Genetic Metabolic Disorders Research Articles

A case study of hypophosphatasia: An underdiagnosed bone disorder characterized by low alkaline phosphatase.

Hypophosphatasia (HPP) is a rare genetic metabolic bone disorder that is underdiagnosed. Although there are many forms of this disease, based on age of onset, symptoms, and severity, HPP is characterized by low serum alkaline phosphatase levels, bone fractures, and dental complications. Diagnosis of HPP is made from clinical, laboratory, and radiologic findings. Genetic testing for an ALPL gene variant responsible for causing HPP confirms a molecular diagnosis. Distinguishing HPP from other more common bone disorders, such as osteoporosis, is important as the treatment for these diseases differs greatly. Although there is no known cure for HPP, treatment should be holistic and multidisciplinary.

Effects of internet-based health education on patients with acute intermittent porphyria

BackgroundAcute intermittent porphyria (AIP) is a rare genetic metabolic disorder characterized by acute attacks of neurovisceral symptoms. This disease not only poses a threat to patients’ physical and mental well-being, but its frequent acute attacks also have a profound impact on patients’ mental state and overall quality of life (QoL).ObjectiveThis study aimed to explore the impact of internet-based health education on the acute attacks, mental health, and QoL of patients with AIP.MethodsThis study employed a pre-post comparison design, recruiting 52 patients diagnosed with AIP and treated at the Second Hospital of Hebei Medical University between September 2021 and May 2023 as the subjects of investigation. All participants underwent a 12-month internet-based health education intervention. Quantitative assessments of the intervention’s efficacy in reducing acute attacks, enhancing mental health status, and improving QoL among AIP patients were conducted using various instruments, including measures of acute episode frequency and severity, the Depression Anxiety Stress Scales-21 (DASS-21), the Positive and Negative Affect Schedule (PANAS), and the MOS 36-Item Short Form Health Survey (SF-36). Data were collected at two distinct time points: pre- and post-health education interventions, which were then subjected to comparative analysis.ResultsCompared to pre-health education, the frequency of acute attacks among patients with AIP significantly decreased post-health education intervention (p < 0.05). Furthermore, notable improvements were observed in the severity of acute attacks, PANAS scores, DASS-21 scores, and SF-36 scores (p < 0.05).ConclusionsThis study validated that health education effectively reduced the frequency and severity of acute attacks in AIP patients while enhancing their mental health status and quality of life. Internet-based health education emerges as a practical and productive strategy for AIP patients.

Genetic landscape of primary mitochondrial diseases in children and adults using molecular genetics and genomic investigations of mitochondrial and nuclear genome

BackgroundPrimary mitochondrial diseases (PMD) are one of the most common metabolic genetic disorders. They are due to pathogenic variants in the mitochondrial genome (mtDNA) or nuclear genome (nDNA) that impair mitochondrial function and/or structure. We hypothesize that there is overlap between PMD and other genetic diseases that are mimicking PMD. For this reason, we performed a retrospective cohort study.MethodsAll individuals with suspected PMD that underwent molecular genetic and genomic investigations were included. Individuals were grouped for comparison: (1) individuals with mtDNA-PMD; (2) individuals with nDNA-PMD; (3) individuals with other genetic diseases mimicking PMD (non-PMD); (4) individuals without a confirmed genetic diagnosis.Results297 individuals fulfilled inclusion criteria. The diagnostic yield of molecular genetics and genomic investigations was 31.3%, including 37% for clinical exome sequencing and 15.8% for mitochondrial genome sequencing. We identified 71 individuals with PMD (mtDNA n = 41, nDNA n = 30) and 22 individuals with non-PMD. Adults had higher percentage of mtDNA-PMD compared to children (p-value = 0.00123). There is a statistically significant phenotypic difference between children and adults with PMD.ConclusionWe report a large cohort of individuals with PMD and the diagnostic yield of urine mitochondrial genome sequencing (16.1%). We think liver phenotype might be progressive and should be studied further in PMD. We showed a relationship between non-PMD genes and their indirect effects on mitochondrial machinery. Differentiation of PMD from non-PMD can be achieved using specific phenotypes as there was a statistically significant difference for muscular, cardiac, and ophthalmologic phenotypes, seizures, hearing loss, peripheral neuropathy in PMD group compared to non-PMD group.

Efficient and safe in vivo treatment of primary hyperoxaluria type 1 via LNP-CRISPR-Cas9-mediated glycolate oxidase disruption

Primary hyperoxaluria type 1 (PH1) is a severe genetic metabolic disorder caused by mutations in the AGXT gene, leading to defects in enzymes crucial for glyoxylate metabolism. PH1 is characterized by severe, potentially life-threatening manifestations due to excessive oxalate accumulation, which leads to calcium oxalate crystal deposits in the kidneys and, ultimately, renal failure and systemic oxalosis. Existing substrate reduction therapies, such as inhibition of liver-specific glycolate oxidase (GO) encoded by HAO1 using siRNA or CRISPR/Cas9 delivered by adeno-associated virus (AAV), either require repeated dosing or have raised safety concerns. To address these limitations, our study employed lipid nanoparticles (LNPs) for CRISPR/Cas9 delivery to rapidly generate a PH1 mouse model and validate the therapeutic efficacy of LNP-CRISPR/Cas9 targeting the Hao1 gene. The LNP-CRISPR/Cas9 system exhibited efficient editing of the Hao1 gene, significantly reducing GO expression and lowering urinary oxalate levels in treated PH1 mice. Notably, these effects persisted for 12 months with no significant off-target effects, liver-induced toxicity, or substantial immune responses, highlighting the approach's safety and specificity. Furthermore, the developed humanized mouse model validated the efficacy of our therapeutic strategy. These findings support LNP-CRISPR/Cas9 targeting HAO1 as a promising and safer alternative for PH1 treatment with a single administration.

Massive detection of cryptic recessive genetic defects in dairy cattle mining millions of life histories

BackgroundDairy cattle breeds are populations of limited effective size, subject to recurrent outbreaks of recessive defects that are commonly studied using positional cloning. However, this strategy, based on the observation of animals with characteristic features, may overlook a number of conditions, such as immune or metabolic genetic disorders, which may be confused with pathologies of environmental etiology.ResultsWe present a data mining framework specifically designed to detect recessive defects in livestock that have been previously missed due to a lack of specific signs, incomplete penetrance, or incomplete linkage disequilibrium. This approach leverages the massive data generated by genomic selection. Its basic principle is to compare the observed and expected numbers of homozygotes for sliding haplotypes in animals with different life histories. Within three cattle breeds, we report 33 new loci responsible for increased risk of juvenile mortality and present a series of validations based on large-scale genotyping, clinical examination, and functional studies for candidate variants affecting the NOA1, RFC5, and ITGB7 genes. In particular, we describe disorders associated with NOA1 and RFC5 mutations for the first time in vertebrates.ConclusionsThe discovery of these many new defects will help to characterize the genetic basis of inbreeding depression, while their management will improve animal welfare and reduce losses to the industry.

Immune remodulation in pediatric inherited metabolic liver diseases.

Inherited metabolic liver diseases arise from genetic mutations that lead to disruptions in liver metabolic pathways and are predominantly observed in pediatric populations. The spectrum of genetic metabolic liver disorders is diverse, encompassing a range of conditions associated with aberrations in iron, copper, carbohydrate, lipid, protein, and amino acid metabolism. Historically, research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations. Nevertheless, emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment, both within the liver and systemically. This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases, aiming to expand the horizons of researchers in this discipline, and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.

From Mechanism-Based Retaining Glycosidase Inhibitors to Activity-Based Glycosidase Profiling.

Activity-based protein profiling (ABPP) is an effective technology for the identification and functional annotation of enzymes in complex biological samples. ABP designs are normally directed to an enzyme active site nucleophile, and within the field of Carbohydrate-Active Enzymes (CAZymes), ABPP has been most successful for those enzymes that feature such a residue: retaining glycosidases (GHs). Several mechanism-based covalent and irreversible retaining GH inhibitors have emerged over the past sixty years. ABP designs based on these inhibitor chemistries appeared since the turn of the millennium, and we contributed to the field by designing a suite of retaining GH ABPs modeled on the structure and mode of action of the natural product, cyclophellitol. These ABPs enable the study of both exo- and endo-acting retaining GHs in human health and disease, for instance in genetic metabolic disorders in which retaining GHs are deficient. They are also finding increasing use in the study of GHs in gut microbiota and environmental microorganisms, both in the context of drug (de)toxification in the gut and that of biomass polysaccharide processing for future sustainable energy and chemistries. This account comprises the authors' view on the history of mechanism-based retaining GH inhibitor design and discovery, on how these inhibitors served as blueprints for retaining GH ABP design, and on some current and future developments on how cyclophellitol-based ABPs may drive the discovery of retaining GHs and their inhibitors.

The Complexity of Premature Coronary Artery Disease

Premature Coronary Artery Disease presents a significant health concern globally, characterized by the onset of coronary atherosclerosis at an early age, typically before the age of 55 in men and 65 in women. This review provides a comprehensive examination of the various aspects of premature CAD, ranging from its underlying pathophysiology to diagnostic modalities such as coronary angiography. Beginning with an overview of the risk factors contributing to premature CAD, including genetic predispositions, lifestyle factors, and metabolic disorders, the review delves into the intricate mechanisms involved in the initiation and progression of atherosclerosis. Furthermore, the review discusses the clinical manifestations and challenges associated with diagnosing premature CAD, particularly in asymptomatic individuals. It examines the utility of non-invasive imaging techniques, stress testing in identifying coronary artery stenosis, cardiovascular risk and the principles of coronary angiography. The review outlines the principles of coronary angiography, including patient preparation, procedural techniques, and interpretation of angiographic findings. In conclusion, this comprehensive review provides insights into the multifaceted nature of premature CAD, elucidating its pathogenesis, clinical presentation, and diagnostic evaluation, with a focus on the pivotal role of coronary angiography in guiding therapeutic interventions and optimizing patient outcomes. Keyword: Coronary Angiography, Premature Coronary Artery Disease, Risk Factor.

2024 European Thyroid Association Guidelines on diagnosis and management of genetic disorders of thyroid hormone transport, metabolism and action.

Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.

An overview of porphyrias

Porphyrias are predominantly genetic metabolic disorders caused by dysregulation of specific enzymes in porphyrin-heme biosynthesis. The enzymatic dysfunction leads to formation and excretion of intermediate metabolic products in the form of porphyrins and/or their precursors δ‑aminolevulinic acid and porphobilinogen, which have cyto- and tissue-toxic properties. Clinically, porphyrias are extremely diverse, with symptoms ranging from skin changes on light-exposed areas of the body to potentially life-threatening neurovisceral attacks. Biochemical tests in urine, blood and stool are used for diagnosis, which can be supplemented by molecular genetic analyses. Treatment of the various forms of porphyria is complex and often requires close interdisciplinary cooperation between different medical specialties.

Clinical and genetic analysis of methylmalonic aciduria in 60 patients from Southern China: a single center retrospective study

BackgroundMethylmalonic aciduria (MMA) is a group of rare genetic metabolic disorders resulting from defects in methylmalonyl coenzyme A mutase (MCM) or intracellular cobalamin (cbl) metabolism. MMA patients show diverse clinical and genetic features across different subtypes and populations.MethodsWe retrospectively recruited 60 MMA patients from a single center and diagnosed them based on their clinical manifestations and biochemical assays. We then performed genetic analysis to confirm the diagnosis and identify the causal variants.ResultsWe confirmed the common clinical manifestations of MMA reported previously. We also described four rare MMA cases with unusual symptoms or genetic variants, such as pulmonary hypertension or limb weakness in late-onset patients. We identified 15 MMACHC and 26 MMUT variants in 57 patients, including 6 novel MMUT variants. Two patients had only one MMAA variant each, and one patient had mild MMA due to mitochondrial DNA depletion syndrome caused by a SUCLA2 variant. Among 12 critically ill patients, isolated MMA was associated with higher C3, blood ammonia, and acidosis, while combined MMA was linked to hydrocephalus on skull MRI. MMACHC c.658-660delAAG and MMUT c.1280G > A variants were correlated with more severe phenotypes.ConclusionsOur study demonstrates the clinical and genotypic heterogeneity of MMA patients and indicates that metabolic screening and genetic analysis are useful tools to identify rare cases.

Gold core@CeO2 halfshell Janus nanocomposites catalyze targeted sulfate radical for periodontitis therapy

The sulfate radical (SO4•-), known for its high reactivity and long lifespan, has emerged as a potent antimicrobial agent. Its exceptional energy allows for the disruption of vital structures and metabolic pathways in bacteria that are usually inaccessible to common radicals. Despite its promising potential, the efficient generation of this radical, particularly through methods involving enzymes and photocatalysis, remains a substantial challenge. Here, we capitalized on the peroxidase (POD)-mimicking activity and photocatalytic properties of cerium oxide (CeO2) nanozymes, integrating these properties with the enhanced concept of plasma gold nanorod (GNR) to develop a half-encapsulated core@shell GNRs@CeO2 Janus heterostructure impregnated with persulfate. Under near-infrared irradiation, the GNRs generate hot electrons, thereby boosting the CeO2's enzyme-like activity and initiating a potent reactive oxygen species (ROS) storm. This distinct nanoarchitecture facilitates functional specialization, wherein the heterostructure and efficient light absorption ensured continuous hot electron flow, not only enhancing the POD-like activity of CeO2 for the production of SO4•- effectively, but also contributing a significant photothermal effect, disrupting periodontal plaque biofilm and effectively eradicating pathogens. Furthermore, the local temperature elevation synergistically enhances the POD-like activity of CeO2. Transcriptomics analysis, as well as animal experiments of the periodontitis model, have revealed that pathogens undergo genetic information destruction, metabolic disorders, and pathogenicity changes in the powerful ROS system, and profound therapeutic outcomes in vivo, including anti-inflammation and bone preservation. This study demonstrated that energy transfer to augment nanozyme activity, specifically targeting ROS generation, constitutes a significant advancement in antibacterial treatment.

Impact of Transgenerational Nutrition on Nonalcoholic Fatty Liver Disease Development: Interplay between Gut Microbiota, Epigenetics and Immunity.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent pediatric liver disorder, primarily attributed to dietary shifts in recent years. NAFLD is characterized by the accumulation of lipid species in hepatocytes, leading to liver inflammation that can progress to steatohepatitis, fibrosis, and cirrhosis. Risk factors contributing to NAFLD encompass genetic variations and metabolic disorders such as obesity, diabetes, and insulin resistance. Moreover, transgenerational influences, resulting in an imbalance of gut microbial composition, epigenetic modifications, and dysregulated hepatic immune responses in offspring, play a pivotal role in pediatric NAFLD development. Maternal nutrition shapes the profile of microbiota-derived metabolites in offspring, exerting significant influence on immune system regulation and the development of metabolic syndrome in offspring. In this review, we summarize recent evidence elucidating the intricate interplay between gut microbiota, epigenetics, and immunity in fetuses exposed to maternal nutrition, and its impact on the onset of NAFLD in offspring. Furthermore, potential therapeutic strategies targeting this network are also discussed.

Simple and sensitive galactose monitoring based on capillary SERS sensor.

Galactosemia, a severe genetic metabolic disorder, results from the absence of galactose-degrading enzymes, leading to harmful galactose accumulation. In this study, we introduce a novel capillary-based surface-enhanced Raman spectroscopy (SERS) sensor for convenient and sensitive galactose detection. The developed sensor enhances SERS signals by introducing gold nanoparticles (Au NPs) onto the surface of silver nanoshells (Ag NSs) within a capillary, creating Ag NSs with Au NPs as satellites. Utilizing 4-mercaptophenylboronic acid (4-MPBA) as a Raman reporter molecule, the detection method relies on the conversion of 4-MPBA to 4-mercaptophenol (4-MPhOH) driven by hydrogen peroxide (H2O2) generated during galactose oxidation by galactose oxidase (GOx). A new SERS signal was observed, which was generated by H2O2 produced when galactose and GOx reacted. Our strategy yielded a quantitative change in the SERS signal, specifically in the band intensity ratio of 998 to 1076 cm-1 (I998/I1076) as the galactose concentration increased. Our capillary-based SERS biosensor provides a promising platform for early galactosemia diagnosis.

Neuro-regression Assessment- A Case Report

Introduction: Neuro-regression can occur for various reasons, including neurodegenerative diseases such as Alzheimer's disease, certain genetic disorders, brain injuries, infections, toxic exposures, or metabolic disorders. It is often characterized by a progressive deterioration of neurological function over time. Neuro-regression can be caused by a variety of factors, including, Neurodegenerative diseases, Genetic disorders, Brain injuries, Infections, Toxic exposures, and Metabolic disorders. Objective: The goal of this case report is to highlight the difference between developmental delay and developmental regression also known as Neuro-Regression in terms of differential diagnosis. Case Report: A 2.2-year-old male child, with a background of developmental delay and epilepsy was admitted with multiple episodes of breakthrough seizures. Developmental milestones were age-appropriate till 11 months of age (before the seizure). After the seizure, the child’s motor development regressed and the child was not able to sit, or stand. The speech and language milestones were appropriate to the age before the seizure and regressed after the seizure. Conclusion: In our study, it's very clear that the child experiencing neuro-regression which is evident based on the parents’ report, previous and present clinical assessments as well and clinical observation. Regression is an indication that more investigation is necessary and team members like a Developmental Paediatrician, Neurologist, and Clinical Psychologist should be involved.

Identification of GM1-Ganglioside Secondary Accumulation in Fibroblasts from Neuropathic Gaucher Patients and Effect of a Trivalent Trihydroxypiperidine Iminosugar Compound on Its Storage Reduction.

Gaucher disease (GD) is a rare genetic metabolic disorder characterized by a dysfunction of the lysosomal glycoside hydrolase glucocerebrosidase (GCase) due to mutations in the gene GBA1, leading to the cellular accumulation of glucosylceramide (GlcCer). While most of the current research focuses on the primary accumulated material, lesser attention has been paid to secondary storage materials and their reciprocal intertwining. By using a novel approach based on flow cytometry and fluorescent labelling, we monitored changes in storage materials directly in fibroblasts derived from GD patients carrying N370S/RecNcil and homozygous L444P or R131C mutations with respect to wild type. In L444P and R131C fibroblasts, we detected not only the primary accumulation of GlcCer accumulation but also a considerable secondary increase in GM1 storage, comparable with the one observed in infantile patients affected by GM1 gangliosidosis. In addition, the ability of a trivalent trihydroxypiperidine iminosugar compound (CV82), which previously showed good pharmacological chaperone activity on GCase enzyme, to reduce the levels of storage materials in L444P and R131C fibroblasts was tested. Interestingly, treatment with different concentrations of CV82 led to a significant reduction in GM1 accumulation only in L444P fibroblasts, without significantly affecting GlcCer levels. The compound CV82 was selective against the GCase enzyme with respect to the β-Galactosidase enzyme, which was responsible for the catabolism of GM1 ganglioside. The reduction in GM1-ganglioside level cannot be therefore ascribed to a direct action of CV82 on β-Galactosidase enzyme, suggesting that GM1 decrease is rather related to other unknown mechanisms that follow the direct action of CV82 on GCase. In conclusion, this work indicates that the tracking of secondary storages can represent a key step for a better understanding of the pathways involved in the severity of GD, also underlying the importance of developing drugs able to reduce both primary and secondary storage-material accumulations in GD.

Atypical Kleine Levin Syndrome: Atypical or “Something Else”

Objective: To describe in some detail published cases who were diagnosed as atypical Kleine-Levin syndrome (KLS), and discuss the validity and usefulness of this diagnostic term. Methods: The English written literature was reviewed using the search terms Atypical KLS, KLS mimic, KLS like and KLS variant. Only reports which provided complete clinical features were reviewed. The present diagnostic criteria of KLS were applied in each case and the reasons why each case was considered as atypical were outlined in a table form. The cases were grouped according to the primary etiologies which could explain the symptoms into infectious, autoimmune, cerebrovascular, head trauma, brain tumor and genetic metabolic disorders. Cases in whom we could not establish a definite diagnosis were coined “atypical “and a few which could not be assigned to a specific group were coined “miscellaneous”. Results: Fifty seven reports describing 60 “atypical“ cases were found. Out of those, 14 suffered from a variety of medical conditions which could explain the symptomology while in 19 cases a definite diagnosis could not reached. Five cases were coined as “miscellaneous” since we could not assign them to a specific group. Conclusion: The eponym “atypical” KLS, refers to patients in whom a variety of medical disorders were associated with sleep-wake disorder, however, it seems appropriate that in such cases the diagnosis should express the primary cause of the symptoms rather than suggesting that those cases are a variant of KLS.

Chapter 4 - Primary mitochondrial diseases

Primary mitochondrial diseases (PMDs) are a heterogeneous group of hereditary disorders characterized by an impairment of the mitochondrial respiratory chain. They are the most common group of genetic metabolic disorders, with a prevalence of 1 in 4,300 people. The presence of leukoencephalopathy is recognized as an important feature in many PMDs and can be a manifestation of mutations in both mitochondrial DNA (classic syndromes such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; myoclonic epilepsy with ragged-red fibers [RRFs]; Leigh syndrome; and Kearns-Sayre syndrome) and nuclear DNA (mutations in maintenance genes such as POLG, MPV17, and TYMP; Leigh syndrome; and mitochondrial aminoacyl-tRNA synthetase disorders). In this chapter, PMDs associated with white matter involvement are outlined, including details of clinical presentations, brain MRI features, and elements of differential diagnoses. The current approach to the diagnosis of PMDs and management strategies are also discussed. A PMD diagnosis in a subject with leukoencephalopathy should be considered in the presence of specific brain MRI features (for example, cyst-like lesions, bilateral basal ganglia lesions, and involvement of both cerebral hemispheres and cerebellum), in addition to a complex neurologic or multisystem disorder. Establishing a genetic diagnosis is crucial to ensure appropriate genetic counseling, multidisciplinary team input, and eligibility for clinical trials.

Portuguese Consensus on Acute Porphyrias: Diagnosis, Treatment, Monitoring and Patient Referral.

Acute porphyrias are a group of rare genetic metabolic disorders, caused by a defect in one of the enzymes involved in the heme biosynthesis, which results in an abnormally high accumulation of toxic intermediates. Acute porphyrias are characterized by potentially life-threatening attacks and, for some patients, by chronic manifestations that negatively impact daily functioning and quality of life. Clinical manifestations include a nonspecific set of gastrointestinal, neuropsychiatric, and/or cutaneous symptoms. Effective diagnostic methods are widely available, but due to their clinical heterogeneity and non-specificity, many years often elapse from symptom onset to diagnosis of acute porphyrias, delaying the treatment and increasing morbidity. Therefore, increased awareness of acute porphyrias among healthcare professionals is paramount to reducing disease burden. Treatment of acute porphyrias is centered on eliminating the potential precipitants, symptomatic treatment, and suppressing the hepatic heme pathway, through the administration of hemin or givosiran. Moreover, properly monitoring patients with acute porphyrias and their relatives is fundamental to preventing acute attacks, hospitalization, and long-term complications. Considering this, a multidisciplinary panel elaborated a consensus paper, aiming to provide guidance for an efficient and timely diagnosis of acute porphyrias, and evidence-based recommendations for treating and monitoring patients and their families in Portugal. To this end, all authors exhaustively reviewed and discussed the current scientific evidence on acute porphyrias available in the literature, between November 2022 and May 2023.

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.