Glycogen is a glucose polymer that plays a crucial role in glucose homeostasis by functioning as a short-term energy storage reservoir in animals and bacteria. Abnormalities in its metabolism and structure can cause several problems, including diabetes, glycogen storage diseases (GSDs) and muscular disorders. Defects in the enzymes involved in glycogen synthesis or breakdown, resulting in either excessive accumulation or insufficient availability of glycogen in cells seem to account for the most common pathogenesis. This review discusses glycogen metabolism and structure, including molecular architecture, branching dynamics, and the role of associated components within the granules. The review also discusses GSD type XV and Lafora disease, illustrating the broader implications of aberrant glycogen metabolism and structure. These conditions also impart information on important regulatory mechanisms of glycogen, which hint at potential therapeutic targets. Knowledge gaps and potential future research directions are identified.

BACKGROUND: Cohort data on continuous glucose monitoring (CGM) metrics are scarce for liver glycogen storage diseases (GSDs) and idiopathic ketotic hypoglycemia (IKH). The aim of this study was to retrospectively describe CGM metrics for people with liver GSDs and IKH.
METHODS: CGM metrics (descriptive, glycemic variation and glycemic control parameters) were calculated for 47 liver GSD and 14 IKH patients, categorized in cohorts by disease subtype, age and treatment status, and compared to published age-matched CGM metrics from healthy individuals. Glycemic control was assessed as time-in-range (TIR; ≥3.9 - ≤7.8 and ≥3.9 - ≤10.0 mmol/L), time-below-range (TBR; <3.0 mmol/L and ≥3.0 - ≤3.9 mmol/L), and time-above-range (TAR; >7.8 and >10.0 mmol/L).
RESULTS: Despite all patients receiving dietary treatment, GSD cohorts displayed significantly different CGM metrics compared to healthy individuals. Decreased TIR together with increased TAR were noted in GSD I, GSD III, and GSD XI (Fanconi-Bickel syndrome) cohorts (all p < 0.05). In addition, all GSD I cohorts showed increased TBR (all p < 0.05). In GSD IV an increased TBR (p < 0.05) and decreased TAR were noted (p < 0.05). In GSD IX only increased TAR was observed (p < 0.05). IKH patient cohorts, both with and without treatment, presented CGM metrics similar to healthy individuals.
CONCLUSIONS: Despite dietary treatment, most liver GSD cohorts do not achieve CGM metrics comparable to healthy individuals. International recommendations on the use of CGM and clinical targets for CGM metrics in liver GSD patients are warranted, both for patient care and clinical trials.

Glycogen storage diseases (GSDs) are a group of autosomal recessive disorders of glucose metabolism.GSDs are caused by congenital deficiency of enzymes in glycogen synthesis or decomposition,which results in glycogen accumulation in organs.According to the types of enzyme deficiency,GSDs can be classified into more than ten types,among which GSD Ⅻ is a super-rare type of GSD.Two brothers with a 5-year age difference presented severe neonatal asphyxia,myasthenia,myocardial damage,anemia,and mental retardation,being GSD Ⅻ homozygous cases with neonatal onset.The results of gene detection showed that nucleotide and amino acid alterations (c.619G>A,p.E207K) of the ALDOA gene existed in the two brothers,being homozygous,and the genotypes in the parents were heterozygous.This article summarized the clinical features,diagnosis,and treatment of GSD Ⅻ,providing reference for exploring the etiology and treatment of severe asphyxia,myasthenia,anemia,and multiple organ damage in neonates after birth.
糖原累积病(GSD)是一组常染色体隐性遗传的糖代谢障碍性疾病,在糖原的合成或分解途径中发生先天性酶缺乏而引起代谢障碍,导致糖原在脏器组织上累积。根据酶缺乏的种类,GSD分为十几个类型,其中GSD Ⅻ是一种超罕见的GSD分型。本文报道年龄相差5岁的兄弟两人以新生儿重度窒息、肌无力、心肌损害、贫血、智力低下为主要临床表现,在新生儿期发病的GSD Ⅻ纯合型病例。基因检测结果显示两患儿ALDOA基因存在核苷酸与氨基酸改变:c.619G>A,p.E207K,为纯合型,患儿父母的基因为杂合型。本文通过对GSD Ⅻ型的临床特点、诊断及治疗进行总结,为出生后即出现重度窒息、肌无力、贫血及多脏器损害新生儿的病因探寻及治疗提供参考。.

Adult polyglucosan body disease (APBD) is a rare autosomal recessive glycogen storage disorder that leads to slowly progressive multi-organ dysfunction in adulthood. A novel disease-specific patient-reported outcome measure was created and administered to assess symptom burden and health-related quality of life (HR-QOL) in APBD. Thirty-six participants between 30 and 79 years of age (83% ≥60 years, 56% male) completed the anonymous questionnaire independently or with a caregiver proxy (75% self-report). Unemployment predicted an 18.3 (95% CI: 2.8, 33.8; p = 0.028) higher composite disease severity score and a 28.8 (95% CI: 8.2, 49.4; p = 0.010) higher composite HR-QOL score. Use of one or more assistive devices also predicted a 29.3 (95% CI: 8.3, 50.4; p = 0.011) higher composite disease severity score and a 41.8 (95% CI: 10.9, 72.8; p = 0.013) higher composite HR-QOL score. Proxy survey completion predicted a 19.4 (95% CI: 4.1, 34.7; p = 0.020) higher composite disease severity score compared to self-report. Older age at survey completion predicted a 27.4 higher composite HR-QOL score (95% CI: 2.5, 52.4; p = 0.039) for participants in their sixties compared to those between 30 and 59 years old. The development of the Adult Polyglucosan Body Disease questionnaire on Symptom burden and health-related Quality of life (APBD-SQ) marks an important stride forward in capturing the patient experience as a tool for disease monitoring and future research.

BACKGROUND: Glycogen storage disease type 0a (GSD0a) is a rare autosomal recessive disorder caused by glycogen synthase deficiency. Short stature is a characteristic feature in 29% of GSD0a patients, but isolated short stature as the only presenting symptom is exceedingly rare, with only 2 cases reported worldwide.
METHODS: A 4-year-old girl presented with persistent growth retardation despite previous treatment for renal tubular acidosis.
METHODS: Based on clinical presentation and whole exome sequencing results, the patient was diagnosed with GSD0a.
METHODS: Uncooked cornstarch therapy was initiated at 2 g/kg every 6 hours.
RESULTS: After 3 years of treatment, the patient\'s height SDS improved from -2.24 to -1.06, with enhanced glycemic control and no complications.
CONCLUSIONS: This case emphasizes considering GSD0a in unexplained short stature and the value of continuous glucose monitoring. Early diagnosis and treatment can optimize growth in GSD0a patients.

OBJECTIVE: Glycogen storage disease type V is caused by the mutations in muscle glycogen phosphorylase gene. This is the first report which DL-3-hydroxybutyric acid was used in combination with modified Atkins diet for the treatment of a patient with glycogen storage disease type V and quadriceps femoris shear wave elastography was performed to evaluate the treatment efficacy.
METHODS: A 13-year-old girl was referred with fatigue and muscle cramps with exercise and there were no pathological findings in physical examination. Creatine kinase levels with 442 U/L. No phosphorylase enzyme activity was detected in muscle biopsy, a homozygous c.1A>G (p.M1V) pathogenic mutation was found in PYGM gene. She was started on DL-3-hydroxybutyric acid and modified Atkins diet at age 16. Her walking and stair climbing capacity increased, the need for rest during exercise decreased. The stiffness of the quadriceps femoris exhibited a reduction.
CONCLUSIONS: DL-3-hydroxybutyric acid and modified Atkins diet may provide an alternative fuel and shear wave elastography may be useful in demonstrating treatment efficacy. More clinical and pre-clinical studies are obviously needed to reach more definite conclusions.

暂无摘要。

Late-onset Pompe Disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction due to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage - a classic manifestation of the disease - has been extensively studied by analysing the whole muscle tissue; however, little, if any, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single nuclei RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age and gender matched healthy controls. We matched these changes with histology findings using GeoMx Spatial Transcriptomics to compare the transcriptome of control myofibers from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibers of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibers and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibers, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes, and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. The upregulation of the genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibers. Notably, enzyme replacement therapy - the only available therapy for the disease - showed a tendency to restore metabolism dysregulation, particularly within slow fibers. A combination of single nuclei RNA sequencing and spatial transcriptomics revealed the landscape of normal and the diseased muscle, and highlighted the early abnormalities associated with the disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention.

BACKGROUND: Hypoglycaemia is the primary manifestation of all the hepatic types of glycogen storage disease (GSD). In 2008, Glycosade®, an extended-release waxy maize cornstarch, was reported as an alternative to uncooked cornstarch (UCCS) which could prolong the duration of fasting in the GSD population. To date, there has been minimal published experience in (a) young children, (b) the ketotic forms of GSD, and (c) with daytime dosing. The Glyde study was created as a prospective, global initiative to test the efficacy and tolerance of Glycosade use across a broader and more diverse population.
METHODS: A randomised double-blind cross-over fasting study assessing the tolerance and efficacy of Glycosade compared with cornstarch was performed across disease types and ages. Participants and clinicians chose the product deemed superior, whilst still blinded. Participants were followed for 2 years to assess long-term metabolic control, growth, and quality of life.
RESULTS: Sixty-one participants (age 2-62 years; 59% female) were enrolled, and 58 participants completed the fasting studies (28 GSD I; 30 GSD III, VI, IX). Glycosade improved duration of fasting in GSD I and duration of fasting without ketosis in the ketotic forms. Chronic Glycosade use was chosen by 69% of participants. Those treated with Glycosade for the 2-year chronic phase used fewer doses of therapy while markers of metabolic control remained stable.
CONCLUSIONS: The Glyde study is the first multi-centre international trial demonstrating the efficacy and tolerance of Glycosade in a large cohort of hepatic GSD patients across a diverse international population. The ability to use fewer doses of therapy per day and avoidance of overnight therapy may improve compliance, safety, and quality of life without sacrificing metabolic control.

OBJECTIVE: Polyglucosan storage disorders represent an emerging field within neurodegenerative and neuromuscular conditions, including Lafora disease (EPM2A, EPM2B), adult polyglucosan body disease (APBD, GBE1), polyglucosan body myopathies associated with RBCK1 deficiency (PGBM1, RBCK1) or glycogenin-1 deficiency (PGBM2, GYG1). While the storage material primarily comprises glycans, this study aimed to gain deeper insights into the protein components by proteomic profiling of the storage material in glycogenin-1 deficiency.
METHODS: We employed molecular genetic analyses, quantitative mass spectrometry of laser micro-dissected polyglucosan bodies and muscle homogenate, immunohistochemistry and western blot analyses in muscle tissue from a 45-year-old patient with proximal muscle weakness from late teenage years due to polyglucosan storage myopathy.
RESULTS: The muscle tissue exhibited a complete absence of glycogenin-1 due to a novel homozygous deep intronic variant in GYG1 (c.7+992T>G), introducing a pseudo-exon causing frameshift and a premature stop codon. Accumulated proteins in the polyglucosan bodies constituted components of glycogen metabolism, protein quality control pathways and desmin. Muscle fibres containing polyglucosan bodies frequently exhibited depletion of normal glycogen.
CONCLUSIONS: The absence of glycogenin-1, a protein important for glycogen synthesis initiation, causes storage of polyglucosan that displays accumulation of several proteins, including those essential for glycogen synthesis, sequestosome 1/p62 and desmin, mirroring findings in RBCK1 deficiency. These results suggest shared pathogenic pathways across different diseases exhibiting polyglucosan storage. Such insights have implications for therapy in these rare yet devastating and presently untreatable disorders.