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PubMed2025

Hypercalcemia and co-occurring TBX1 mutation in Glycogen Storage Disease Type Ib: case report.

Glycogen Storage Disease Type Ib (GSD-Ib) is a rare autosomal recessive metabolic disorder caused by mutations in SLC37A4, leading to a deficiency in glucose-6-phosphate translocase. This disorder is characterized by impaired glycogenolysis and gluconeogenesis, resulting in clinical and metabolic manifestations. We report a three-month-old Moroccan female patient presenting with doll-like facies, hepatomegaly, dysmorphic features, and developmental delays. Laboratory analysis revealed hypoglycemia, elevated triglyceride levels, hypercalcemia, and neutropenia. Genetic testing confirmed a homozygous pathogenic variant in SLC37A4 and a heterozygous variant of uncertain significance in TBX1. Initial management included a lactose-free and galactose-free diet, multivitamin supplementation, and granulocyte colony-stimulating factor (G-CSF) therapy to address neutropenia. A novel aspect of this case involves hypercalcemia as an unusual finding in GSD-Ib and the co-occurrence of a variant in the TBX1 gene, which is not typically associated with the disease but may contribute to the patient's clinical presentation. These findings add a new dimension to our understanding of GSD-Ib and suggest potential avenues for future research to elucidate these genetic interactions and their impact on clinical outcomes.

Humans↗
PubMed2026

RNA sequencing resolves a novel noncanonical splice-region variant in PHKA2 causing glycogen storage disease type IX α2: a case report.

BACKGROUND: Glycogen storage disease type IX α2 (GSD IX α2) is an X-linked hepatic glycogenosis caused by pathogenic variants in PHKA2. Noncanonical splice-region variants located outside the invariant GT/AG dinucleotides pose significant interpretive challenges, as in silico predictions alone are often insufficient for definitive classification. CASE DESCRIPTION: We report a 2.9-year-old boy presenting with short stature, hepatomegaly, markedly elevated aminotransferases, fasting hypoglycemia with ketonuria, hypercholesterolemia, coagulation parameter abnormalities (decreased fibrinogen and prolonged thrombin time), and histological evidence of early hepatic fibrosis as demonstrated by Masson's trichrome staining (portal fibrosis and perisinusoidal fibrosis). Whole-exome sequencing (WES) identified a hemizygous, previously unreported PHKA2 variant [NM_000292.3:c.2517+5G>T, genomic location (GRCh38): NC_000023.11: g.18907895G>T], initially classified as a variant of uncertain significance (VUS) under American College of Medical Genetics and Genomics (ACMG) criteria. RNA sequencing of peripheral blood leukocytes demonstrated predominant exon 22 skipping in 94.2% of informative junction reads, predicting a frameshift and premature termination codon [p.(Gly788Profs*74)] with predicted loss of the C-terminal CBL 2 subdomain. Incorporating this transcript-level evidence, the variant was reclassified as pathogenic (PVS1 + PM2_Supporting + PP4). Following dietary management with uncooked cornstarch supplementation, the patient showed progressive biochemical improvement over a 2.2-year follow-up. CONCLUSIONS: This case expands the mutational spectrum of PHKA2 and demonstrates that RNA sequencing of accessible tissues is a practical and diagnostically informative strategy for resolving noncanonical splice-region variants in pediatric hepatic GSD. Early hepatic fibrosis detected by histological examination before age 3 years underscores the importance of longitudinal hepatic surveillance in GSD IX α2.

Glycogen storage disease type IX α2 (GSD IX ↗
PubMed2025

Long-Term Correction of Murine Glycogen Storage Disease Type III by AAV-Mediated Gene Therapy Using an Immunotolerizing Dual Promoter to Express Bacterial Pullulanase.

BACKGROUND: We recently reported an innovative gene therapy approach for GSD III using a recombinant adeno-associated virus serotype 9 vector (AAV9-Dual-Pull) expressing a bacterial debranching enzyme (pullulanase) driven by a tandem dual promoter that consists of an immunotolerizing liver-specific promoter (LSP) and the ubiquitous CMV enhance/chicken β-actin (CB) promoter. In this follow-up study, we evaluated the long-term efficacy of this gene therapy in GSD IIIa mice. METHODS: Three-month-old GSD IIIa mice were intravenously injected with AAV9-LSP-Pull or AAV9-Dual-Pull at the same dose (2.5 × 1013 vg/kg). Tissues were collected after 9 months for AAV genome quantification, pullulanase expression determination, and glycogen content measurement. Liver and muscle enzymes in plasma and disease biomarker in urine were analyzed at multiple time points to examine the correction of liver and muscle damage. Behavioral tests were performed during the course of AAV treatment to evaluate the improvement of muscle function. RESULTS: The AAV-Dual-Pull treatment led to persistent pullulanase expression and effective glycogen reduction in the liver, heart, and skeletal muscle, accompanied by the reversal of liver fibrosis, decrease of plasma enzyme activities, and long-term improvement of muscle function. The AAV-LSP-Pull treatment showed a better therapeutic efficacy in the liver but had no effect on the cardiac and skeletal muscles. CONCLUSION: Our results demonstrated the long-term efficacy and safety of systemic AAV9-Dual-Pull delivery in GSD IIIa mice. Future studies will test this gene therapy approach in GSD IIIa dogs prior to the clinical translation to GSD III patients.

AAV gene therapy↗
PubMed2026

Genome Editing for Glycogen Storage Diseases.

Gene therapy has been developed for several glycogen storage diseases and has advanced into clinical trials. However, the limitations of these gene therapies with regard to stability following treatment early in life have led to the development of genome editing. Early results for genome editing in both glycogen storage disease type Ia and Pompe disease have demonstrated promising efficacy, and proof-of-concept studies as well as a clinical trial are underway. These studies will determine whether genome editing fulfills its promise with regard to stably treating glycogen storage diseases early in life.

Humans↗
PubMed2026

Base editing for precision therapeutics.

Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, β-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.

Humans↗
PubMed2026

A therapeutic atlas of monogenic inflammatory bowel disease.

BACKGROUND AND AIMS: Evidence-based, mechanism-guided therapies are urgently needed for treating monogenic inflammatory bowel disease (mIBD). For such rare diseases, mechanistic insight is essential to guide treatment when conventional clinical trials are often not feasible. We aimed to summarize literature-based evidence and to identify knowledge gaps. METHODS: We conducted a systematic review of published manuscripts evaluating the therapeutic efficacy in mIBD. We quantified and compared the global therapeutic response score across treatments and conditions. In a subset of conditions, biomarkers of longitudinal therapeutic response were evaluated in comparison to non-monogenic pediatric IBD cohorts. RESULTS: Responses to 35 therapeutics across the 102 known genetic causes of mIBD were evaluated in 241 articles and 669 patients, summarizing 302 gene-drug responses. The efficacy of at least one pharmacological intervention was identified in 61% (n = 62/102) of the mIBD conditions, highlighting a major unmet need for effective medications in many others. Gene- and pathway-specific responses were demonstrated for several therapies, including allogeneic hematopoietic stem cell transplantation, gene therapy, and advanced therapies such as anti-TNF agents, IL-1 inhibitors, mTOR inhibitors, as well as eculizumab in CD55 deficiency, abatacept in CTLA4 deficiency, and the immunometabolic agent empagliflozin in glycogen storage disease type 1b. CONCLUSIONS: This study highlights the potential of precision medicine approaches tailored to genetic and pathway-specific mechanisms, while underscoring the urgent need for effective therapies in many monogenic conditions that remain without established treatment options.

Humans↗
PubMed2026

Proteomics profiling of serum and liver in GSD Ia and Ib patients: insights into complication mechanisms and circulation biomarkers.

BACKGROUND: Glycogen Storage Disease (GSD) Types Ia and Ib are rare metabolic diseases caused by gene variants in G6PC1 and SLC37A4, respectively. Although life-threatening fasting hypoglycemia can be controlled by a strict diet, patients often suffer from multiple metabolic abnormalities and severe long-term complications. However, the underlying mechanisms remain incompletely understood, and there is a lack of effective monitoring biomarkers. Therefore, the aims of this study are to investigate the pathological mechanisms of the disease and disease complications in GSD I and identify potential protein biomarkers. METHODS: Comprehensive untargeted proteomics was performed on 18 GSD Ia and 8 GSD Ib sera samples from patients with 21 matched control sera, complemented by liver 3 GSD Ia samples and 1 GSD Ib sample from patient liver tissues, compared to 10 donor liver samples. RESULTS: We identified 415 proteins in total. Significantly changed (FDR&#x2009;<&#x2009;0.05) were observed in 158 (38%) proteins for GSD Ia vs Control, 116 (28%) for GSD Ib vs. Control, and 151 (36%) for GSD Ia vs. Ib. Pathway analysis revealed distinct alterations in serum/plasma, with 58, 32, and 29 significantly changed biological processes (FDR&#x2009;<&#x2009;0.05) in these three comparisons, respectively. The coagulation pathway was the most significantly changed one in the GSD Ia patients. Immune response-associated proteins, especially immunoglobulins, were increased in GSD Ib specifically. Proteins related to liver injury, cholesterol, and amyloidosis were altered in two subtypes, though more pronounced in GSD Ia. Potential biomarkers with significant alterations both in the circulation and in the liver tissue were identified specifically for monitoring GSD I subtypes and prognosing liver deterioration, namely APOC1 and CD5L to distinguish between GSD Ia and Ib and ALDOB for the presence of hepatocellular carcinoma (HCC) in GSD Ia patients. CONCLUSIONS: These findings provide new insights into the differences between the two GSD I subtypes and the pathogenesis of GSD I-related complications, as well as highlighting the potential of protein circulating biomarkers for monitoring complication progression in GSD I and assessing HCC risk in GSD Ia patients.

Humans↗
PubMed2025

Reduction of false-positive results with biochemical second-tier testing for newborn screening of Pompe disease.

PURPOSE: To review the performance and outcomes of a second-tier newborn screening test for Pompe disease. METHODS: We followed our previously published screening approach that reduces false-positive results by incorporating creatine and creatinine levels and postanalytic tools in a second-tier test. RESULTS: We reviewed 1879 blood samples from neonates born in 11 states. Second-tier testing effectively reduced false-positive results, compared with first-tier enzyme testing alone. Only a small number of screen-positive cases (n = 7) were confirmed to have infantile-onset Pompe disease. No false-negative cases of infantile-onset Pompe disease were identified in this cohort, and 6 cases of possible late-onset Pompe disease were not detected with this approach. CONCLUSION: This tiered screening strategy discriminated well between true- and false-positive results and improved the positive predictive value. However, it did not reliably differentiate between infantile- and late-onset Pompe disease.

Humans↗
PubMed2026

Prenatal diagnosis of glucose-6-phosphatase catalytic subunit 3 deficiency (Dursun syndrome) using whole-exome sequencing: A case report of severe fetal cardiomyopathy in a consanguineous family.

Glucose-6-phosphatase catalytic subunit 3 deficiency, also known as Dursun syndrome, is a rare autosomal recessive disorder characterized by severe congenital neutropenia and variable multisystem malformations, particularly affecting the cardiovascular system. Most reported cases have been identified postnatally, following infectious or hematologic complications. Prenatal identification remains exceptionally rare. We describe the case of a fetus from consanguineous parents with a history of multiple neonatal deaths. Serial prenatal imaging demonstrated progressive fetal growth restriction, cardiomegaly with biventricular hypertrophy, significant tricuspid regurgitation, right-sided cardiac dominance, right atrial enlargement, ventriculomegaly, and evolving craniofacial dysmorphism. Whole-exome sequencing revealed a homozygous nonsense variant in G6PC3 (NM_138387.3:c.481C&#x2009;>&#x2009;T; p.(Arg161Ter)), confirming that both parents were heterozygous carriers. Postnatally, the neonate developed severe neutropenia, complex right-sided cardiac outflow obstruction physiology, and refractory cardiorespiratory failure, leading to death on day 4 of life. This report expands the prenatal phenotypic spectrum of glucose-6-phosphatase catalytic subunit 3 deficiency and emphasizes the importance of considering this diagnosis in fetuses presenting with cardiomyopathy, dysmorphic features, fetal growth restriction, and parental consanguinity. Early molecular diagnosis enables accurate counseling, informed reproductive planning, and consideration of preconception or early prenatal genomic testing in high-risk families.

Humans↗
PubMed2025

Rescue of common and rare exon 2 skipping variants of the GAA gene using modified U1 snRNA.

BACKGROUND: Pompe disease (PD) is an autosomal recessive lysosomal storage disorder caused by the deficient activity of acid alpha glucosidase (GAA) enzyme due to mutations in the GAA gene. As a result, undigested glycogen accumulates within lysosomes causing their dysfunction. From a clinical point of view, the disease can be classified in infantile-onset (IO) and late-onset (LO) forms. The common GAA c.-32-13T>G variant, found in 40-70% of LO-PD alleles, is a leaky splicing mutation interfering with the correct GAA exon 2 recognition by the spliceosome leading to the production of non-functional GAA transcripts. In this study, we used modified, GAA-tailored U1 snRNAs to correct the aberrant splicing determined by the c.-32-13T>G and other GAA exon 2-skipping mutations. METHODS: A set of constructs expressing 5 different engineered U1 snRNAs was generated. A functional splicing assay using a GAA hybrid minigene carrying different variants known to affect GAA exon 2 splicing was used to test the effect of engineered U1 snRNAs on exon 2 inclusion. The effect on endogenously expressed GAA transcript and GAA enzymatic activity was assessed by transfecting patient-derived fibroblasts bearing the common c.-32-13T>G with the best performing modified U1 snRNA. RESULTS: Modified U1-3, U1+1 and U1+6 snRNAs were all able to increase, in a dose-dependent manner, the inclusion of exon 2 within the transcript derived from the GAA minigene harbouring the c.-32-13T>G variant. The U1+1 was the most effective one (2,5&#xa0;fold increase). Moreover, U1+1 snRNA partially rescued the correct splicing of GAA minigenes harbouring mutations that affect the 3'ss (c.-32-3C>G, c.-32-2A>G) and the 5'ss (c.546G>A, c.546G>C, c.546G>T). Notably, the treatment of patient-derived fibroblasts carrying the c.-32-13T>G mutation with the U1+1 snRNA increased the amount of normal GAA mRNA by 1,8&#xa0;fold and the GAA enzymatic activity by 70%. CONCLUSIONS: we provide the proof-of-concept for the use of modified GAA-tailored U1 snRNAs, designed to potentiate the recognition of the GAA exon 2 5'ss, as therapeutic tools to correct the aberrant transcripts carrying variants that affect exon 2 splicing, including the common c.-32-13T>G variant.

Humans↗
PubMed2025

Identification of a novel RBCK1 splice site donor variant in Basset Hounds with glycogen storage disease myopathy.

Glycogen storage diseases (GSDs) are rare, typically inherited, disorders caused by various defects in glycogen metabolism enzymes, generally resulting in the accumulation of glycogen in several tissues. Recently, two young adult Basset Hound (BH) littermates were diagnosed with GSD via postmortem histopathology, with excess glycogen manifesting in both cardiac and smooth muscle. Using whole genome sequencing, a homozygous splice site donor variant was identified in exon 8 of RBCK1, a gene which encodes an E3 ubiquitin ligase, in both littermates, suggesting an autosomal recessive mode of inheritance. The presumptive loss of the splice site donor is predicted to result in premature termination in the mid-domain of the protein. Screening for the variant in related (n&#xa0;=&#xa0;21) and unrelated (n&#xa0;=&#xa0;124) BHs identified one additional affected littermate and nine familial heterozygous carriers. No variant alleles were present in the unrelated BH population, establishing the novelty of the identified mutation. RBCK1 variants have previously been associated with polyglucosan body myopathy type 1 (PGBM1), a type of GSD characterized by skeletal muscle myopathy, cardiomyopathy, and polyglucosan accumulation in humans. To date, no reported variants in RBCK1 have been identified in dogs or other large animals associated with GSD, making this the first naturally occurring large animal model of PGBM1 due to an RBCK1 defect.

Animals↗
PubMed2026

Neonatal gene therapy with AAV2/8-LSPhGAA improves hypertrophic cardiomyopathy in the Gaac.1826dupA knock-in murine model.

Pompe disease (PD) results from lysosomal acid &#x3b1;-glucosidase (GAA) deficiency, causing lysosomal glycogen accumulation in cardiac and skeletal muscles. We previously characterized a murine model carrying the orthologous human infantile-onset PD (IOPD) pathogenic variant, c.1826dupA (p.Y609*), introduced into the mouse Gaa gene. Compared to wild-type (WT; C57BL/6NJ) controls, Gaac.1826dupA mice exhibit reduced GAA activity and develop early-onset hypertrophic cardiomyopathy-evidenced by increased left ventricular wall thickness and left ventricular mass index (LVMI)- as well as impaired grip strength and gait abnormalities. To benchmark the model's disease fidelity and assess its responsiveness to established therapeutic intervention, Gaac.1826dupA mice received a single retro-orbital dose of AAV2/8-LSPhGAA (2&#xa0;&#xd7;&#xa0;109 vg/g body weight) at postnatal day 12-14. Twelve weeks post-treatment, mice exhibited supraphysiological GAA enzymatic activity in the heart (550% of WT) and liver (400% of WT) with a 93% reduction in cardiac glycogen. No sex-dependent differences in therapeutic efficacy were observed. Echocardiography revealed robust reversal of cardiac pathology, with wall thicknesses and LVMI values approaching WT levels. In contrast to this profound cardiac rescue, skeletal muscle improvements were modest; while forelimb grip strength remained unchanged, automated gait analysis showed benefit limited to hind paw base of support. These findings demonstrate that the Gaac.1826dupA model mirrors the critical cardiomyopathy characteristic of IOPD. While systemic AAV treatment yields definitive cardiac correction, the partial skeletal muscle response highlights a clear need for optimization. Consequently, the Gaac.1826dupA mouse serves as a high-fidelity platform for evaluating next-generation genomic correction strategies targeting both cardiac and refractory neuromuscular manifestations of PD.

Acid &#x3b1;-glucosidase↗