conceptual models were developed following the analysis of results. In all, 29 adults and 46 caregivers completed the online survey and/or the interviews with 73 survey and 19 interview respondents. Adults and caregivers reported digestive, musculoskeletal, growth and physical appearance, and cardiac signs and symptoms. Liver conditions were reported by most respondents (83%). Adults and caregivers frequently reported impacts such as difficulty keeping up with peers (77%) and difficulty exercising/difficulty with physical activity (53%). Hypoglycemia was frequently reported in both adults and children, with more than half reporting hospitalizations due to hypoglycemia. Caregivers focused on hypoglycemia when reporting signs/symptoms that most interfere with their child's life and prevention of hypoglycemia as a desired outcome for an effective therapy. Adults most often reported muscle weakness as a top interfering symptom and the most important goal of a potential therapy. Impacts were also reported in activities of daily living, cognitive, emotional, work/school, and sleep domains. Individuals with GSD III experience a broad spectrum of symptoms and disease impacts. There is an unmet need for therapies that improve metabolic control, reduce the burden of dietary management, reduce fatigue and liver problems, and improve muscle strength and function.