Diagnosis Of Glycogen Storage Disease Research Articles

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.

A novel PHKA2 variant in a Chinese boy with glycogen storage diseases type IXa.

Glycogen storage diseases (GSDs) are a group of heterogeneous inherited metabolic disorders with an incidence of 4%-5%. There are 19 types of GSDs, making diagnosis one of the greatest challenges. The proband and his parents were referred to our hospital for genetic diagnosis. Ultrasound screening suggested hepatomegaly. A novel insertion variant NM_000292 c.1155_1156insT (p. 386N>*) in PHKA2 gene was identified using trio whole exome sequencing (Trio-WES), which resulted in the codon of amino acid 386 from asparagine to termination (p. 386N>*). The 3D mutant protein structure was predicted using AlphaFold, and the results showed that the truncated PHKA2 protein contained 385 of the 1,235 amino acids of the mature protein. We describe a previously unreported case of a GSDs IXa type Chinese boy caused by a novel PHKA2 variant. This clinical case contributes to the understanding of the characteristics of GSDs type IXa and expands the variants spectrum of genes related to GSDs type IXa. Our findings demonstrated the significance of genetic testing in the diagnosis of GSDs.

Glycogen Storage Disease Type III Presenting as Recurrent Seizure Disorder in a Second Twin: A Case Report

Glycogen storage diseases (GSDs) are a group of genetic autosomal recessive metabolic disorders resulting from deficiencies of enzymes of glycogen metabolism occurring in the liver, muscles or kidneys. Various types and sub-types exist based on genetic classification presenting with symptoms and signs of hypoglycaemia, hepatomegaly and myopathy depending on severity, and age of onset. A high index of suspicion is required for the diagnosis of GSDs. An eighteen-month-old girl who was apparently healthy with normal development was without any abnormality until about 12 months of age when she had the first episode of afebrile seizure which was treated with sodium valproate but continued to have occasional seizures. She had a status seizure, which was only aborted with a glucose infusion. Intra-ictal incident glucose level was 1.4mmol/L. Biochemical investigation revealed deranged liver enzymes, normal serum cortisol, C-peptide and insulin. Liver histology showed features consistent with GSD III and diagnosis of glycogen storage disease type III was made based on the liver histology and other supportive laboratory features. Following dietary management, the child responded very well, was seizure-free and off anticonvulsant therapy. This case highlights the occurrence of symptomatic seizures due to factors other than epilepsy.

Clinical and biochemical characteristics of glycogen storage disease in Bangladeshi children from a tertiary care center

Abstract Background: Glycogen storage diseases (GSDs) are a group of metabolic diseases that results in aberrant glycogen metabolism due to genetic abnormalities of various enzymes. Glycogen degradation disorders primarily affect the liver, muscles, or both, which are the most seriously affected organs. Aim: This study aimed to determine the clinical and biochemical characteristics of GSD in children at Pediatric Gastroenterology and Nutrition Department, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Materials and Methods: This cross-sectional study was conducted over a period of 1 year and 6 months from October 2021 to March 2023. All children diagnosed with GSD on liver biopsy were enrolled in the study. Results: Among 437 children, 21 (4.8%) had a clinical diagnosis of GSD. The mean age at presentation to BSMMU was 2.3 ± 1.3 years. The male-to-female ratio was 1:1.1. Hepatomegaly was the primary cause of abdominal distension in all 21 patients (100%), whereas splenomegaly was found in nine (41.8%) patients. No patient had exhibited jaundice. One patient (4.7%) had experienced delayed development. The levels of serum glutamic-pyruvic transaminase and uric acid were both increased in 16 (76.1%) and 20 (95.2%) patients, respectively. Around 4.7% of cases had neutropenia, hypoglycemia, and nephromegaly. Eighteen (85.7%) patients had short stature. Cirrhotic changes were absent in liver biopsy though periportal fibrosis was detected in 4 (19%) of the individuals. Conclusions: Children with GSD commonly present with short stature, hypertriglyceridemia, and hyperuricemia. Histopathology of the liver remains the preferred diagnostic means in Bangladesh.

Non-Progressive Hepatic Form of Andersen Disease as a Mimic of Hypertrophic Cardiomyopathy.

An 18-year-old male patient presented to our ambulatory services due to a 3-month course of progressive dyspnea and non-productive cough. Symptoms were present even at rest, and he exhibited severe limitation at physical activity. He had a diagnosis of glycogen storage disease (GSD) type IV attained by liver biopsy since three years of age, when he developed hepatomegaly and mild hepatic dysfunction. At the time, histopathological examination showed grade 2 fibrosis along with numerous intracytoplasmic PAS-positive deposits that were resistant [...]

Effects of various fixatives and temperature on the quality of glycogen demonstration in the brain and liver tissues

The visualization of glycogen deposits in cells and tissues is important for studying glycogen metabolism as well as diagnosis of glycogen storage diseases. Evidence suggests that the demonstration of glycogen can better be enhanced by factors such the choice of fixative and temperature during fixation. Here, we assessed efficacy of neutral buffered formalin (NBF), alcoholic formalin (AF) and paraformaldehyde (PFA) at 4 °C, 37 °C and 40 °C using Periodic Acid Schiff's staining method. Each liver specimen was fixed in NBF and AF while the brain tissues were fixed in NBF, AF and PFA. We found that there was a better PAS staining intensity with the liver tissues fixed in AF compared with NBF. Also, there was no difference in the quality of the staining for tissues fixed in AF at 37 °C, 4 °C and 40 °C, but fixation with NBF at 4 °C gave the best staining quality when compared with 40 °C and 37 °C. Furthermore, hippocampal tissues fixed in AF showed better quality of PAS staining compared with NBF and PFA. A significant increase in staining intensity was observed for PFA when compared with NBF. Superior staining intensity for PAS was observed at 4 °C for hippocampal tissues fixed with NBF, AF and PFA. Taken together our results show that AF at a temperature of 4 °C gave the best result. Hence, glycogen demonstration can better be enhanced by the choice of fixative and temperature during fixation.

Glycogen storage diseases-time to flip the outdated diagnostic approach centered on liver biopsy with the molecular testing

The glycogen storage diseases (GSDs) are a group of inherited metabolic disorders that result from a defect in any one of several enzymes required for either glycogen synthesis or glycogen degradation. The traditional diagnostic approach is based on the invasive hepatic or muscle biopsies, which are neither cost effective nor convenient. Molecular (gene testing) has emerged over the course of past few years as a robust alternative diagnostic tool, which not only confirms the diagnosis of GSDs but also clearly differentiates the types of GSDs allowing the initiation of the type-specific appropriate treatment for the particular type of GSDs. The aim of this update is to highlight the limitations of undertaking a liver biopsy for the diagnosis of GSDs; and to further describe the pros of the molecular testing for better patient centered care.

CLINICAL APPLICATION OF MASSIVE PARALLEL SEQUENCING IN MOLECULAR DIAGNOSTICS OF HEREDITARY DISEASES OF GLYCOGEN ACCUMULATION IN THE CHILDREN POPULATION OF THE RUSSIAN FEDERATION

There has been developed and validated the technology for massive parallel sequencing for the purpose of molecular genetic diagnosis of hereditary glycogen storage diseases. Among 96 patients aged of from 15 months up to 18 years, the diagnosis was verified in 89 (92.6%) children. Glycogen storage disease (GSD) type IX appeared to be the most frequent form of glycogenosis in children, diagnosed in 29.3% of cases, GSD type IV, verified in 1.1% of cases, was a rare form of glycogenesis. In 39 (43.8%) out of 89 genetically confirmed children, there were revealed 35 (44.3%) of the previously undescribed mutations from 79 pathogenic variants found in 9 (45%) of different genes of 20 examined cases, indicating to a significant heterogeneity of genetic factors of the development of GSD in the Russian population. Mutations c.247C>T of the G6PC gene, c.1042_1043del of the SLC37A4 gene, c.3980G>A and c.1423+1G>A of the AGL gene, c.-32-13T>G of the GAA gene, and c.884G>A of the PHKA2 gene were been established to be characteristic for the Russian population of GSD children. There was shown the high sensitivity and specificity of the massive parallel sequencing for the search for single nucleotide substitutions in coding and adjacent intron regions, as well as small deletions and duplications of genes, mutations in which lead to the development of GSD. Massive parallel sequencing is necessary for the rapid diagnosis of GSD, timely appointment of the adequate treatment, prevention of complications, which will improve the quality of the life of GSD patients.

Forbes Disease: A Case Report

Glycogen storage disease (GSD) type 3 (Forbes disease) is an autosomal recessive inborn error of metabolism caused by loss of function mutations of the glycogen debranching enzyme (Amylo- 1, 6-glucosidase [AGL]) and (oligo-1,4-1,4-glucanotransferase) gene, which is located at chromosome band 1p21.2. GSD 3 is characterized by the storage of structurally abnormal glycogen, termed limit dextrin, in both skeletal and cardiac muscle and/or liver, with great variability in resultant organ dysfunction. Here we describe a 16 yearold boy diagnosed as a case of epilepsy at the ageof 8. He presented to us with inadequately controlled seizure, profound proximal weakness, hepatosplenomegaly and right-sided ballotable kidney. The final diagnosis of glycogen storage disease was made by clinical features, lab reports and liver histopathology that revealed PAS positive diastase labile glycogen accumulation within swollen hepatocytes. The particular interest of this paper is to present a case of glycogen storage disease and demonstrate the difference between that entity and other storage diseases.Birdem Med J 2017; 7(1): 60-63

Novel method for detection of glycogen in cells.

Glycogen, a branched polymer of glucose, functions as an energy reserve in many living organisms. Abnormalities in glycogen metabolism, usually excessive accumulation, can be caused genetically, most often through mutation of the enzymes directly involved in synthesis and degradation of the polymer leading to a variety of glycogen storage diseases (GSDs). Microscopic visualization of glycogen deposits in cells and tissues is important for the study of normal glycogen metabolism as well as diagnosis of GSDs. Here, we describe a method for the detection of glycogen using a renewable, recombinant protein which contains the carbohydrate-binding module (CBM) from starch-binding domain containing protein 1 (Stbd1). We generated a fusion protein containing g lutathione S-transferase, a cM c eptitope and the tbd1 BM (GYSC) for use as a glycogen-binding probe, which can be detected with secondary antibodies against glutathione S-transferase or cMyc. By enzyme-linked immunosorbent assay, we demonstrate that GYSC binds glycogen and two other polymers of glucose, amylopectin and amylose. Immunofluorescence staining of cultured cells indicate a GYSC-specific signal that is co-localized with signals obtained with anti-glycogen or anti-glycogen synthase antibodies. GYSC-positive staining inside of lysosomes is observed in individual muscle fibers isolated from mice deficient in lysosomal enzyme acid alpha-glucosidase, a well-characterized model of GSD II (Pompe disease). Co-localized GYSC and glycogen signals are also found in muscle fibers isolated from mice deficient in malin, a model for Lafora disease. These data indicate that GYSC is a novel probe that can be used to study glycogen metabolism under normal and pathological conditions.

PHKA2 mutation spectrum in Korean patients with glycogen storage disease type IX: prevalence of deletion mutations.

BackgroundMolecular diagnosis of glycogen storage diseases (GSDs) is important to enable accurate diagnoses and make appropriate therapeutic plans. The aim of this study was to evaluate the PHKA2 mutation spectrum in Korean patients with GSD type IX.MethodsThirteen Korean patients were tested for PHKA2 mutations using direct sequencing and a multiplex polymerase chain reaction method. A comprehensive review of the literature on previously reported PHKA2 mutations in other ethnic populations was conducted for comparison.ResultsAmong 13 patients tested, six unrelated male patients with GSD IX aged 2 to 6 years at the first diagnostic work-up for hepatomegaly with elevated aspartate transaminase (AST) and alanine transaminase (ALT) were found to have PHKA2 mutations. These patients had different PHKA2 mutations: five were known mutations (c.537 + 5G > A, c.884G > A [p.Arg295His], c.3210_3212delGAG [p.Arg1072del], exon 8 deletion, and exons 27–33 deletion) and one was a novel mutation (exons 18–33 deletion). Notably, the most common type of mutation was gross deletion, in contrast to other ethnic populations in which the most common mutation type was sequence variant.ConclusionsThis study expands our knowledge of the PHKA2 mutation spectrum of GSD IX. Considering the PHKA2 mutation spectrum in Korean patients with GSD IX, molecular diagnostic methods for deletions should be conducted in conjunction with direct sequence analysis to enable accurate molecular diagnosis of this disease in the Korean population.

Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing.

Glycogen storage disease (GSD) is an umbrella term for a group of genetic disorders that involve the abnormal metabolism of glycogen; to date, 23 types of GSD have been identified. The nonspecific clinical presentation of GSD and the lack of specific biomarkers mean that Sanger sequencing is now widely relied on for making a diagnosis. However, this gene-by-gene sequencing technique is both laborious and costly, which is a consequence of the number of genes to be sequenced and the large size of some genes. This work reports the use of massive parallel sequencing to diagnose patients at our laboratory in Spain using either a customized gene panel (targeted exome sequencing) or the Illumina Clinical-Exome TruSight One Gene Panel (clinical exome sequencing (CES)). Sequence variants were matched against biochemical and clinical hallmarks. Pathogenic mutations were detected in 23 patients. Twenty-two mutations were recognized (mostly loss-of-function mutations), including 11 that were novel in GSD-associated genes. In addition, CES detected five patients with mutations in ALDOB, LIPA, NKX2-5, CPT2, or ANO5. Although these genes are not involved in GSD, they are associated with overlapping phenotypic characteristics such as hepatic, muscular, and cardiac dysfunction. These results show that next-generation sequencing, in combination with the detection of biochemical and clinical hallmarks, provides an accurate, high-throughput means of making genetic diagnoses of GSD and related diseases.Genet Med 18 10, 1037-1043.

Braın abscess due to Streptococcus intermedius secondary to mastoiditis in a child.

BackgroundBrain abscess is a rare but serious, life-threatening infection in children. It may arise from parameningeal infections such as otitis media, sinusitis and mastoiditis.Case descriptionA ten-year-old boy with the diagnosis of glycogen-storage disease and obesity was admitted to the emergency room with complaints of vomiting, decreased level of consciousness, imbalance on walking. On neurological examination, the patient was ataxic. His cranial magnetic resonance imaging (MRI) examination showed mastoiditis on the right side and 39 × 34 mm abscess formation with surrounding edema on the right cerebellar hemisphere. The patient underwent surgery to drain the abscess, microbiological samples were obtained and empirical antibiotic treatment with vancomycin and piperacillin–tazobactam were started. Postoperative cranial MRI examination showed that the lesion regressed 10 × 10 mm with a reduction in the edema. On the second week of the treatment, the antibiotics were switched to vancomycin and meropenem because of the relapsing fever. The therapy was continued for 6 weeks. A final MRI (after completing antibiotherapy) showed resolution of the cerebellar abscess. The child’s clinical condition improved and he was discharged without any sequelae.Discussion and evaluationChildren with congenital heart disease and an immonocompromised state are particularly at risk. Streptococcus intermedius is usually a commensal microorganism in the normal flora of the mouth which can cause brain abscess rarely in children. Brain abscess induced mortality rates are still relatively high, even with the advancement of imaging technologies, the combination of surgical drainage and antimicrobial therapy.ConclusionThis case is one of the few reported cases of cerebellar abscess caused by S. intermedius in an immunocompetent child, due to its low virulence, a rare occurence and timely management resulting in fully healed.

Application of whole exome sequencing to a rare inherited metabolic disease with neurological and gastrointestinal manifestations: A congenital disorder of glycosylation mimicking glycogen storage disease

BackgroundRare inherited metabolic diseases with neurological and gastrointestinal manifestations can be misdiagnosed as other diseases or remain as disorders with indeterminate etiologies. This study aims to provide evidence to recommend the utility of whole exome sequencing in clinical diagnosis of a rare inherited metabolic disease. Methods and resultsA 4-month-old female baby visited an outpatient clinic due to poor weight gain, repeated seizure-like episodes, developmental delay, and unexplained hepatomegaly with abnormal liver function test results. Although liver biopsy revealed moderate fibrosis with a suggested diagnosis of glycogen storage disease (GSD), no mutations were identified either by single gene approach for GSD (G6PC and GAA) or by next generation sequencing panels for GSD (including 21 genes). Whole exome sequencing of the patient revealed compound heterozygous mutations of PMM2: c.580C>T (p.Arg194*) and c.713G>C (p.Arg238Pro) which mutations were associated with congenital disorder of glycosylation Ia (CDG-Ia: PMM2-CDG). ConclusionsWe successfully applied exome sequencing to diagnose the first reported Korean patient with CDG-Ia, which was misdiagnosed as GSD. Whole exome sequencing may prove to be the preferred strategy for analysis of clinical features that do not readily suggest a specific diagnosis, such as those observed in inherited metabolic diseases, including CDG.

DGUOK‐Related Mitochondrial DNA Depletion Syndrome in a Child With an Early Diagnosis of Glycogen Storage Disease

<i>DGUOK</i>‐Related Mitochondrial DNA Depletion Syndrome in a Child With an Early Diagnosis of Glycogen Storage Disease

Neonatal presentation of lethal neuromuscular glycogen storage disease type IV

A total of 11 types of glycogen storage disorders have been recognized with variable clinical presentations. Type IV, also known as Andersen disease, represents a rare subtype that can induce severe clinical findings early in life. We report on a patient with early fetal onset of symptoms with severe neuromuscular findings at birth. The pregnancy was further complicated by polyhydramnios and depressed fetal movement. At birth severe hypotonia was noticed requiring active resuscitation and then mechanical ventilation. His lack of expected course for hypoxic ischemic encephalopathy prompted genetic testing, including a muscle biopsy, which confirmed the diagnosis of glycogen storage disease IV (GSD IV). Mutation analysis of the glycogen branching enzyme 1 gene demonstrated a previously unrecognized mutation. We review recent information on early presentation of GSD IV with particular interest in the presentation of the neonatal lethal neuromuscular form of this rare disorder.

Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin

Glycogen storage diseases are a group of inborn errors of glycogen synthesis or catabolism. The outcome for untreated patients can be devastating. Given the genetic heterogeneity and the limited availability of enzyme study data, the definitive diagnosis of glycogen storage diseases is made on the basis of sequence analysis of selected potentially causative genes. A massively parallel sequencing test was developed for simultaneous sequencing of 16 genes known to cause muscle and liver forms of glycogen storage diseases: GYS2, GYS1, G6PC, SLC37A4, GAA, AGL, GBE1, PYGM, PYGL, PFKM, PHKA2, PHKB, PHKG2, PHKA1, PGAM2, and PGM1. All the nucleotides in the coding regions of these 16 genes have been enriched with sufficient coverage in an unbiased manner. Massively parallel sequencing demonstrated 100% sensitivity and specificity as compared with Sanger sequencing. Massively parallel sequencing correctly identified all types of mutations, including single-nucleotide substitutions, small deletions and duplications, and large deletions involving one or more exons. In addition, we have confirmed the molecular diagnosis in 11 of 17 patients in whom glycogen storage diseases were suspected. This report demonstrates the clinical utility of massively parallel sequencing technology in the diagnostic testing of a group of clinically and genetically heterogeneous disorders such as glycogen storage diseases, in a cost- and time-efficient manner.

Novel mutations in PHKA2 gene in glycogen storage disease type IX patients from Hong Kong, China

The diagnosis of glycogen storage disease (GSD) type IX is often complicated by the complexity of the phosphorylase kinase enzyme (PHK), and molecular analysis is the preferred way to provide definitive diagnosis. Here we reported two novel mutations found in two GSD type IX patients with different residual enzyme activities from Hong Kong, China using genetic analysis and, provided the molecular interpretation of the deficient PHK activity. These two newly described mutations would be useful for the study of future GSD patients.

007—Accurate Diagnosis of Glycogen Storage Disease in a Child Presenting With Hepatomegaly and Hypoglycemia

007—Accurate Diagnosis of Glycogen Storage Disease in a Child Presenting With Hepatomegaly and Hypoglycemia

Renal sonographic findings of type I glycogen storage disease in infancy and early childhood

Type I glycogen storage disease (GSD-I) is an inherited disorder affecting glycogenolysis and gluconeogenesis. The characteristic manifestations are hepatomegaly, hypoglycemia, hyperlacticacidemia, hyperuricemia, and hyperlipidemia. Renal disease is regarded as a long-term complication and is reported mainly in older patients. We report the renal manifestations and renal ultrasonographic findings of GSD-I in infancy and early childhood in order to assess the role of renal sonography in the diagnosis of GSD-I. We retrospectively reviewed our hospital's database for patients with GSD-I from January 1993 to September 2004. The records of five patients were reviewed for this study. These five patients were diagnosed when they were younger than 3 years old. Data extracted from the charts included the initial extrarenal and renal manifestations, laboratory data, and imaging studies. We analyzed the indications for, and results of, renal sonography. In addition to the clinical presentations and laboratory abnormalities, all five children had nephromegaly and increased echogenicity on ultrasonography on their first visit, although only a minor degree of tubular dysfunction was noted clinically. Three of these five patients had nephrocalcinosis or renal stones or both. Hyperechoic large kidneys, nephrocalcinosis, and renal stones are common in GSD-I. They can be present in early infancy. Abnormalities on renal sonography might suggest GSD-I in a patient with suspected inborn errors of metabolism.