A Rare Case of Glycogen Storage Disease Type IIIa with a Novel Homozygous AGL Splice Variant in a Two-Year-Old Female born out of Consanguineous Marriage

A Rare Case of Glycogen Storage Disease Type IIIa with a Novel Homozygous AGL Splice Variant in a Two-Year-Old Female born out of Consanguineous Marriage | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A Rare Case of Glycogen Storage Disease Type IIIa with a Novel Homozygous AGL Splice Variant in a Two-Year-Old Female born out of Consanguineous Marriage Rajashree Ratnaparkhe This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7936702/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Glycogen Storage Disease IIIa (GSD IIIa) is a hereditary disorder which is caused by the mutations in AGL gene that lead in the production of nonfunctional glycogen debranching enzyme. This enzymatic defect impairs the breakdown of glycogen, causing abnormal glycogen build up in tissues like liver, muscles and heart. This situation manifests in early childhood with symptoms such as hypoglycemia, poor growth, hepatomegaly and progressive muscle weakness that requires lifelong dietary and medical management. GSD IIIa, one of the most prevalent forms of hepatic and muscular glycogenoses, remains a significant clinical challenge due to its involvement of multiple organ systems and its persistent, progressive nature. We report a case study of a two-year-old female born out of consanguineous marriage who was evaluated for progressive abdominal distension and diagnosed with GSD IIIa. Glycogen Storage Disorder type IIIa (GSD IIIa) Hepatomegaly Hypoglycemia Convulsions Consanguineous parents AGL gene Homozygous Splice variant Figures Figure 1 Key message This case highlights the distinctive clinical and diagnostic features of Glycogen Storage Disease Type IIIa, differentiating it from other GSD subtypes by the presentation of hepatomegaly with early morning hypoglycemic symptoms, notably without convulsions, which are commonly observed in other forms. Despite the absence of typical seizures, a high index of clinical suspicion based on hepatomegaly, delayed walking and early morning awakening with hypoglycemia along with other biochemical abnormalities facilitated early diagnosis. Genetic testing confirming a novel homozygous splice variant in the AGL gene underscored the critical role of molecular studies in diagnosis, especially in consanguineous populations. Early dietary intervention, regular monitoring, and comprehensive management are essential to mitigate progressive multisystemic complications and optimize long-term outcomes in this rare metabolic disorder. Introduction Glycogen Storage Disorder (GSD) or glycogenosis are a group of rare inherited metabolic disorders with prevalence of 1 in 20,000 to 43,000 live births, characterized by the abnormal storage of glycogen in various tissues. [ 1 ] Glycogen Storage Disorder IIIa (GSD IIIa) also known as Cori disease or Forbes disease or limit dextrinosis, is caused by biallelic pathogenic variants in the AGL gene on chromosome 1p2.2, which encodes the glycogen debranching enzyme, amylo-1,6-glucosidase (4-α-glucanotransferase) that results in abnormal accumulation of glycogen specifically in liver and muscle tissues. [ 2 , 3 , 4 ] This situation manifests in early childhood with symptoms including hypoglycemia, poor growth, hepatomegaly and progressive muscle weakness, that requires lifelong dietary and medical management. [ 2 ] Abdominal distension and enlarged liver are generally observed with the episodes of fasting hypoglycemia that can lead to neurological compromise and seizures, especially in younger children. In Glycogen Storage Disease type III, low blood sugar is usually seen along with ketosis, yet without the high blood lactate or uric acid typically observed in GSD type I. [ 2 , 5 ] As children with GSD III grow older, many liver symptoms tend to gradually stabilize or even improve, offering some reassurance for families. However, the risk of complications like liver scarring, cirrhosis, or in rare situations, the development of liver tumours such as hepatic adenomas, still remains when patients reach adulthood. [ 1 , 2 ] We report a case study of a two-year-old female born out of consanguineous marriage who was evaluated for progressive abdominal distension and diagnosed with GSD IIIa. Case Presentation A two-year-old female (1st baby) born out of 3º consanguineous marriage, who presented to the outpatient department (OPD) with a history of progressive abdominal distension over the past five to six months, history of weight loss, delayed walking shows the involvement of muscle. There was a history of getting up early in the morning with hunger but never had convulsions and during day time she had hunger pangs. Additionally, there was no significant family history identified that can be related to genetic cause for glycogen storage disorder and there was no history of vomiting, loose motions, nausea, jaundice or symptoms of hepatic failure. Despite the significant abdominal distension, there were no signs of icterus, anaemia or of portal hypertension. Considering history of consanguinity (IIIº), the progressive nature of the distension, along with a clinical context of raised clinical suspicion for an underlying metabolic disorder. On physical examinations, the most prominent finding was gross hepatomegaly without signs of hepatic failure. Table 1 Biochemical findings of the individual. Blood Investigations Haemoglobin (Hb) 11.30 g/dl Total Leukocyte Count (TLC) 9830 cells/µl Neutrophil/Lymphocyte (N/L) 23/67 cells/µl Platelet 338000 /µl of blood Random Blood Sugar (RBS) 86.5 mg/dl Fasting Blood Sugar (FBS) 42.6 mg/dl LFT Investigations Bilirubin T/D 0.51/0.09 mg/dl SGPT 418.70 u/l Alkaline Phosphatase 1363 u/l Lactate Dehydrogenase (LDH) 494 u/l 2D ECHO Investigations Findings Normal, no shunt noted Ophthalmology Investigations Findings Normal, Fundus Normal Urine Analysis Urobilinogen Trace Bilirubin 1+ Urinary Ketones 2+ Urinary pH 6.0 WBC 3.5 HPF Other Investigations Creatine Phosphokinase (CPK) 679.3 u/l Gamma-Glutamyl Transferase (GGT) 126.25 u/l Triglycerides 297.2 mg/dl Total Cholesterol 181.40 mg/dl Uric acid 8.36 mg/dl Notably, the laboratory findings from Table 1 revealed that the LFT investigations are not within the normal ranges and this elevated SGPT, ALK. Phos and LDH shows liver involvement. Even in blood investigations, FBS is suggestive of hypoglycemia along with urinary ketones that points towards the diagnosis of GSD. The elevated levels of CPK shows the muscle involvement in the disease. Further 2D echo was done to check whether heart muscles are involved but there was no significant involvement seen as the investigations were normal. Diagnostic Evaluation and Management: Biochemical analysis coupled with genetic testing played a pivotal role in the evaluation of the patient. The suspicion of glycogen storage disorder was further reinforced by the laboratory findings. The most compelling evidence came from genetic studies, which identified a homozygous splice site intronic variant in the AGL gene. Specifically, the variant identified was c.293 + 5G > C (located in intron 3, transcript NM_000642.3) at chromosomal position chr1:99861718:G > C with a total depth of 53X. This variant, which has not been reported in ClinVar, dbSNP, or large population frequency databases such as gnomAD and ExAC was classified as “Uncertain Significance” based on American College of Medical Genetics and Genomics (ACMG) criteria (PM2 and PP3). [ 6 , 7 , 8 ] In addition to the genetic data, the clinical presentation-including hepatomegaly and hypoglycemia-supported the diagnosis of GSD type IIIa. Although the variant’s clinical significance remains uncertain, the correlation with the patient’s phenotype and the known role of the AGL gene in glycogen metabolism substantiates the diagnosis. Management of GSD type IIIa largely revolves around dietary interventions aimed at preventing hypoglycemia and reducing glycogen accumulation. In this patient, dietary therapy was initiated with the administration of uncooked cornstarch (1.6gm/kg/day), a well-recognized intervention that provides a slow-release form of glucose. Frequent feeding and a diet enriched with complex carbohydrates, Vitamin D enriched sachet and Calcimax syrup were recommended for maintaining euglycemia and supporting normal growth and development. Regular monitoring through biochemical assays and imaging studies is essential, given the potential development of complications such as progressive hepatomegaly, liver fibrosis, and in later stages, the onset of myopathy and cardiomyopathy. In this case, follow-up assessments were planned, including serial liver function tests and ultrasound examinations to monitor liver size and structure and 2D Echo for monitoring early onset of myopathy or cardiomyopathy. Discussion Autosomal recessive disorders consequently become prominent in communities where consanguinity is prevalent as in comparison to non-consanguineous relations, the likelihood of both parents expressing an identical recessive gene is considerably more probable in consanguineous marriages. [ 9 ] Thus in this case, the sharing of mutant AGL genes from both parents lead to GSD type IIIa to their two year offspring. Type IIIa GSD represents a challenging clinical scenario that requires prompt diagnosis and a multidisciplinary approach to management. The identification of the homozygous splice site variant c.293 + 5G > C in the AGL gene highlights the importance of advanced genetic testing in diagnosing metabolic disorders with specific clinical presentations. Although the pathogenicity of the detected variant remains uncertain, its location in the gene and the potential for a splice defect provide plausible explanation for the altered enzyme function, leading to the accumulation of abnormal glycogen. [ 2 , 4 ] Hepatomegaly, as observed in this patient, is a common finding in Glycogen Storage Disorders involving the liver and early dietary interventions have been shown to prevent complications such as liver fibrosis and subsequent cirrhosis. The tailored diet with frequent feeding intervals and starch supplementation not only helps in maintaining normoglycemia but also minimizes the metabolic burden on the liver. [ 2 , 5 ] Continued follow-up is critical as clinical manifestations can evolve over time. Future clinical research may offer further insights into the role of specific AGL gene mutations and the potential benefits of emerging therapies such as gene therapy. Conclusion This case report of a two year old female with diagnosed glycogen storage disorder type IIIa underscores the importance of combining clinical, biochemical and genetic evaluations in the diagnosis and management of rare metabolic disorders. The detection of a homozygous splice site variant in the AGL gene, despite its current classification as of uncertain significance aligns with the patient's clinical presentation of progressive abdominal distension, hepatomegaly, and hypoglycemia. Early diagnosis, dietary management with starch supplementation, and regular follow up are paramount to optimizing patient outcomes and preventing long term complications. Declarations The parent of the patient was read (and/or explained) the purpose of the study in a language they understand and gave their consent voluntarily to participate/allow the patient's data to be used for research and academic purposes. Acknowledgement: We acknowledge the pathology department for all the major findings including whole exome sequencing (genetical studies) which were useful to diagnose the GSD IIIa in early childhood and paediatric department for maintaining the clinical investigations and treatment for the individual. Author contributions: The sole author is responsible for the conception, design, data collection, analysis, interpretation, manuscript writing, and final approval of the version to be published. Financial support and sponsorship: No financial support or sponsorship was received for this study. Conflicts of interest statement: The author declare that they have no conflicts of interest. Data availability statement: The data supporting the findings of this study were generated by the author and are available from the corresponding author upon reasonable request. Ethical aspects: Ethical approval was not required for this case report as it involved anonymized patient information and posed no risk to the participant. Written informed consent was obtained from the patient for publication of their clinical details. Statement on approval from all contributors: I, the sole author, have read and approved the final version of the manuscript and take full responsibility for its content. References Gümüş E, Özen H (2023) Glycogen storage diseases: An update. World J Gastroenterol 29(25):3932–3963. 10.3748/wjg.v29.i25.3932 PMID: 37476587; PMCID: PMC10354582 Schreuder AB, Rossi A, Grünert SC, Derks TGJ, Glycogen Storage Disease Type III (2010) Mar 9 [updated 2022 Jan 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A (eds) GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA). 1993–2025. PMID: 20301788. Goldstein JL, Austin SL, Boyette K, Kanaly A, Veerapandiyan A, Rehder C, Kishnani PS, Bali DS (2010) Molecular analysis of the AGL gene: identification of 25 novel mutations and evidence of genetic heterogeneity in patients with glycogen storage disease type III. Genet Sci 12(7):424–430 Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, Chung WK, Desai DM, El-Gharbawy A, Haller R, Smit GP, Smith AD, Hobson-Webb LD, Wechsler SB, Weinstein DA, Watson MS, ACMG (2010). Glycogen storage disease type III diagnosis and management guidelines. Genet Med. ;12(7):446 – 63. 10.1097/GIM.0b013e3181e655b6 . Erratum in: Genet Med. 2010;12(9):566. PMID: 20631546 Stone WL, John TA, Anastasopoulou C, Basit H, Adil A, Glycogen Storage D (2025) Jan 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 29083788 Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J, Jang W, Katz K, Ovetsky M, Riley G, Sethi A, Tully R, Villamarin-Salomon R, Rubinstein W, Maglott DR (2016) ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 44(D1):D862–D868. 10.1093/nar/gkv1222 Epub 2015 Nov 17. PMID: 26582918; PMCID: PMC4702865 Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. 10.1038/gim.2015.30 Epub 2015 Mar 5. PMID: 25741868; PMCID: PMC4544753 Miller DT, Lee K, Abul-Husn NS, Amendola LM, Brothers K, Chung WK, Gollob MH, Gordon AS, Harrison SM, Hershberger RE, Klein TE, Richards CS, Stewart DR, Martin CL, ACMG Secondary Findings Working Group (2022) Electronic address: [email protected] . ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med 24(7):1407–1414. 10.1016/j.gim.2022.04.006 Epub 2022 Jun 17. PMID: 35802134 Khayat AM, Alshareef BG, Alharbi SF, AlZahrani MM, Alshangity BA, Tashkandi NF (2024) Consanguineous Marriage and Its Association With Genetic Disorders in Saudi Arabia: A Review. Cureus 16(2):e53888. 10.7759/cureus.53888 PMID: 38465157; PMCID: PMC10924896 Kliegman RM, Behrman RE, Jenson HB, Stanton BM (2007) Nelson textbook of pediatrics e-book. Elsevier Health Sciences. Aug 15 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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09:24:09","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54405,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7936702/v1/de323f0e1b3626d5190efdee.html"},{"id":94989170,"identity":"f26cc18e-081a-44a5-9e84-9db47ac16706","added_by":"auto","created_at":"2025-11-03 07:12:19","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":105209,"visible":true,"origin":"","legend":"\u003cp\u003ePathophysiology of Glycogen Storage Disorder IIIa.\u003c/p\u003e\n\u003cp\u003e(\u003csup\u003e10\u003c/sup\u003e \u003csup\u003eKliegman RM, Behrman RE, Jenson HB, Stanton BM. Nelson textbook of pediatrics e-book. Elsevier Health Sciences; 2007 Aug 15.)\u003c/sup\u003e\u003c/p\u003e","description":"","filename":"Figure.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7936702/v1/7dbc10ba738efd99d1ae304f.jpg"},{"id":94990997,"identity":"8a3aad62-cc00-42c8-a89d-ce085b8cf958","added_by":"auto","created_at":"2025-11-03 07:18:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":540660,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7936702/v1/1dcd3c8c-5e8c-4ca0-832d-5266f92f0668.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eA Rare Case of Glycogen Storage Disease Type IIIa with a Novel Homozygous AGL Splice Variant in a Two-Year-Old Female born out of Consanguineous Marriage\u003c/p\u003e","fulltext":[{"header":"Key message","content":"\u003cp\u003eThis case highlights the distinctive clinical and diagnostic features of Glycogen Storage Disease Type IIIa, differentiating it from other GSD subtypes by the presentation of hepatomegaly with early morning hypoglycemic symptoms, notably without convulsions, which are commonly observed in other forms. Despite the absence of typical seizures, a high index of clinical suspicion based on hepatomegaly, delayed walking and early morning awakening with hypoglycemia along with other biochemical abnormalities facilitated early diagnosis. Genetic testing confirming a novel homozygous splice variant in the AGL gene underscored the critical role of molecular studies in diagnosis, especially in consanguineous populations. Early dietary intervention, regular monitoring, and comprehensive management are essential to mitigate progressive multisystemic complications and optimize long-term outcomes in this rare metabolic disorder.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eGlycogen Storage Disorder (GSD) or glycogenosis are a group of rare inherited metabolic disorders with prevalence of 1 in 20,000 to 43,000 live births, characterized by the abnormal storage of glycogen in various tissues. \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e Glycogen Storage Disorder IIIa (GSD IIIa) also known as Cori disease or Forbes disease or limit dextrinosis, is caused by biallelic pathogenic variants in the AGL gene on chromosome 1p2.2, which encodes the glycogen debranching enzyme, amylo-1,6-glucosidase (4-α-glucanotransferase) that results in abnormal accumulation of glycogen specifically in liver and muscle tissues. \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e This situation manifests in early childhood with symptoms including hypoglycemia, poor growth, hepatomegaly and progressive muscle weakness, that requires lifelong dietary and medical management. \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAbdominal distension and enlarged liver are generally observed with the episodes of fasting hypoglycemia that can lead to neurological compromise and seizures, especially in younger children. In Glycogen Storage Disease type III, low blood sugar is usually seen along with ketosis, yet without the high blood lactate or uric acid typically observed in GSD type I. \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e As children with GSD III grow older, many liver symptoms tend to gradually stabilize or even improve, offering some reassurance for families. However, the risk of complications like liver scarring, cirrhosis, or in rare situations, the development of liver tumours such as hepatic adenomas, still remains when patients reach adulthood. \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e We report a case study of a two-year-old female born out of consanguineous marriage who was evaluated for progressive abdominal distension and diagnosed with GSD IIIa.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA two-year-old female (1st baby) born out of 3\u0026ordm; consanguineous marriage, who presented to the outpatient department (OPD) with a history of progressive abdominal distension over the past five to six months, history of weight loss, delayed walking shows the involvement of muscle. There was a history of getting up early in the morning with hunger but never had convulsions and during day time she had hunger pangs. Additionally, there was no significant family history identified that can be related to genetic cause for glycogen storage disorder and there was no history of vomiting, loose motions, nausea, jaundice or symptoms of hepatic failure. Despite the significant abdominal distension, there were no signs of icterus, anaemia or of portal hypertension. Considering history of consanguinity (III\u0026ordm;), the progressive nature of the distension, along with a clinical context of raised clinical suspicion for an underlying metabolic disorder. On physical examinations, the most prominent finding was gross hepatomegaly without signs of hepatic failure.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBiochemical findings of the individual.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eBlood Investigations\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHaemoglobin (Hb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.30 g/dl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal Leukocyte Count (TLC)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9830 cells/\u0026micro;l\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeutrophil/Lymphocyte (N/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23/67 cells/\u0026micro;l\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlatelet\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e338000 /\u0026micro;l of blood\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRandom Blood Sugar (RBS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e86.5 mg/dl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFasting Blood Sugar (FBS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42.6 mg/dl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eLFT Investigations\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBilirubin T/D\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.51/0.09 mg/dl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSGPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e418.70 u/l\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlkaline Phosphatase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e1363 u/l\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLactate Dehydrogenase (LDH)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e494 u/l\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e2D ECHO Investigations\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFindings\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNormal, no shunt noted\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eOphthalmology Investigations\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFindings\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNormal, Fundus Normal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eUrine Analysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrobilinogen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTrace\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBilirubin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1+\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrinary Ketones\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e2+\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrinary pH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWBC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.5 HPF\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eOther Investigations\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatine Phosphokinase (CPK)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e679.3 u/l\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGamma-Glutamyl Transferase (GGT)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e126.25 u/l\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTriglycerides\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e297.2 mg/dl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal Cholesterol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e181.40 mg/dl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUric acid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.36 mg/dl\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eNotably, the laboratory findings from Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e revealed that the LFT investigations are not within the normal ranges and this elevated SGPT, ALK. Phos and LDH shows liver involvement. Even in blood investigations, FBS is suggestive of hypoglycemia along with urinary ketones that points towards the diagnosis of GSD. The elevated levels of CPK shows the muscle involvement in the disease. Further 2D echo was done to check whether heart muscles are involved but there was no significant involvement seen as the investigations were normal.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eDiagnostic Evaluation and Management:\u003c/h2\u003e\u003cp\u003eBiochemical analysis coupled with genetic testing played a pivotal role in the evaluation of the patient. The suspicion of glycogen storage disorder was further reinforced by the laboratory findings. The most compelling evidence came from genetic studies, which identified a homozygous splice site intronic variant in the AGL gene. Specifically, the variant identified was c.293\u0026thinsp;+\u0026thinsp;5G\u0026thinsp;\u0026gt;\u0026thinsp;C (located in intron 3, transcript NM_000642.3) at chromosomal position chr1:99861718:G\u0026thinsp;\u0026gt;\u0026thinsp;C with a total depth of 53X. This variant, which has not been reported in ClinVar, dbSNP, or large population frequency databases such as gnomAD and ExAC was classified as \u0026ldquo;Uncertain Significance\u0026rdquo; based on American College of Medical Genetics and Genomics (ACMG) criteria (PM2 and PP3). \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIn addition to the genetic data, the clinical presentation-including hepatomegaly and hypoglycemia-supported the diagnosis of GSD type IIIa. Although the variant\u0026rsquo;s clinical significance remains uncertain, the correlation with the patient\u0026rsquo;s phenotype and the known role of the AGL gene in glycogen metabolism substantiates the diagnosis.\u003c/p\u003e\u003cp\u003eManagement of GSD type IIIa largely revolves around dietary interventions aimed at preventing hypoglycemia and reducing glycogen accumulation. In this patient, dietary therapy was initiated with the administration of uncooked cornstarch (1.6gm/kg/day), a well-recognized intervention that provides a slow-release form of glucose. Frequent feeding and a diet enriched with complex carbohydrates, Vitamin D enriched sachet and Calcimax syrup were recommended for maintaining euglycemia and supporting normal growth and development.\u003c/p\u003e\u003cp\u003eRegular monitoring through biochemical assays and imaging studies is essential, given the potential development of complications such as progressive hepatomegaly, liver fibrosis, and in later stages, the onset of myopathy and cardiomyopathy. In this case, follow-up assessments were planned, including serial liver function tests and ultrasound examinations to monitor liver size and structure and 2D Echo for monitoring early onset of myopathy or cardiomyopathy.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAutosomal recessive disorders consequently become prominent in communities where consanguinity is prevalent as in comparison to non-consanguineous relations, the likelihood of both parents expressing an identical recessive gene is considerably more probable in consanguineous marriages. \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e Thus in this case, the sharing of mutant AGL genes from both parents lead to GSD type IIIa to their two year offspring. Type IIIa GSD represents a challenging clinical scenario that requires prompt diagnosis and a multidisciplinary approach to management. The identification of the homozygous splice site variant c.293\u0026thinsp;+\u0026thinsp;5G\u0026thinsp;\u0026gt;\u0026thinsp;C in the AGL gene highlights the importance of advanced genetic testing in diagnosing metabolic disorders with specific clinical presentations. Although the pathogenicity of the detected variant remains uncertain, its location in the gene and the potential for a splice defect provide plausible explanation for the altered enzyme function, leading to the accumulation of abnormal glycogen. \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e Hepatomegaly, as observed in this patient, is a common finding in Glycogen Storage Disorders involving the liver and early dietary interventions have been shown to prevent complications such as liver fibrosis and subsequent cirrhosis. The tailored diet with frequent feeding intervals and starch supplementation not only helps in maintaining normoglycemia but also minimizes the metabolic burden on the liver. \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e Continued follow-up is critical as clinical manifestations can evolve over time. Future clinical research may offer further insights into the role of specific AGL gene mutations and the potential benefits of emerging therapies such as gene therapy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case report of a two year old female with diagnosed glycogen storage disorder type IIIa underscores the importance of combining clinical, biochemical and genetic evaluations in the diagnosis and management of rare metabolic disorders. The detection of a homozygous splice site variant in the AGL gene, despite its current classification as of uncertain significance aligns with the patient's clinical presentation of progressive abdominal distension, hepatomegaly, and hypoglycemia. Early diagnosis, dietary management with starch supplementation, and regular follow up are paramount to optimizing patient outcomes and preventing long term complications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe parent of the patient was read (and/or explained) the purpose of the study in a language they understand and gave their consent voluntarily to participate/allow the patient's data to be used for research and academic purposes.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u0026nbsp;\u003c/strong\u003eWe acknowledge the pathology department for all the major findings including whole exome sequencing (genetical studies) which were useful to diagnose the GSD IIIa in early childhood and paediatric department for maintaining the clinical investigations and treatment for the individual.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eThe sole author is responsible for the conception, design, data collection, analysis, interpretation, manuscript writing, and final approval of the version to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial support and sponsorship:\u0026nbsp;\u003c/strong\u003eNo financial support or sponsorship was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest statement:\u0026nbsp;\u003c/strong\u003eThe author declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u0026nbsp;\u003c/strong\u003eThe data supporting the findings of this study were generated by the author and are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical aspects:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eEthical approval was not required for this case report as it involved anonymized patient information and posed no risk to the participant.\u003c/li\u003e\n \u003cli\u003eWritten informed consent was obtained from the patient for publication of their clinical details.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eStatement on approval from all contributors:\u0026nbsp;\u003c/strong\u003eI, the sole author, have read and approved the final version of the manuscript and take full responsibility for its content.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eG\u0026uuml;m\u0026uuml;ş E, \u0026Ouml;zen H (2023) Glycogen storage diseases: An update. 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Elsevier Health Sciences. Aug 15\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Dr. Hedgewar Rugnalaya","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Glycogen Storage Disorder type IIIa (GSD IIIa), Hepatomegaly, Hypoglycemia, Convulsions, Consanguineous parents, AGL gene, Homozygous Splice variant","lastPublishedDoi":"10.21203/rs.3.rs-7936702/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7936702/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGlycogen Storage Disease IIIa (GSD IIIa) is a hereditary disorder which is caused by the mutations in AGL gene that lead in the production of nonfunctional glycogen debranching enzyme. This enzymatic defect impairs the breakdown of glycogen, causing abnormal glycogen build up in tissues like liver, muscles and heart. This situation manifests in early childhood with symptoms such as hypoglycemia, poor growth, hepatomegaly and progressive muscle weakness that requires lifelong dietary and medical management. GSD IIIa, one of the most prevalent forms of hepatic and muscular glycogenoses, remains a significant clinical challenge due to its involvement of multiple organ systems and its persistent, progressive nature. We report a case study of a two-year-old female born out of consanguineous marriage who was evaluated for progressive abdominal distension and diagnosed with GSD IIIa.\u003c/p\u003e","manuscriptTitle":"A Rare Case of Glycogen Storage Disease Type IIIa with a Novel Homozygous AGL Splice Variant in a Two-Year-Old Female born out of Consanguineous Marriage","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-02 09:24:05","doi":"10.21203/rs.3.rs-7936702/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"47064768-4b87-495b-a6ac-1ce93784c33b","owner":[],"postedDate":"November 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-02T09:24:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-02 09:24:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7936702","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7936702","identity":"rs-7936702","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}