Search Results (125)

Background/Objectives: Glycogen storage disease type IX (GSD IX) is an inherited metabolic disorder characterized by marked clinical heterogeneity and variable severity. Dietary therapy is considered the cornerstone of management, but evidence on treatment strategies, efficacy, and safety remains limited. This study aimed to systematically synthesize available data on therapeutic approaches and clinical outcomes in GSD IX. Methods: A focused analysis of treatment-related data was conducted from a previously performed PRISMA-based systematic review. Clinical studies reporting treatment and follow-up data in genetically confirmed GSD IX patients were included. Results: Among 400 patients identified in the original review, 129 from 26 studies had treatment and follow-up data available. Dietary management combined with uncooked cornstarch (UCCS) was the most common approach (96.1%), with highly heterogeneous protocols. Hepatic manifestations improved in 59/129 (45.7%) of patients, and hypoglycemia in 45/129 (34.9%). Growth outcomes were variable, with catch-up growth in 14.0% and persistent impairment in 19.4%, although data were often missing. Muscle involvement was rarely assessed. No treatment-related adverse events were reported. However, disease-related complications were described, including liver cirrhosis, neurological involvement, osteopenia/osteoporosis, and two deaths in GSD IXa patients. Conclusions: Dietary therapy combined with UCCS remains the mainstay of treatment in GSD IX and is associated with improvement in key clinical domains. However, evidence is limited, heterogeneous, and largely based on small studies. Data on modified cornstarch formulations, such as Glycosade^®, are scarce. Prospective studies and standardized treatment protocols are needed to support evidence-based management. Full article

Skeletal muscle is vital for movement and metabolism, and its dysfunction underpins disorders like muscular dystrophy and sarcopenia, severely impacting life quality. In these diseases, various cell death pathways are pivotal, driving core pathological features such as fiber loss and chronic inflammation. This study reviews the central role of cell death in skeletal muscle diseases, and analyzes its roles and mechanisms in genetic muscle disorders such as Duchenne muscular dystrophy (DMD), glycogen storage diseases (GSD), mitochondrial myopathies, as well as acquired muscle disorders such as idiopathic inflammatory myopathy, sarcopenia, rhabdomyolysis, and myasthenia gravis (MG). We also explore the potential of cell death-related molecules as biomarkers and discuss emerging therapeutic strategies that target these pathways, aiming to provide new insights for diagnosis and treatment. Full article

Background/Objectives: Patients with hepatic glycogen storage disease (GSD) require frequent nighttime intake of uncooked corn starch (UCCS) to prevent fasting hypoglycemia, which imposes a substantial burden. Glycosade, an extended-release cornstarch, was developed to prolong overnight glucose availability. However, data regarding South Korean patients are limited. Therefore, we aimed to evaluate the efficacy and safety of Glycosade in South Korean patients with hepatic GSD. Methods: In this single-center prospective observational study, patients with hepatic GSD underwent laboratory evaluations before and 1 month after Glycosade administration. Continuous glucose monitoring (CGM) was performed during UCCS and Glycosade administration periods. The nocturnal mean glucose, coefficient of variation, time in range (70–180 mg/dL), and time below the range (<70 and <54 mg/dL) were compared between the periods using paired analyses. Results: No significant differences were observed in the nocturnal CGM metrics between the treatment periods. However, time-aligned CGM profiles revealed distinct temporal patterns, with a decline in glucose levels approximately 3–4 h after UCCS intake, whereas Glycosade showed a more sustained glucose profile over an extended period. Liver enzyme and lipid levels improved significantly after 1 month of Glycosade supplementation. Conclusions: In a cohort of South Korean patients with hepatic GSD, Glycosade maintained nocturnal glycemic stability comparable to that of conventional cornstarch without increasing the risk of hypoglycemia. Glycosade was also associated with improved biochemical parameters, supporting its role in nighttime dietary management. Full article

Background: HyperCKemia, defined as elevated serum creatine kinase, commonly reflects muscle injury but may also indicate underlying metabolic disease. Metabolic aetiologies, including glycogen storage disorders, fatty acid oxidation defects, mitochondrial cytopathies, and purine metabolism disorders, are clinically important owing to diagnostic complexity, therapeutic implications, and potential reversibility. Objective: To summarise current evidence on metabolic causes of hyperCKemia in adults, with emphasis on disorders of carbohydrate, lipid, and purine metabolism and mitochondrial disease. Methods: Semi-systematic narrative review of pathophysiology, clinical features, diagnostic approaches, and management of metabolic disorders associated with hyperCKemia. Results: Metabolic myopathies often present with nonspecific or exercise-related symptoms, with creatine kinase levels ranging from mild-to-severe elevations. Conditions such as McArdle disease, carnitine palmitoyltransferase II deficiency, and mitochondrial cytopathies demonstrate characteristic metabolic vulnerabilities leading to episodic or persistent hyperCKemia. Medications, including statins and antiretrovirals, may precipitate symptoms in predisposed individuals. Diagnosis requires a structured, multidisciplinary approach incorporating biochemical testing, genetic analysis, functional studies, and muscle biopsy. Many causes are amenable to targeted therapy, including dietary modification, endocrine correction, and medication withdrawal. Conclusion: Metabolic causes of hyperCKemia are under-recognised but clinically significant. Early identification allows targeted treatment and prevention of complications. Full article

Background: PRKAG2 cardiac syndrome is a rare autosomal dominant glycogen-storage cardiomyopathy that mimics sarcomeric hypertrophic cardiomyopathy (HCM) but features ventricular pre-excitation, progressive conduction disease and concentric hypertrophy due to intracellular glycogen accumulation. The c.905G>A (p.Arg302Gln) variant is one of the most frequently reported pathogenic substitutions. Case summary: We describe a three-generation family carrying the heterozygous PRKAG2 p.Arg302Gln variant. The proband, a 41-year-old man, presented with paroxysmal atrial fibrillation, short PR interval and abnormal intraventricular conduction associated with concentric left ventricular hypertrophy and preserved ejection fraction. Holter monitoring disclosed episodes of high-grade atrioventricular block, prompting implantation of a primary-prevention dual-chamber ICD. Two gene-positive brothers exhibited milder hypertrophy but shared sinus bradycardia, ventricular pre-excitation and supraventricular arrhythmias; one underwent catheter ablation of a posteroseptal accessory pathway. The affected mother displayed a hypertrophic phenotype complicated by sick sinus syndrome and permanent atypical atrial flutter requiring pacemaker implantation. No relevant extracardiac involvement was detected in any family member. Review and novelty: Using this family as a starting point, we provide a concise narrative review of PRKAG2 syndrome with emphasis on the Arg302Gln genotype, molecular mechanisms and emerging treatment strategies. We highlight key multimodality imaging and tissue-characterization features that help distinguish diffuse, concentric glycogen-storage hypertrophy from the often-asymmetric pattern of sarcomeric HCM. Integration of our findings with published Arg302Gln cohorts illustrates the broad phenotypic variability in conduction disease, pre-excitation and atrial arrhythmias. Conclusions: PRKAG2 p.Arg302Gln-related cardiomyopathy should be suspected in patients with otherwise unexplained left ventricular hypertrophy associated with short PR interval, pre-excitation or early brady–tachy arrhythmias. Early recognition of red-flag features, systematic genetic testing, family screening and tailored arrhythmia/device management are crucial, while emerging gene- and pathway-targeted therapies may offer future disease-modifying potential. Full article

Insulin is an anabolic hormone involved in the regulation of several processes, such as the storage of glucose into glycogen, decrease of glucose output, stimulation of glucose transport into cells, etc. The hormone binds to its receptor, thereby activating an intracellular signaling cascade. Once activated, the insulin receptor (INSR) phosphorylates multiple intracellular substrates, which initiate the downstream signaling pathway. The nature of insulin signaling pathways may vary depending on the organ or tissue. In the central nervous system (CNS), INSRs are expressed in all cell types. This observation may suggest that insulin signaling is involved in important and diverse processes. It regulates glucose metabolism, supports cognitive functions, enhances the outgrowth of neurons, as well as plays a role in the modulation of release and uptake of catecholamine, among other roles. Importantly, insulin can freely cross the blood–brain barrier (BBB) from the circulation and is also synthesized locally within the brain. Insulin resistance (IR) impairs insulin signaling, which may accelerate brain aging, affect plasticity, and potentially contribute to neurodegeneration. Dysregulation of insulin signaling has been implicated in several diseases, including diabetes mellitus, metabolic syndrome, certain cancers, and neurodegenerative diseases, such as Alzheimer’s disease. There are two principal insulin signaling pathways: the PI3K/AKT pathway, primarily associated with metabolic effects, and the MAPK pathway, which is involved in cell growth, survival, and gene expression. Our review describes the role of insulin in the human brain, as well as the disturbances in insulin signaling resulting from brain insulin resistance, with a particular focus on its association with Alzheimer’s disease. Full article

Alcoholic liver disease (ALD) is a spectrum of alcohol-induced disorders and represents a major global health challenge. B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum-resident chaperone involved in protein transport, apoptosis, cancer biology, and lipid metabolism. To explore its role in ALD, we used hepatocyte-specific BAP31 knockout mice (BAP31-LKO) and wild-type (WT) littermates exposed to ethanol to assess BAP31′s biochemical and metabolic impact. Following ethanol exposure, BAP31-LKO mice exhibited elevated serum alanine transaminase (23.2%, p < 0.05) and aspartate transaminase (31.4%, p < 0.05) levels compared to WT mice. Increased malondialdehyde (8.5%, p < 0.05) and reduced superoxide dismutase (22.8%, p < 0.05) in BAP31-LKO mice indicate exacerbated liver injury. Furthermore, BAP31 deficiency increased triglyceride (35.7%, p < 0.05) and free fatty acid (16.2%, p < 0.05) accumulation following ethanol treatment, while the expression of fatty acid oxidation-related genes, including Pparα, Cd36, Fatp2, Cpt2, and Acox1, was reduced in BAP31-LKO mice. The mRNA levels of Xbp1, Xbp1s, and Chop, as well as protein levels of p-eIF2α, IRE1α, GRP78, and CHOP, were increased in BAP31-LKO mice compared to WT controls, indicating aggravated ethanol-induced ER stress. Hepatic glycogen content was also reduced in BAP31-LKO mice, along with reduced Ppp1r3c expression, demonstrating impaired glycogen synthesis. Consistently, BAP31 knockdown amplified ethanol-induced lipid accumulation, inflammation, impaired glycogen storage, ER stress, and suppression of Pparα signaling in HepG2 cells. Together, these findings demonstrate that BAP31 deficiency exacerbates ethanol-induced liver steatosis, inflammation, and liver injury by impairing fatty acid oxidation and glycogen synthesis, and by amplifying ER stress responses. Full article

Among cardiomyopathies, the hypertrophic phenotype is the most common, and hypertrophic cardiomyopathy (HCM) phenocopies represent a heterogeneous group of conditions. They are defined by a left ventricular wall thickness ≥15 mm in the absence of other causes such as loading conditions, ischemia, or valvular disease. Although they mimic similar clinical and morphological features, their etiologies are distinct and include genetic, metabolic, and infiltrative mechanisms. Therefore, accurate classification and differential diagnosis are crucial for effective management and treatment. Sarcomeric HCM is the most frequent form, accounting for up to 60% of cases. However, numerous non-sarcomeric phenocopies exist, including amyloidosis, Fabry disease, glycogen storage disorders, RASopathies, and mitochondrial diseases. Clinical and imaging findings are essential to distinguish these entities from sarcomeric HCM. Electrocardiography, echocardiography, advanced modalities such as cardiac magnetic resonance (CMR), and specific laboratory tests all play a central role in guiding diagnosis. Genetic testing provides key insights into mutations and inheritance patterns, further supporting definitive diagnosis. Correct identification of an HCM phenocopy carries important therapeutic implications, as disease-specific treatments can significantly improve prognosis. For example, targeted therapies exist for amyloidosis, Fabry disease, and certain metabolic or mitochondrial disorders, underlining the clinical relevance of an accurate diagnosis. This review aims to provide an overview of HCM phenocopies and assist clinicians in diagnostic reasoning. The first part addresses classification according to pathophysiological mechanisms, clinical features, and genetic background. The second part focuses on the stepwise approach to differential diagnosis, integrating clinical assessment, laboratory evaluation, ECG, echocardiography, and CMR findings. Full article

Introduction. Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is an autosomal recessive metabolic disorder resulting from mutations in the genes that encode the electron transfer flavoprotein (ETF) or its associated dehydrogenase (ETFDH), resulting in defects in mitochondrial fatty acid oxidation and a broad range of clinical presentations, most notably in the form of muscle weakness; exercise intolerance; and, in some cases, life-threatening metabolic crises. Late-onset MADD represents the most common form of lipid storage myopathy, but its diagnosis can be elusive due to its varied and often nonspecific clinical symptoms and may resemble other neuromuscular conditions, like inflammatory myopathies or other peripheral neuropathies, complicating the diagnostic process and delaying appropriate treatment. Aims. This case series aims to provide additional insights into the clinical presentation of MADD, highlighting diagnostic challenges in differentiating metabolic myopathies and emphasizing the role of muscle biopsy in diagnosing these conditions. Results. We describe five clinical cases of patients who were diagnosed with MADD, their clinical manifestations, and the diagnostic processes undertaken to arrive at this diagnosis. Notably, three patients were initially misdiagnosed with inflammatory myopathy, and one was misdiagnosed with Guillain–Barré syndrome. The correct diagnosis was established following a muscle biopsy, which revealed characteristic findings consistent with lipid storage myopathy and prompted subsequent biochemical analyses and genetic testing that confirmed the diagnosis of MADD. Conclusions. MADD is an underdiagnosed condition, and the description of new patients with various clinical presentations could support the development of clinical tools to promptly recognize this disease and allow physicians to deliver the most appropriate and effective therapy protocol, with Riboflavin and Carnitine supplementations, avoiding inappropriate treatments. The muscle biopsy was essential for a correct diagnostic assessment. Full article

Pompe disease is an autosomal recessive metabolic disorder caused by acid alpha-glucosidase (GAA) deficiency. The use of umbilical cord blood (UCB) for newborn screening (NBS) of Pompe disease, compared to heel-prick sampling, has not been widely studied. This study compared GAA activity in UCB from term newborns with peripheral or heel-prick blood samples obtained on days 1, 2, and 3 after birth. Enzyme assays were performed using UPLC-MS/MS. Sanger sequencing was conducted in infants with low GAA activity to identify pathogenic variants. Among 4091 UCB samples analyzed over 18 months, the mean GAA activity was 10.04 ± 5.95 μM/h, higher in females than males [Median (IQR): 9.83 (5.45) vs. 9.08 (4.97) μM/h, respectively, p < 0.001], and similar across ethnicities. GAA levels in UCB and Day 3 heel-prick samples were comparable. A GAA cut-off value of 1.54 μM/h (0.1% of study population) identified one infant (0.024% prevalence) with a novel bi-allelic variant—c.2005_2010del (p.Pro669_Phe670del) and c.1123C>T (p.Arg375Cys), and 12 infants with non-pathogenic pseudodeficiency alleles. This study supports GAA measurement in UCB as a viable alternative for NBS, with enzyme activity remaining stable for up to 72 h post-collection. Larger-scale multicenter nationwide studies are warranted to confirm this prevalence in our population. Full article

Background/Objectives: Pompe disease (PD) is a rare autosomal recessive disorder caused by a deficiency of the lysosomal acid α-1,4-glucosidase (GAA) encoded by the GAA gene, leading to muscular dysfunctions due to pathological accumulation of glycogen in skeletal and cardiac muscles. PD has been reported in several animals and Japanese quails (JQ; Coturnix japonica), but a causative mutation has yet to be found in JQs with PD. Here, we aimed to identify a pathogenic mutation in JQs associated with PD. Methods: Paraffin-embedded skeletal muscle blocks from four JQs stored since the 1970s were used in this study. After confirming the histopathological phenotypes of PD, Sanger sequencing was performed to identify a pathological mutation in the GAA I gene of JQs. A genotyping survey was conducted using a real-time polymerase chain reaction assay targeting a candidate mutation using DNA samples extracted from 70 new-hatched JQs and 10 eggs from commercial farms. Results: Microscopic analysis confirmed the presence of the PD phenotype in three affected JQs based on abnormal histopathological changes and accumulated glycogen in the affected muscles, while one JQ was unaffected and served as a control. Sanger sequencing revealed that the three affected JQs were homozygous for the deletion of guanine at position 1096 in the open reading frame (c.1096delG). A genotyping survey of 70 JQs and 10 eggs from commercial farms showed that none carried this deletion mutation. Conclusions: This study identified c.1096delG as the pathogenic mutation for PD in JQs. This mutation induces a frameshift and substitution of amino acids at position 366 (alanine to histidine), resulting in premature termination at the 23rd codon (p.A366Hfs*23). This suggests that this mutation causes the deficient activity of GAA in JQs with PD. The identification of the c.1096delG mutation enabled the systematic maintenance of the flock colony in the PD model. Furthermore, this PD model can be used to clarify unknown aspects of PD pathogenesis and develop therapeutic strategies. Full article

Genome-wide paternal uniparental isodisomy mosaicism (GWpUPIDM) is an extremely rare condition characterized by varying proportions of an androgenetic cell line across different tissues. It is primarily associated with severe congenital hyperinsulinism (CHI), Beckwith–Wiedemann syndrome (BWS) stigmata, a high risk (69–79%) of developing neoplasia and, in some cases, additional manifestations of multilocus paternal imprinting disorders (MPIDs). We herein report the first Mexican/Latin American female patient GWpUPIDM presenting with non-syndromic CHI requiring subtotal pancreatectomy and persistent but unexplained asymptomatic diffuse hepatopathy. When she was 8.5 years old, whole-exome sequencing (WES) in blood revealed an unexpectedly high (~92%) proportion of regions of homozygosity. DNA profiling confirmed a single haploid set of paternal chromosomes in both biparental and androgenetic cell lines, with varying proportions of the androgenetic lineage in leukocytes (84%), resected pancreas (74%), buccal cells (47%), and hair follicles (0.7%). Additional WES trio analysis using gDNA from the patient’s buccal cells and blood samples from both parents revealed an allelic frequency of ~75% for the paternally inherited variant NM_000158.4(GBE1):c.555+1G>T [ClinVar:632422; dbSNP:rs759707498]. At age 8.5, the patient exhibited no clinical features of BWS, MPIDs, or neoplasia. However, she presented persistent hepatic abnormalities that warrant further investigation to rule out an unmasked glycogen storage disease type IV (OMIM#232500). Our findings emphasize the critical need for early diagnosis of GWpUPIDM using SNP-based microarray or WES with further confirmation through DNA profiling in patients presenting with CHI, placental mesenchymal dysplasia, BWS stigmata, or other MPID-related conditions, including neoplasia, to facilitate timely cancer surveillance and management. Full article

Background/Objectives: Glycogen storage disease type II, also known as Pompe disease (PD), is a rare autosomal recessive genetic disorder triggered by a deficiency in lysosomal acid α-glucosidase (GAA). Recently, we discovered two deleterious missense variants of the GAA gene, c.1799G>A (p.Arg600His) (a pathogenic mutation) and c.55G>A (p.Val19Met), in a domestic short-haired cat with PD. This study aimed to design genotyping assays for these two variants and ascertain their allele frequencies in Japanese cat populations. Methods: We developed fluorescent probe-based real-time polymerase chain reaction assays to genotype the c.1799G>A and c.55G>A variants. A total of 738 cats, comprising 99 purebred cats from 20 breeds and 540 mixed-breed cats, were screened using these assays. Results: Genotyping assays clearly differentiated all known genotypes of the two variants. None of the 738 cats tested carried the c.1799G>A variant. However, we identified cats with c.55G/A and c.55A/A genotypes in the purebred (A allele frequency: 0.081) and mixed-breed cats (0.473). A significant difference (p < 0.001) was observed in the A allele frequency between the two groups. Conclusions: The c.1799G>A mutation appears rare in cat populations, suggesting it may be confined to specific pedigree Japanese mixed-breed cats. The c.55G>A variant was detected in purebred and mixed-breed cats, suggesting that it may not be directly linked to feline PD. However, additional studies are required to elucidate the precise relationship between this variant and cardiac function. Genotyping assays will serve as valuable tools for diagnosing and genotyping feline PD. Full article

Background/Objectives: Hepatic glycogen storage diseases (GSDs) are inherited metabolic disorders that affect glycogen synthesis or breakdown, primarily involving the liver and muscles. Treatment typically consists of strict dietary management, including the consumption of uncooked cornstarch. However, there is limited research on feeding challenges and the associated stress experienced by parents of children with GSDs. This study aims to assess feeding difficulties in children with GSDs and the level of parental stress. Methods: A total of 29 caregivers of children aged 6 months to <7 years participated. Feeding difficulties were evaluated using the Brazilian Infant Feeding Scale (Escala Brasileira de Alimentação Infantil—EBAI), while parental stress was measured using the Parental Stress Scale (Escala de Estresse Parental—EEPa). Data were collected in 2020, and the study was approved by the ethics committee. Results: The majority of the children were male (19/10), with a mean age of 47.75 months and an average age of diagnosis of 8.39 months. GSD type Ia (n = 15) and type Ib (n = 5) were the most prevalent, followed by types III and IX (n = 2). Among the participants, 22 out of 29 (76%) reported feeding difficulties, categorized as mild (n = 7, 24%), moderate (n = 7, 24%), and severe (n = 8, 28%). EBAI scores were higher in female patients and in those who did not eat meals with their family. Only one caregiver exhibited high levels of parental stress, as measured by the EEPA scale. No significant correlation was found between feeding difficulties and parental stress. Conclusions: The findings confirm a high prevalence of feeding issues in children with GSDs, which significantly affects caregivers’ quality of life. Although no significant link between feeding difficulties and parental stress was identified, further research is needed to improve GSD management and provide better support for caregivers. Full article

Background/Objectives: Glycogen storage disease type IX (GSD IX) is a group of inherited metabolic disorders caused by phosphorylase kinase deficiency affecting the liver or muscle. Despite being relatively common among GSDs, GSD IX remains underexplored. Methods: A systematic review of GSD IX was conducted per PRISMA guidelines using SCOPUS and PubMed, registered with PROSPERO. Inclusion focused on human clinical studies published up to 31 December 2024. Results: A total of 400 patients with GSD IX were analyzed: 274 IXa (mean age at diagnosis 5.1 years), 72 IXc (mean age at diagnosis 4.9 years), 39 IXb (mean age at diagnosis 4.2 years), and 15 IXd (mean age at diagnosis 44.9 years). Hepatomegaly was commonly reported in types IXa, IXb, and especially IXc (91.7%), but was rare in IXd. Elevated transaminases were frequently observed in types IXa, IXb, and particularly IXc, while uncommon in IXd. Fasting hypoglycemia was occasionally observed in types IXa and IXb, more frequently in IXc (52.7%), and was not reported in IXd. Growth delay or short stature was observed in a substantial proportion of patients with types IXa (43.8%), IXb, and IXc, but was rare in IXd. Muscle involvement was prominent in IXd, with all patients showing elevated CPK (mean 1011 U/L). Neurological involvement was infrequently reported in types IXa and IXc. Conclusions: This systematic review includes the most extensive clinical case history of GSD IX described in the literature. The clinical spectrum of GSD IX varies widely among subtypes, with IXc being the most aggressive. While liver forms are generally present in early childhood, muscle-type IXd shows delayed onset and milder symptoms, often leading to diagnostic delays. For diagnosis, it is essential not to underestimate key clinical features such as hepatic involvement and hypoglycemia in a child under 5 years of age. Other manifestations, including the as-yet unexplored systemic involvement of bone and kidney, remain insufficiently understood and require further investigation. Next-generation sequencing has improved diagnostic precision over traditional biopsy. Dietary management, including uncooked cornstarch, Glycosade^®, and high-protein intake, remains the cornerstone of treatment. However, there is a paucity of well-designed, evidence-based studies to determine the most effective therapeutic approach. Despite its historically perceived benign course, the broad phenotypic variability of GSD IX, including progressive liver involvement and potential neurological complications, highlights its substantial clinical relevance and underscores the need for accurate diagnostic classification and long-term multidisciplinary follow-up. Full article