肝型糖原病

BACKGROUND: Fatty liver is considered the pathological basis for the development of glycogen storage disease type Ia (GSDIa); however, due to the lack of suitable animal models, the mechanism underlying fatty liver development in GSDIa is largely unknown. METHODS: This study employed surrogate breastfeeding to enable the survival of glucose-6-phosphatase catalytic (G6PC) knockout (KO) mice into adulthood, and then analyzed fatty liver phenotypes in 3-month-old KO (KO-3), 6-month-old KO (KO-6), and 9-month-old KO (KO-9) mice. RESULTS: KO-6 and KO-9 mice exhibited typical fatty liver phenotypes, and upregulation of glucose-6-phosphate (G6P). Moreover, both Western blot and qRT-PCR analysis showed significant upregulation of ChREBP, SREBP1 and fatty acid synthesis enzymes. RNA-seq heat maps revealed that KO-6 and KO-9 mice exhibited similar expression patterns, distinct from those observed in the wild-type (WT) and KO-3 groups. GO and KEGG analysis further revealed changes in lipid metabolism pathways in KO-6 and KO-9 mice, as well as PI3K-Akt, AMPK, and MAPK signaling. Western blot analysis showed that the Akt and mTOR pathways were activated, while the AMPK pathway was downregulated, indicating impaired autophagy. Finally, bezafibrate, a proliferator-activated receptor α (PPAR-α) agonist, enhanced autophagic activity and attenuated inflammatory responses, fat deposition, and glycogen storage in G6PC KO mice. CONCLUSION: This study successfully generated a fatty liver model using G6PC KO adult mice and demonstrated that pharmacological activation of PPAR-α may have therapeutic potential in adult G6PC KO mice.

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.

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.

Hepatic glucose production, essential for maintaining glycemia, is often altered in metabolic-associated fatty liver and glycogen storage diseases. Therefore, understanding the mechanisms that regulate the glucose production by hepatocyte is pivotal. Recent studies have identified endocytic trafficking as a key modulator of liver glucose production. Particularly, its role in directing protein trafficking toward lysosomal degradation influences gluconeogenesis. However, the contribution of endocytic recycling to liver glucose production remains yet poorly understood. Here, we demonstrate that hepatocyte-specific disruption of endocytic recycling, achieved through Rab4b knockout in male, leads to fasting hyperglycemia. Mechanistically, hepatocytes lacking Rab4b exhibit an increased capacity to produce glucose independently of gluconeogenesis by depleting their glycogen stores. This is driven by enhanced glycophagy, leading to excessive glucose release and fasting hyperglycemia. Notably, liver Rab4b expression also correlates with glycemia in both mice and human, highlighting a critical role of Rab4b-dependent endocytic recycling in regulating blood glucose homeostasis during fasting.

Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by pathogenic variants in AGL, which encodes the glycogen debranching enzyme (GDE). Loss of GDE function impairs glycogen degradation, leading to accumulation of abnormal glycogen in liver and skeletal muscle. Clinical manifestations arise in early childhood and include hypoglycemia, hepatomegaly, and progressive myopathy. Despite significant morbidity, no disease-modifying therapies exist, due in part to a lack of rigorously validated cellular models. Patient-derived fibroblasts provide an accessible and scalable system that preserves each patient's endogenous AGL genotype and broader genetic background, enabling investigation of disease heterogeneity, genotype-phenotype relationships, and potential genetic modifiers. We performed whole-genome sequencing and phenotypic characterization of nine fibroblast lines originating from patients who were diagnosed with GSD III. Eight lines harbored biallelic pathogenic or likely pathogenic AGL variants, while one was reclassified based on absence of AGL variants and the presence of a pathogenic variant in an alternative metabolic gene. Validated GSD III fibroblasts exhibited consistent disease features, including absence of GDE protein, impaired glycogen utilization, and distinct lipidomic signatures. We generated an isogenic immortalized AGL-deficient fibroblast model which recapitulated these phenotypes. Together, these patient-derived and isogenic models provide a robust, genomically defined platform for studying the pathogenesis and phenotypic heterogenity of GSD III. Refined characterization and accessibility of these models will be useful to evaluate candidate GSD III therapeutics.