Glycogen Storage Disease Research Articles

A case study of a liver transplant-treated patient with glycogen storage disease type Ia presenting with multiple inflammatory hepatic adenomas: an analysis of clinicopathologic and genetic data

BackgroundGlycogen storage disease (GSD) is a disease caused by excessive deposition of glycogen in tissues due to genetic disorders in glycogen metabolism. Glycogen storage disease type I (GSD-I) is also known as VonGeirk disease and glucose-6-phosphatase deficiency. This disease is inherited in an autosomal recessive manner, and both sexes can be affected. The main symptoms include hypoglycaemia, hepatomegaly, acidosis, hyperlipidaemia, hyperuricaemia, hyperlactataemia, coagulopathy and developmental delay.Case presentationHere, we present the case of a 13-year-old female patient with GSD Ia complicated with multiple inflammatory hepatic adenomas. She presented to the hospital with hepatomegaly, hypoglycaemia, and epistaxis. By clinical manifestations and imaging and laboratory examinations, we suspected that the patient suffered from GSD I. Finally, the diagnosis was confirmed by liver pathology and whole-exome sequencing (WES).WES revealed a synonymous mutation, c.648 G > T (p.L216 = , NM_000151.4), in exon 5 and a frameshift mutation, c.262delG (p.Val88Phefs*14, NM_000151.4), in exon 2 of the G6PC gene. According to the pedigree analysis results of first-generation sequencing, heterozygous mutations of c.648 G > T and c.262delG were obtained from the patient's father and mother.Liver pathology revealed that the solid nodules were hepatocellular hyperplastic lesions, and immunohistochemical (IHC) results revealed positive expression of CD34 (incomplete vascularization), liver fatty acid binding protein (L-FABP) and C-reactive protein (CRP) in nodule hepatocytes and negative expression of β-catenin and glutamine synthetase (GS). These findings suggest multiple inflammatory hepatocellular adenomas. PAS-stained peripheral hepatocytes that were mostly digested by PAS-D were strongly positive.This patient was finally diagnosed with GSD-Ia complicated with multiple inflammatory hepatic adenomas, briefly treated with nutritional therapy after diagnosis and then underwent living-donor liver allotransplantation.After 14 months of follow-up, the patient recovered well, liver function and blood glucose levels remained normal, and no complications occurred.ConclusionThe patient was diagnosed with GSD-Ia combined with multiple inflammatory hepatic adenomas and received liver transplant treatment. For childhood patients who present with hepatomegaly, growth retardation, and laboratory test abnormalities, including hypoglycaemia, hyperuricaemia, and hyperlipidaemia, a diagnosis of GSD should be considered. Gene sequencing and liver pathology play important roles in the diagnosis and typing of GSD.

Clinical profile of children with metabolic liver diseases presenting in a tertiary care hospital of Eastern India

Clinical profile of children with metabolic liver diseases presenting in a tertiary care hospital of Eastern India

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.

Acid α-glucosidase (GAA) activity and glycogen content in muscle biopsy specimens of patients with Pompe disease: A systematic review

Pompe disease is a rare genetic disorder characterized by a deficiency of acid α-glucosidase (GAA), leading to the accumulation of glycogen in various tissues, especially in skeletal muscles. The disease manifests as a large spectrum of phenotypes from infantile-onset Pompe disease (IOPD) to late-onset Pompe disease (LOPD), depending on the age of symptoms onset. Quantifying GAA activity and glycogen content in skeletal muscle provides important information about the disease severity. However, the distribution of GAA and glycogen levels in skeletal muscles from healthy individuals and those impacted by Pompe disease remains poorly understood, and there is currently no universally accepted standard assay for GAA activity measurement. This systematic literature review aims to provide an overview of the available information on GAA activity and glycogen content levels in skeletal muscle biopsies from patients with Pompe disease.A structured review of PubMed and Google Scholar literature (with the latter used to check that no additional publications were identified) was conducted to identify peer-reviewed publications on glycogen storage disease type II [MeSH term] + GAA, protein human (supplementary concept), Pompe, muscle; and muscle, acid alpha-glucosidase. A limit of English language was applied. Results were grouped by methodologies used to quantify GAA activity and glycogen content in skeletal muscle. The search and selection strategy were devised and carried out in line with Preferred Reporting of Items in Systematic Reviews and Meta-Analysis guidelines and documented using a flowchart. Bibliographies of papers included in the analysis were reviewed and applicable publications not already identified in the search were included.Of the 158 articles retrieved, 24 (comprising >100 muscle biopsies from >100 patients) were included in the analysis, with four different assays. Analysis revealed that patients with IOPD exhibited markedly lower GAA activity in skeletal muscles than those with LOPD, regardless of the measurement method employed. Additionally, patients with IOPD had notably higher glycogen content levels in skeletal muscles than those with LOPD. In general, however, it was difficult to fully characterize GAA activity because of the different methods used. The findings underscore the challenges in the interpretation and comparison of the results across studies because of the substantial methodological variations. There is a need to establish standardized reference ranges of GAA activity and glycogen content in healthy individuals and in Pompe disease patients based on globally standardized methods to improve comparability and reliability in assessing this rare disease.

Long-term personalized high-protein, high-fat diet in pediatric patients with glycogen storage disease type IIIa: Evaluation of myopathy, metabolic control, physical activity, growth, and dietary compliance.

Dietary lipid manipulation has recently been proposed for managing glycogen storage disease (GSD) type IIIa. This study aimed to evaluate the myopathic, cardiac, and metabolic status, physical activity, growth, and dietary compliance of a personalized diet high in protein and fat for 24 months. Of 31 patients with type IIIa GSD, 12 met the inclusion criteria. Of these, 10 patients (mean age 11.2 ± 7.4 years) completed the study. Patients were prescribed a personalized high-protein, high-fat diet, comprising 3.0-3.5 g/kg/day of protein and 3.0-4.5 g/kg/day of fat, constituting 18.5%-28% and 70.5%-75.7% of daily energy, respectively. Dietary compliance was ensured and assessed via the regular administration of questionnaires. Our results revealed consistent and significant decreases of 22%, 54%, and 30% in the creatinine kinase, creatine kinase-myocardial band, and lactate dehydrogenase levels, respectively. Echocardiography revealed improvements in the Z-scores of the left ventricular mass and interventricular septum thickness. A significant increase in body muscle mass was observed, and a higher score was achieved using the Daily Activity Questionnaire. Growth monitoring revealed an arrest in the height-SDS at the 6th and 12th months, followed by subsequent improvement at the end of the second year. A gradual and persistent decline in the periods of hypo- and hyperglycemia has been reported. Biotinidase activity decreased, whereas hepatosteatosis increased and then decreased by the end of the study. Implementing a high-protein, high-fat diet and monitoring key parameters in patients with type IIIa GSD can lead to myopathic and cardiac improvements and increased physical activity.

Broadening the Phenotype and Genotype Spectrum of Glycogen Storage Disease by Unraveling Novel Variants in an Iranian Patient Cohort.

Glycogen storage diseases (GSDs) are a group of rare inherited metabolic disorders characterized by clinical, locus, and allele heterogeneity. This study aims to investigate the phenotype and genotype spectrum of GSDs in a cohort of 14 families from Iran using whole-exome sequencing (WES) and variant analysis. WES was performed on 14 patients clinically suspected of GSDs. Variant analysis was performed to identify genetic variants associated with GSDs. A total of 13 variants were identified, including six novel variants, and seven previously reported pathogenic variants in genes such as AGL, G6PC, GAA, PYGL, PYGM, GBE1, SLC37A4, and PHKA2. Most types of GSDs observed in the cohort were associated with hepatomegaly, which was the most common clinical presentation. This study provides valuable insights into the phenotype and genotype spectrum of GSDs in a cohort of Iranian patients. The identification of novel variants adds to the growing body of knowledge regarding the genetic landscape of GSDs and has implications for genetic counseling and future therapeutic interventions. The diverse nature of GSDs underscores the need for comprehensive genetic testing methods to improve diagnostic accuracy. Continued research in this field will enhance our understanding of GSDs, ultimately leading to improved management and outcomes for individuals affected by these rare metabolic disorders.

Improvement of neutropenia in 2 adolescent cases treated with empagliflozin for glycogen storage disease type Ib

Neutropenia and elevated concentrations of hepatic transaminases often lead to referrals from emergency or outpatient departments to relevant specialists to diagnose underlying inborn errors of metabolism. Glycogen storage disease type (GSD) Ib, a rare congenital disorder of glucose metabolism caused by the SLC37A4 gene mutations, shows various manifestations, including persistent neutropenia and elevated hepatic transaminases. Empagliflozin has demonstrated its efficacy in treating GSD Ib-associated neutropenia by reducing the entry of 1,5-anhydroglucitol-6-phosphate into the neutrophils. This article reports successful empagliflozin therapy for GSD Ib-related neutropenia in 2 Korean adolescents. Diagnosing GSD Ib is complex and usually initiated by a referral from emergency or outpatient departments when there is a high index of suspicion. Once diagnosed, empagliflozin shows promising outcomes in restoring counts and function of the neutrophils without severe adverse effects in children with GSD Ib, supporting it as a safe and effective therapeutic option for GSD Ib-associated neutropenia.

Empagliflozin in children with glycogen storage disease-associated inflammatory bowel disease: a prospective, single-arm, open-label clinical trial

Glycogen storage disease type Ib (GSD-Ib) is a rare inborn error of glycogen metabolism caused by mutations in SLC37A4. Patients with GSD-Ib are at high risk of developing inflammatory bowel disease (IBD). We evaluated the efficacy of empagliflozin, a renal sodium‒glucose cotransporter protein 2 (SGLT2) inhibitor, on colonic mucosal healing in patients with GSD-associated IBD. A prospective, single-arm, open-label clinical trial enrolled eight patients with GSD-associated IBD from Guangdong Provincial People's Hospital in China from July 1, 2022 through December 31, 2023. Eight patients were enrolled with a mean age of 10.34 ± 2.61 years. Four male and four female. The endoscopic features included deep and large circular ulcers, inflammatory hyperplasia, obstruction and stenosis. The SES-CD score significantly decreased at week 48 compared with before empagliflozin. Six patients completed 48 weeks of empagliflozin therapy and endoscopy showed significant improvement or healing of mucosal ulcers, inflammatory hyperplasia, stenosis, and obstruction. One patient had severe sweating that required rehydration and developed a urinary tract infection. No serious or life-threatening adverse events. This study suggested that empagliflozin may promote colonic mucosal healing and reduce hyperplasia, stenosis, and obstruction in children with GSD-associated IBD.

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

Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.

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

Characterizing the clinical course of pediatric-onset neuromuscular glycogen storage disease IV: An international, collaborative study

Characterizing the clinical course of pediatric-onset neuromuscular glycogen storage disease IV: An international, collaborative study

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

A New Mutation of Pompe Disease in a 2-Month-Old Infant

Pompe disease, also known as type 2 glycogen storage disease (GSD), is an autosomal recessive disorder. It occurs due to the deficiency of an enzyme, acid maltase, which degrades glycogen in lysosomes. This deficiency leads to glycogen accumulation in several tissues, such as cardiac muscle cells [1]. The disease is classified into infantile and late-onset types. Infantile Pompe disease (IPD) can manifest with feeding problems, hepatomegaly, generalized muscle weakness, hypotonia, macroglossia, and hypertrophic cardiomyopathy [1-3], from the first day to weeks of life [1]. If left untreated, IPD leads to cardiorespiratory failure and death within one year. Late-onset Pompe disease (LOPD), which includes juvenile-, childhood-, and adult-onset disease, is characterized by proximal muscle weakness, respiratory muscle involvement (especially the diaphragm), and arrhythmia. The prognosis of LOPD is less severe than that of IPD [1]. Diagnosis can be made by gene sequencing of the acid alpha-glucosidase (GAA) gene and enzyme assay in dried blood, muscle, skin, and blood cells [5,6]. During pregnancy, diagnosis can also be made by amniocentesis [1]. Treatment with enzyme replacement using recombinant human acid α-glucosidase is effective. As IPD is rapidly progressive, treatment should be initiated as soon as possible. Enzyme therapy can prevent and reverse cardiac and muscle involvement [1]. According to the information the authors have about Pompe disease, in most cases, the initial signs and symptoms are common with other diseases. In these cases, genetic testing significantly helps to definitively diagnose the disease. With the progress made in genetic tests, sometimes new mutations are added to the existing genetic bank. In this case report, the authors introduce a Pompe patient with a new genetic mutation of pathogenic types. This patient had presented with signs of severe hypotonia and cardiomegaly, increased cardiac enzymes, and abnormal liver tests. Despite enzyme therapy immediately after diagnosis, the patient died.

Prevalence of common autosomal recessive mutation carriers in women in the Southern Vietnam following the application of expanded carrier screening

The common autosomal recessive (AR) mutation carrier is still unknown in Vietnam. This study aims to identify the most common AR gene mutation carriers in women of reproductive age to build a Vietnamese-specific carrier screening panel for AR and X-linked disorders in the preconception and prenatal healthcare program. A cross-sectional study was conducted at University Medical Center–Branch 2 in Ho Chi Minh City from December 1st, 2020, to June 30th, 2023. 338 women have consented to take a 5 mL blood test to identify 540 recessive genes. The carrier screening panel was designed based on the American College of Medical Genetics and Genomics (ACMG)-recommended genes and suggestions from 104 clinical experts in Vietnam. Obstetricians and genetic experts counseled all positive testing results to discuss the possibility of recessive diseases in their offspring. The most common recessive disorders were defined at a prevalence of 1 in 60 or greater, and those were added to a Vietnamese-specific carrier screening panel. 338 non-pregnant and pregnant women underwent the expanded carrier screening (ECS). The carrier frequency was 63.6%, in which 215 women carried at least one AR gene mutation. GJB2 hearing impairment was identified as the most common chronic condition (1 in 5). The second most common AR disorder was beta-thalassemia (1 in 16), followed by cystic fibrosis (1 in 23), G6PD deficiency (1 in 28), Wilson’s disease (1 in 31), Usher’s syndrome (1 in 31), and glycogen storage disease (1 in 56). Seven common recessive genes were added in ethnic-based carrier screening. Women in the South of Vietnam have been carried for many recessive conditions at high frequency, such as hearing impairment, genetic anemia, and cystic fibrosis. It is necessary to implement a preconception and prenatal screening program by using seven widely popular AR genes in a Vietnamese-specific carrier screening panel to reduce the burden related to AR and X-linked disorders.