scholarly journals Evaluation of Glycogen Storage Patients: Report of Twelve Novel Variants and New Clinical Findings in a Turkish Population

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1987
Author(s):  
Melike Ersoy ◽  
Bulent Uyanik ◽  
Asuman Gedikbasi
Keyword(s):  
Rare Variants ◽  
Demographic Data ◽  
Glycogen Synthesis ◽  
Turkish Population ◽  
Glycogen Storage ◽  
Clinical Findings ◽  
Molecular Diagnostic ◽  
Imaging Features ◽  
Glycogen Storage Diseases ◽  
Novel Variants

Glycogen storage diseases (GSDs) are clinically and genetically heterogeneous disorders that disturb glycogen synthesis or utilization. Although it is one of the oldest inherited metabolic disorders, new genetic methods and long-time patient follow-ups provide us with unique insight into the genotype–phenotype correlations. The aim of this study was to share the phenotypic features and molecular diagnostic results that include new pathogenic variants in our GSD cases. Twenty-six GSD patients were evaluated retrospectively. Demographic data, initial laboratory and imaging features, and current findings of the patients were recorded. Molecular analysis results were classified as novel or previously defined variants. Novel variants were analyzed with pathogenicity prediction tools according to American College of Medical Genetics and Genomics (ACGM) criteria. Twelve novel and rare variants in six different genes were associated with the disease. Hearing impairment in two patients with GSD I, early peripheral neuropathy after liver transplantation in one patient with GSD IV, epilepsy and neuromotor retardation in three patients with GSD IXA were determined. We characterized a heterogeneous group of all diagnosed GSDs over a 5-year period in our institution, and identified novel variants and new clinical findings. It is still difficult to establish a genotype–phenotype correlation in GSDs.

Late presentation of glycogen storage disease types Ia and III in children with short stature and hepatomegaly

2018 ◽  
Vol 31 (4) ◽  
pp. 473-478 ◽  
Author(s):  
David Quackenbush ◽  
Justin Devito ◽  
Luigi Garibaldi ◽  
Melissa Buryk
Keyword(s):  
Short Stature ◽  
Glycogen Storage Disease ◽  
Storage Disease ◽  
Novel Mutation ◽  
Glycogen Synthesis ◽  
Previous History ◽  
Severe Hypoglycemia ◽  
Late Presentation ◽  
Glycogen Storage ◽  
Glycogen Storage Diseases

AbstractBackground:Glycogen storage diseases (GSDs) are a collection of disorders related to glycogen synthesis or degradation that classically present in infancy with hypoglycemia, failure to thrive and hepatomegaly; however, their phenotype can vary significantly.Case presentation:We present the cases of two children, 5 years old and 3.5 years old, who were referred to endocrinology for short stature. They were ultimately found to have hepatomegaly, fasting hypoglycemia, mild elevation of transaminases and ketosis. Laboratory and genetic studies were consistent with double heterozygosity for GSDs Ia and III, with one novel mutation discovered in each patient. Nightly, both children were treated with cornstarch, which resulted in resolution of laboratory abnormalities and improvement in their growth velocity. These cases are unusual in that GSD was diagnosed relatively late in life in patients with no previous history of severe hypoglycemia.Conclusions:They highlight the importance of considering glycogen storage disease in a child presenting with short stature, as it is a treatable disease that can be diagnosed non-invasively with genetic testing.

Clinical, pathological and molecular spectrum of patients with glycogen storage diseases in Pakistan

2022 ◽  
Vol 0 (0) ◽  
Author(s):  
Sibtain Ahmed ◽  
Fizza Akbar ◽  
Amyna Jaffar Ali ◽  
Bushra Afroze
Keyword(s):  
Molecular Analysis ◽  
High Frequency ◽  
Glycogen Storage ◽  
Storage Diseases ◽  
Pathogenic Variants ◽  
Glycogen Storage Diseases ◽  
Initial Symptoms ◽  
Novel Variants ◽  
Novel Variant ◽  
Spectrum Of Patients

Abstract Objectives Evaluation of clinical, biochemical and molecular analysis of Pakistani patients with hepatic GSDs. Methods Medical charts, biochemical, histopathological and molecular results of patients with hepatic GSD were reviewed. Results Out of 55 GSD patients, 41 (74.5%) were males and 14 (25.5%) were females with consanguinity in 50 (91%) patients. The median age of initial symptoms, clinic diagnosis and molecular diagnosis were 450 (IQR: 270–960), 1,095 (IQR: 510–1,825) and 1717 (IQR: 796–3,011) days, respectively. Molecular analysis and enzyme activity was available for 33 (60%) and two patients, respectively. GSD III (n=9) was most prevalent followed by GSD Ib (n=7), GSD IXc (n=6), GSD VI (n=4), GSD Ia (n=3), GSD XI (n=3), GSD IXb (n=2) and GSD IXa (n=1). In patients (n=33) who underwent molecular analysis; 19 different variants in eight genes associated with GSD were identified. We also report five novel variants, two in SLC37A4, one in AGL and two in PYGL contributing to the diagnosis of GSD Ib, GSD III and GSD VI, respectively. Conclusions Fifty-five patients of GSDs in 26 families from a single care provider indicate a relatively high frequency of GSD in Pakistan, with multiple unrelated families harboring identical disease-causing variants, on molecular analysis, including two known pathogenic variants in SLC37A4 and PHKG2, and a novel variant in AGL.

scholarly journals Renal Calculi as Initial Presenting Symptom of Glycogen Storage Disease (Type 1 A) in Early Infancy

2020 ◽  
Vol 10 (01) ◽  
pp. e45-e47
Author(s):  
Nida Mirza ◽  
Smita Malhotra ◽  
Anupam Sibal
Keyword(s):  
Glycogen Storage Disease ◽  
Storage Disease ◽  
Case Reports ◽  
Glycogen Synthesis ◽  
Renal Stones ◽  
Renal Calculi ◽  
Glycogen Storage ◽  
Storage Diseases ◽  
Glycogen Storage Diseases

AbstractGlycogen storage diseases are a group of heterogeneous metabolic disorders that result from a defect in enzymatic pathway of either glycogen synthesis or glycogen degradation. Here we are reporting a case of glycogen storage diseases type 1 with renal stone as initial manifestation of disease at 2 months of age. There were case reports of recurrent renal calculi in older age group with this disease and considered to be arisen due to metabolic derangements. Although the exact mechanism of renal stones in glycogen storage disease is not clear, in this unique case occurrence of renal stones at 2 months of age suggests that the pathogenesis of renal calculi is probably multifactorial or a part of disease.

scholarly journals Mechanism of glycogen synthase inactivation and interaction with glycogenin

2021 ◽  
Author(s):  
Laura Marr ◽  
Dipsikha Biswas ◽  
Leonard A Daly ◽  
Christopher Browning ◽  
John Pollard ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Metabolism ◽  
Glycogen Storage ◽  
Moderate Increase ◽  
Storage Diseases ◽  
Future Studies ◽  
Glycogen Storage Diseases ◽  
Structure Lead

The macromolecule glycogen is the major glucose reserve in eukaryotes and defects of glycogen metabolism and structure lead to glycogen storage diseases and neurodegeneration. Glycogenesis begins with self-glucosylation of glycogenin (GN), which recruits glycogen synthase (GS). GS is activated by glucose-6-phosphate (G6P) and inactivated by phosphorylation, but how these opposing processes are coupled is unclear. We provide the first structure of phosphorylated human GS-GN complex revealing an autoinhibited GS tetramer flanked by two GN dimers. Phosphorylated N- and C-terminal tails from two GS protomers converge to form dynamic "spike" regions, which are buttressed against GS regulatory helices. This keeps GS in a constrained "tense" conformation that is inactive and more resistant to G6P activation. Mutagenesis that weaken the interaction between the regulatory helix and phosphorylated tails leads to a moderate increase in basal/unstimulated GS activity, supporting the idea that phosphorylation contributes to GS inactivation by constraining GS inter-subunit movement. We propose that multivalent phosphorylation supports GS autoinhibition through interactions from a dynamic "spike" region, thus allowing a "tuneable rheostat" for regulating GS activity. Our structures of human GS-GN provide new insights into the regulation of glycogen synthesis, facilitating future studies of glycogen storage diseases.

Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in Hereditary Haemorrhagic Telangiectasia

2018 ◽  
Vol 55 (12) ◽  
pp. 824-830 ◽  
Author(s):  
Whitney L. Wooderchak-Donahue ◽  
Jamie McDonald ◽  
Andrew Farrell ◽  
Gulsen Akay ◽  
Matt Velinder ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Rare Variants ◽  
Diagnostic Testing ◽  
Clinical Findings ◽  
Molecular Diagnostic ◽  
Hereditary Haemorrhagic Telangiectasia ◽  
Coding Region ◽  
Clinical Sensitivity ◽  
Coding Regions ◽  
Testing Algorithms

IntroductionHereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder caused by mutations in the genes ENG, ACVRL1, and SMAD4. Yet the genetic cause remains unknown for some families even after exhaustive exome analysis. We hypothesised that non-coding regions of the known HHT genes may harbour variants that disrupt splicing in these cases.MethodsDNA from 35 individuals with clinical findings of HHT and 2 healthy controls from 13 families underwent whole genome sequencing. Additionally, 87 unrelated cases suspected to have HHT were evaluated using a custom designed next-generation sequencing panel to capture the coding and non-coding regions of ENG, ACVRL1 and SMAD4. Individuals from both groups had tested negative previously for a mutation in the coding region of known HHT genes. Samples were sequenced on a HiSeq2500 instrument and data were analysed to identify novel and rare variants.ResultsEight cases had a novel non-coding ACVRL1 variant that disrupted splicing. One family had an ACVRL1intron 9:chromosome 3 translocation, the first reported case of a translocation causing HHT. The other seven cases had a variant located within a ~300 bp CT-rich ‘hotspot’ region of ACVRL1intron 9 that disrupted splicing.ConclusionsDespite the difficulty of interpreting deep intronic variants, our study highlights the importance of non-coding regions in the disease mechanism of HHT, particularly the CT-rich hotspot region of ACVRL1intron 9. The addition of this region to HHT molecular diagnostic testing algorithms will improve clinical sensitivity.

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

2019 ◽  
Vol 36 (2) ◽  
Author(s):  
Sibtain Ahmed ◽  
Bushra Afroze
Keyword(s):  
Liver Biopsy ◽  
Glycogen Synthesis ◽  
Cost Effective ◽  
Glycogen Storage ◽  
Diagnostic Approach ◽  
Molecular Testing ◽  
Storage Diseases ◽  
Creative Commons ◽  
Gene Testing ◽  
Glycogen Storage Diseases

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. doi: https://doi.org/10.12669/pjms.36.2.1310 How to cite this:Ahmed S, Afroze B. Glycogen storage diseases-time to flip the outdated diagnostic approach centered on liver biopsy with the molecular testing. Pak J Med Sci. 2020;36(2):---------. doi: https://doi.org/10.12669/pjms.36.2.1310 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

scholarly journals Neurological Involvement in Glycogen Storage Disease Type IXa due to PHKA2 Mutation

2020 ◽  
Vol 47 (3) ◽  
pp. 400-403 ◽  
Author(s):  
Chelsea Smith ◽  
Marie-Josée Dicaire ◽  
Bernard Brais ◽  
Roberta La Piana ◽  
Keyword(s):  
Storage Disease ◽  
Glycogen Synthesis ◽  
Missense Variant ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Regulatory Subunit ◽  
Neurological Involvement ◽  
Phosphorylase Kinase ◽  
Glycogen Storage Diseases ◽  
Whole Exome

ABSTRACT:Glycogen storage diseases (GSDs) result from the deficiency of enzymes involved in glycogen synthesis and breakdown into glucose. Mutations in the gene PHKA2 encoding phosphorylase kinase regulatory subunit alpha 2 have been linked to GSD type IXa. We describe a family with two adult brothers with neonatal hepatosplenomegaly and later onset of hearing loss, cognitive impairment, and cerebellar involvement. Whole-exome sequencing was performed on both subjects and revealed a shared hemizygous missense variant (c.A1561G; p.T521A) in exon 15 of PHKA2. The phenotype broadens the clinical and magnetic resonance imaging spectrum of GSD type IXa to include later onset neurological manifestations.

scholarly journals Glycogen Storage Disease Ib and Severe Periodontal Destruction: A Case Report

2018 ◽  
Vol 6 (4) ◽  
pp. 53 ◽  
Author(s):  
Rui Ma ◽  
Fardad Moein Vaziri ◽  
Gregory Sabino ◽  
Nima Sarmast ◽  
Steven Zove ◽  
...  
Keyword(s):  
Case Report ◽  
Genetic Disorders ◽  
Glycogen Synthesis ◽  
Neutrophil Migration ◽  
Cell Types ◽  
Glycogen Storage ◽  
Histological Evaluation ◽  
Oral Manifestations ◽  
Dental Tissues ◽  
Glycogen Storage Diseases

Background: Glycogen storage diseases (GSDs) are genetic disorders that result from defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types. It also manifests with impaired neutrophil chemotaxis and neutropenic episodes which results in severe destruction of the supporting dental tissues, namely the periodontium. Although GSD Type Ib cannot be cured, associated symptoms and debilitating oral manifestations of the disease can be managed through collaborative medical and dental care where early detection and intervention is of key importance. This objective of the case report was to describe a child with GSD Ib and its associated oral manifestations with microbial, immunological and histological appearances. Case Presentation: An eight-year-old Hispanic male with a history of GSD type Ib presented with extensive intraoral generalized inflammation of the gingiva, ulcerations and bleeding, and intraoral radiographic evidence of bone loss. Tannerella forsythia was readily identifiable from the biofilm samples. Peripheral blood neutrophils were isolated and a deficient host response was observed by impaired neutrophil migration. Histological evaluation of the soft and hard tissues of the periodontally affected primary teeth showed unaffected dentin and cementum. Conclusions: This case illustrates the association between GSD Ib and oral manifestations of the disease. A multi-disciplinary treatment approach was developed in order to establish healthy intraoral conditions for the patient. Review of the literature identified several cases describing GSD and its clinical and radiographic oral manifestations; however, none was identified where also microbial, immunological, and histological appearances were described.

scholarly journals Hypertrophic Cardiomyopathy and Primary Restrictive Cardiomyopathy: Similarities, Differences and Phenocopies

2021 ◽  
Vol 10 (9) ◽  
pp. 1954
Author(s):  
Riccardo Vio ◽  
Annalisa Angelini ◽  
Cristina Basso ◽  
Alberto Cipriani ◽  
Alessandro Zorzi ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Restrictive Cardiomyopathy ◽  
Glycogen Storage ◽  
Left Ventricular ◽  
Pathophysiological Mechanism ◽  
Storage Diseases ◽  
Glycogen Storage Diseases ◽  
Similar Genetic Background ◽  
Ventricular Wall Thickness ◽  
And Storage

Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These “sarcomeric cardiomyopathies” also share diastolic dysfunction as the prevalent pathophysiological mechanism. Starting from the observation that patients with HCM and primary RCM may coexist in the same family, a characteristic pathophysiological profile of HCM with restrictive physiology has been recently described and supports the hypothesis that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy. To further complicate this scenario some infiltrative (amyloidosis) and storage diseases (Fabry disease and glycogen storage diseases) may show either a hypertrophic or restrictive phenotype according to left ventricular wall thickness and filling pattern. Establishing a correct etiological diagnosis among HCM, primary RCM, and hypertrophic or restrictive phenocopies is of paramount importance for cascade family screening and therapy.

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