Identification of a novel mutation in the PHKA2 gene in a child with liver cirrhosis

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Zahra Beyzaei ◽  
Fatih Ezgu ◽  
Mohammad Hadi Imanieh ◽  
Bita Geramizadeh
Keyword(s):  
Liver Cirrhosis ◽  
Metabolic Diseases ◽  
Novel Mutation ◽  
Laboratory Data ◽  
Glycogen Storage ◽  
Hepatic Involvement ◽  
Glycogen Storage Diseases ◽  
Novel Variant ◽  
Severe Liver Damage ◽  
Targeted Gene Sequencing

Abstract Objectives Glycogen storage diseases (GSDs) are heterogeneous disorders caused by various enzyme deficiencies. GSD type IX α2, the most common subtype of GSD IX, is due to a deficiency of hepatic phosphorylase kinase. Herein we will report a novel mutation in this disease with an unusual presentation. Case presentation we describe a 3-year-old boy who suffered from hepatomegaly, fatty liver disease, and liver cirrhosis. The cause of cirrhosis at a young age was unknown based on the laboratory data and liver biopsy, so we performed a targeted-gene sequencing (TGS) covering 450 genes involved in inborn metabolic diseases consisting of glycogen storage disorders genes with hepatic involvement. He was found out to have a rare novel pathogenic variant in the PHKA2 gene. Conclusions This novel variant c.2226+2T > C expands the mutational spectrum of the PHKA2 gene. Also, severe liver damage (cirrhosis) in patients with GSD- IX α2 has rarely been reported, which needs further discussion. We hypothesize that unidentified PHKA2 variants may be a rare cause of childhood liver cirrhosis.

scholarly journals Clinical and genetic spectrum of glycogen storage disease in Iranian population using targeted gene sequencing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zahra Beyzaei ◽  
Fatih Ezgu ◽  
Bita Geramizadeh ◽  
Mohammad Hadi Imanieh ◽  
Mahmood Haghighat ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Molecular Genetic ◽  
Gene Sequencing ◽  
Glycogen Storage ◽  
Loss Of Function ◽  
Retrospective Case ◽  
Complex Disorders ◽  
Glycogen Storage Diseases ◽  
Targeted Gene Sequencing ◽  
Retrospective Case Study

AbstractGlycogen storage diseases (GSDs) are known as complex disorders with overlapping manifestations. These features also preclude a specific clinical diagnosis, requiring more accurate paraclinical tests. To evaluate the patients with particular diagnosis features characterizing GSD, an observational retrospective case study was designed by performing a targeted gene sequencing (TGS) for accurate subtyping. A total of the 15 pediatric patients were admitted to our hospital and referred for molecular genetic testing using TGS. Eight genes namely SLC37A4, AGL, GBE1, PYGL, PHKB, PGAM2, and PRKAG2 were detected to be responsible for the onset of the clinical symptoms. A total number of 15 variants were identified i.e. mostly loss-of-function (LoF) variants, of which 10 variants were novel. Finally, diagnosis of GSD types Ib, III, IV, VI, IXb, IXc, X, and GSD of the heart, lethal congenital was made in 13 out of the 14 patients. Notably, GSD-IX and GSD of the heart-lethal congenital (i.e. PRKAG2 deficiency) patients have been reported in Iran for the first time which shown the development of liver cirrhosis with novel variants. These results showed that TGS, in combination with clinical, biochemical, and pathological hallmarks, could provide accurate and high-throughput results for diagnosing and sub-typing GSD and related diseases.

INHERITED METABOLIC DISORDERS AND HEART DISEASES

2019 ◽  
Author(s):  
Vjekoslav Krželj ◽  
Ivana Čulo Čagalj
Keyword(s):  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Technological Development ◽  
Heart Diseases ◽  
Glycogen Storage ◽  
Acid Oxidation ◽  
Lysosomal Storage ◽  
Glycogen Storage Diseases ◽  
Coronary Diseases ◽  
Inherited Metabolic Disorders

Inherited metabolic disorders can cause heart diseases, cardiomyopathy in particular, as well as cardiac arrhythmias, valvular and coronary diseases. More than 40 different inherited metabolic disorders can provoke cardiomyopathy, including lysosomal storage disorders, fatty acid oxidation defects, organic acidemias, amino acidopathies, glycogen storage diseases, congenital disorders of glycosylation as well as peroxisomal and mitochondrial disorders. If identified and diagnosed on time, some of congenital metabolic diseases could be successfully treated. It is important to assume them in cases when heart diseases are etiologically undefined. Rapid technological development has made it easier to establish the diagnosis of these diseases. This article will focus on common inherited metabolic disorders that cause heart diseases, as well as on diseases that might be possible to treat.

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 Glycogen Storage Disease 1b: Diagnosis and Workup of a Novel Mutation

2016 ◽  
Vol 36 (1) ◽  
pp. 85-87
Author(s):  
Rama Krishna Sanjeev ◽  
Swathi Shetty ◽  
Arun Harith ◽  
Bindu T Nair ◽  
Sajith Surendran
Keyword(s):  
Storage Disease ◽  
Antenatal Diagnosis ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Glycogen Metabolism ◽  
Glycogen Storage ◽  
Carrier State ◽  
Glycogen Storage Diseases ◽  
Added Benefit ◽  
Work Up

Glycogen Storage diseases (Glycogenoses) are a diverse group of disorders, numbering more than 12, resulting from deficiencies of various enzymes & transport proteins in the pathways of glycogen metabolism. GSD 1 is caused by absence or deficiency of glucose-6-phosphatase activity in the liver, kidney or intestinal mucosa. In GSD 1(b), the enzyme which transports Glucose-6-Phosphate across the microsomal membrane is defective, thereby resulting in accumulation of Glycogen. The clinical features of 1a & 1b are similar with fasting hypoglycaemia, hepatomegaly, growth retardation and metabolic abnormalities except for the presence of neutropenia with recurrent gingivitis in GSD 1b. A genetic diagnosis solves this conundrum with the added benefit of antenatal diagnosis of future pregnancies & identification of carrier state in patients. We report the work up of an infant with suspected GSD where a novel mutation with heterozygous carrier state in the parents was diagnosed by genetic testing.J Nepal Paediatr Soc 2016;36(1):85-87.

scholarly journals Proteobacteria Overgrowth and Butyrate-Producing Taxa Depletion in the Gut Microbiota of Glycogen Storage Disease Type 1 Patients

Metabolites ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 133 ◽  
Author(s):  
Camilla Ceccarani ◽  
Giulia Bassanini ◽  
Chiara Montanari ◽  
Maria Cristina Casiraghi ◽  
Emerenziana Ottaviano ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Dietary Intervention ◽  
Metabolic Diseases ◽  
Alpha Diversity ◽  
Dietary Treatment ◽  
Short Chain Fatty Acids ◽  
Glycogen Storage ◽  
Rrna Gene ◽  
Metabolic Complications ◽  
Glycogen Storage Diseases

A life-long dietary intervention can affect the substrates’ availability for gut fermentation in metabolic diseases such as the glycogen-storage diseases (GSD). Besides drug consumption, the main treatment of types GSD-Ia and Ib to prevent metabolic complications is a specific diet with definite nutrient intakes. In order to evaluate how deeply this dietary treatment affects gut bacteria, we compared the gut microbiota of nine GSD-I subjects and 12 healthy controls (HC) through 16S rRNA gene sequencing; we assessed their dietary intake and nutrients, their microbial short chain fatty acids (SCFAs) via gas chromatography and their hematic values. Both alpha-diversity and phylogenetic analysis revealed a significant biodiversity reduction in the GSD group compared to the HC group, and highlighted profound differences of their gut microbiota. GSD subjects were characterized by an increase in the relative abundance of Enterobacteriaceae and Veillonellaceae families, while the beneficial genera Faecalibacterium and Oscillospira were significantly reduced. SCFA quantification revealed a significant increase of fecal acetate and propionate in GSD subjects, but with a beneficial role probably reduced due to unbalanced bacterial interactions; nutritional values correlated to bacterial genera were significantly different between experimental groups, with nearly opposite cohort trends.

scholarly journals Novel PRKAG2 variant presenting as liver cirrhosis: report of a family with 2 cases and review of literature

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Zahra Beyzaei ◽  
Fatih Ezgu ◽  
Bita Geramizadeh ◽  
Alireza Alborzi ◽  
Alireza Shojazadeh
Keyword(s):  
Liver Cirrhosis ◽  
Genetic Defect ◽  
Laboratory Data ◽  
Gene Sequencing ◽  
Adenosine Monophosphate ◽  
Heart Tissue ◽  
Regulatory Subunit ◽  
Autosomal Dominant Disorder ◽  
Heterozygous Variant ◽  
Targeted Gene Sequencing

Abstract Background Mutations in the PRKAG2 gene encoding the 5′ Adenosine Monophosphate-Activated Protein Kinase (AMPK), specifically in its γ2 regulatory subunit, lead to Glycogen storage disease of heart, fetal congenital disorder (PRKAG2 syndrome). These mutations are rare, and their functional roles have not been fully elucidated. PRKAG2 syndrome is autosomal dominant disorder inherited with full penetrance. It is characterized by the accumulation of glycogen in the heart tissue, which is clinically manifested as hypertrophic cardiomyopathy. There is little knowledge about the characteristics of this disease. This study reports a genetic defect in an Iranian family with liver problems using targeted-gene sequencing. Case presentation A 4-year-old girl presented with short stature, hepatomegaly, and liver cirrhosis. As there was no specific diagnosis made based on the laboratory data and liver biopsy results, targeted-gene sequencing (TGS) was performed to detect the molecular basis of the disease. It was confirmed that this patient carried a novel heterozygous variant in the PRKAG2 gene. The echocardiography was a normal. Conclusion A novel heterozygous variant c.592A > T (p.Met198Leu) expands the mutational spectrum of the PRKAG2 gene in this family. Also, liver damage in patients with PRKAG2 syndrome has never been reported, which deserves further discussion.

scholarly journals Analysis of common causes of liver damage among children 12 years and younger in Weifang

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052110066
Author(s):  
Qinghong Meng ◽  
Na Li ◽  
Lianmei Yuan ◽  
Xiaona Gao
Keyword(s):  
Liver Damage ◽  
Epstein Barr Virus ◽  
Metabolic Diseases ◽  
Unknown Etiology ◽  
Severe Liver ◽  
Drug Induced ◽  
Barr Virus ◽  
Common Causes ◽  
Severe Liver Damage ◽  
Epstein Barr

Aims To explore the causes of liver damage among children 12 years and younger in Weifang and to provide a theoretical basis for early diagnosis of liver damage in children. Methods Retrospective study of clinical data from pediatric patients (age ≤12 years) with liver damage in diagnosed at Weifang People's Hospital from June 2010 to May 2020. Results A total of 2632 children (1572 boys, 1060 girls) aged ≤12 years were diagnosed with liver damage including infectious liver damage (2100 cases), non-infectious liver damage (446 cases) and liver damage of unknown etiology (86 cases). The most common causes of infectious liver damage were viral infection (1515 cases), Mycoplasma pneumoniae infection (343 cases), and bacterial infection (197 cases). The most common causes of viral liver damage were Epstein–Barr virus, cytomegalovirus, and enterovirus. The most common causes of non-infectious liver damage were drug-induced liver damage, Kawasaki disease, and genetic metabolic diseases. There were 31 cases of severe liver damage. Conclusion There were many causes of liver damage among children in Weifang. Infections, and especially viral infections such as Epstein–Barr virus, were the most common causes of liver damage. Severe liver damage was primarily caused by drugs or poisons.

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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