| Domain | Key facts | Suggested ontology terms |
|---|---|---|
| Disease identity / identifiers | Late-onset Pompe disease (LOPD) is the attenuated, non-classic form of Pompe disease/glycogen storage disease type II caused by deficient lysosomal acid alpha-glucosidase; typically presents after infancy with progressive skeletal and respiratory muscle involvement and little/no hypertrophic cardiomyopathy (pqac-00000012, pqac-00000015) | MONDO: Late-onset Pompe disease *(exact ID not confirmed here)*; OMIM: Pompe disease **232300**; MeSH: Pompe Disease *(ID not confirmed here)* |
| Synonyms | Acid maltase deficiency; glycogen storage disease type II; late-onset acid alpha-glucosidase deficiency; non-classic Pompe disease (pqac-00000010, pqac-00000012) | MONDO exact synonyms *(curate locally)* |
| Data provenance | Information is disease-level, aggregated from guidelines, reviews, cohorts, clinical trials, and registries rather than individual EHR-only evidence (pqac-00000009, pqac-00000010, pqac-00000012) | Evidence model: aggregated disease knowledge |
| Causal gene / inheritance | Caused by biallelic pathogenic variants in **GAA**; autosomal recessive inheritance. Residual GAA activity is higher in LOPD than infantile disease and correlates with attenuated severity (pqac-00000011, pqac-00000012) | HGNC: **GAA**; GO: glycogen catabolic process; inheritance term: autosomal recessive inheritance |
| Common pathogenic / notable variants | The splice variant **c.-32-13T>G** is the most common in many Caucasian cohorts; substantial allelic heterogeneity exists with hundreds of disease-associated variants. Pseudodeficiency alleles can complicate diagnosis and should not be overcalled as pathogenic (pqac-00000000, pqac-00000002, pqac-00000006) | Sequence ontology classes: splice-region variant, missense variant, frameshift variant, nonsense variant; ClinVar/ACMG classification terms |
| Hallmark phenotype: proximal/axial weakness | Core phenotype is progressive proximal limb-girdle and axial/paraspinal weakness, often with exercise intolerance, fatigue, and difficulty climbing stairs/rising from chairs (pqac-00000008, pqac-00000013) | HPO: **Proximal muscle weakness (HP:0003701)**; **Limb-girdle muscle weakness (HP:0003325)**; **Axial muscle weakness (HP:0003327)**; **Exercise intolerance (HP:0003546)**; **Fatigue (HP:0012378)** |
| Hallmark phenotype: respiratory involvement | Diaphragmatic/intercostal weakness may precede marked limb weakness; restrictive ventilatory insufficiency, sleep-disordered breathing, morning headache, impaired cough, and respiratory failure drive major morbidity/mortality (pqac-00000008, pqac-00000012, pqac-00000015) | HPO: **Respiratory insufficiency (HP:0002093)**; **Restrictive ventilatory defect (HP:0002091)**; **Sleep apnea (HP:0010535)**; **Dyspnea (HP:0002094)** |
| Additional manifestations | HyperCKemia may be present but can be normal; myalgia, scoliosis/spinal deformity, winged scapula, osteopenia/osteoporosis, dysphagia, and reported cerebrovascular abnormalities such as aneurysms/vertebrobasilar dolichoectasia (pqac-00000008, pqac-00000010, pqac-00000012, pqac-00000013) | HPO: **Elevated creatine kinase (HP:0003236)**; **Myalgia (HP:0003326)**; **Scoliosis (HP:0002650)**; **Dysphagia (HP:0002015)**; **Osteoporosis (HP:0000939)**; **Intracranial aneurysm (HP:0004942)** |
| Anatomy affected | Primary organs/tissues: skeletal muscle and respiratory muscles, especially paraspinal, abdominal, hip extensor, and diaphragm-related musculature; secondary systems include bone, GI/swallowing, and cerebrovascular structures (pqac-00000010, pqac-00000012, pqac-00000013) | UBERON: skeletal muscle tissue; diaphragm; respiratory system; CL: **skeletal muscle cell/myofiber** *(exact CL ID not confirmed here)*; **macrophage** |
| Temporal course / natural history | Onset is juvenile-to-adult and often insidious. Diagnostic delay may span **5-30 years**; untreated disease shows progressive decline in respiratory function and ambulation, with FVC deterioration detectable within ~2 years and 6MWT decline within ~9 years in natural-history observations summarized by experts (pqac-00000008, pqac-00000009) | HPO onset modifiers: juvenile onset, adult onset; course: progressive |
| Core mechanism | Loss of lysosomal GAA prevents normal glycogen hydrolysis, causing lysosomal glycogen accumulation, swollen lysosomes, and progressive myofiber dysfunction; skeletal muscle pathology is strongly linked to autophagic buildup and impaired lysosome-autophagosome fusion (pqac-00000021, pqac-00000024, pqac-00000027) | GO: **glycogen catabolic process**; **lysosome organization**; **autophagy**; **macroautophagy**; GO-CC: **lysosome**; **autophagosome** |
| Downstream molecular pathology | Human and model data show autophagy gene upregulation, reduced mTORC1 activity, AMPK activation, impaired oxidative phosphorylation, mitochondrial/ribosomal dysfunction, oxidative stress, ubiquitinated aggregates, and p62/SQSTM1 accumulation (pqac-00000021, pqac-00000022, pqac-00000023, pqac-00000025) | GO: **regulation of mTOR signaling**; **AMPK signaling** *(pathway label; exact GO term curate locally)*; **mitochondrial ATP synthesis coupled electron transport**; **response to oxidative stress**; **protein ubiquitination** |
| Cell types implicated | Main affected cells are skeletal myofibers; 2024 single-nucleus/spatial transcriptomics also found increased regenerative/slow fibers and macrophages in LOPD muscle (pqac-00000021) | CL: **skeletal muscle cell** *(exact ID not confirmed here)*; **slow-twitch skeletal muscle fiber** *(term curate locally)*; **myoblast/regenerating myonucleus** *(term curate locally)*; **macrophage (CL:0000235)** |
| Omics findings | Single-nucleus RNA-seq plus spatial transcriptomics in **8 LOPD** biopsies and **4 controls** identified early reduced glycolysis, increased lipid/amino-acid metabolism, autophagy activation, and vacuole-specific inflammation/apoptosis/regeneration signals; proteomics found **178** altered proteins, with only **47** normalized after 1 year of ERT (pqac-00000021, pqac-00000023) | GO: **glycolytic process**; **lipid catabolic/metabolic process**; **amino acid metabolic process**; **apoptotic process**; **muscle regeneration** *(curate exact GO term)* |
| Diagnostic approach | First-line screening is **dried blood spot GAA enzyme activity** followed by confirmatory GAA testing in leukocytes/fibroblasts/muscle and/or molecular testing. Normal CK, EMG, or biopsy does **not** exclude LOPD (pqac-00000008, pqac-00000015) | NCIT-style diagnostics: dried blood spot assay; enzyme activity assay; molecular genetic testing |
| Diagnostic tests / findings | EMG may show myopathic changes with myotonic discharges, especially in paraspinal muscles; muscle MRI often shows paravertebral/abdominal/hip extensor involvement; biopsy shows vacuolar myopathy with glycogen storage (pqac-00000008, pqac-00000012) | HPO: **Myopathic EMG abnormalities (HP:0003457)** *(confirm locally)*; pathology term: vacuolar myopathy; imaging term: muscle MRI abnormality |
| Biomarkers / monitoring | CK may be mildly elevated or normal; AST/ALT may rise; urinary **glucose tetrasaccharide/Glc4 (Hex4)**, BNP/pro-BNP, vacuolated PAS-positive lymphocytes, dystromirs (**miR-1-3p, miR-133a-3p, miR-206**), and neurofilament light chain are reported monitoring biomarkers (pqac-00000011, pqac-00000012, pqac-00000014, pqac-00000016) | CHEBI: glucose tetrasaccharide *(exact CHEBI ID not confirmed here)*; biomarker labels: CK, BNP, pro-BNP, miR-1-3p, miR-133a-3p, miR-206, NfL |
| Functional monitoring | Recommended serial assessments include seated/supine FVC, polysomnography where indicated, MRC/manual muscle testing, 6-minute walk test, timed tests, hand-held dynamometry, ECG/echocardiography, and periodic brain/cerebrovascular imaging in selected patients (pqac-00000009, pqac-00000010, pqac-00000011, pqac-00000012) | NCIT-style procedures: spirometry; polysomnography; 6-minute walk test; electromyography; echocardiography; magnetic resonance imaging |
| Differential diagnosis | Limb-girdle muscular dystrophies, inflammatory myopathies, mitochondrial disorders, other glycogenoses, and oculopharyngeal muscular dystrophy should be considered; pseudodeficiency alleles can mimic low enzyme activity (pqac-00000010, pqac-00000015, pqac-00000006) | Differential set terms: limb-girdle muscular dystrophy; inflammatory myopathy; mitochondrial myopathy; oculopharyngeal muscular dystrophy |
| Epidemiology / population | Rare disease; often cited prevalence/incidence is roughly **1 in 40,000-57,000**, with under-recognition likely. Geographic/population carrier frequencies and predicted prevalence vary substantially, including higher predicted prevalence in some East Asian datasets (pqac-00000000, pqac-00000004, pqac-00000005) | ORDO/epidemiology labels: rare disease; prevalence estimate |
| Prognosis / burden | Chronic lifelong disorder with reduced survival in adult/non-classic Pompe disease and substantial HRQoL impact. Respiratory insufficiency remains a major cause of morbidity and mortality despite ERT (pqac-00000015, pqac-00000016) | HPO: **Reduced life expectancy (HP:0003676)** *(use cautiously)*; patient-reported outcome domains: physical function, fatigue, mobility, self-care |
| Approved disease-modifying therapy: alglucosidase alfa | First-generation recombinant human GAA; licensed dose **20 mg/kg every 2 weeks IV**. Improves/stabilizes 6MWT and FVC, but benefit often plateaus after ~2-3 years with later decline in many patients (pqac-00000017, pqac-00000020) | NCIT-style intervention: **Enzyme Replacement Therapy**; drug label: **alglucosidase alfa** |
| Approved disease-modifying therapy: avalglucosidase alfa | Next-generation rhGAA with enhanced mannose-6-phosphate targeting; approved FDA 2021 / EMA 2022. In expert-summary data, FVC gain at week 49 was **2.89% vs 0.46%** for alglucosidase comparator (pqac-00000009, pqac-00000020) | NCIT-style intervention: **Enzyme Replacement Therapy**; drug label: **avalglucosidase alfa** |
| Approved disease-modifying therapy: cipaglucosidase alfa + miglustat | Two-component therapy approved in adults with LOPD (EMA 2023 noted in guideline evidence). Long-term studies show maintained/stable respiratory and walking outcomes with biomarker improvement; phase I/II used **20 mg/kg IV biweekly cipaglucosidase alfa + 260 mg oral miglustat** (pqac-00000016, pqac-00000020) | NCIT-style interventions: **Enzyme Replacement Therapy** + **Pharmacological Chaperone Therapy/Enzyme Stabilizer**; drug labels: **cipaglucosidase alfa**, **miglustat** |
| Supportive care | Multidisciplinary management includes pulmonary support/ventilation, airway clearance, physical therapy, swallowing/nutrition assessment, orthopedic/bone health management, psychological care, pregnancy planning, and QoL monitoring (pqac-00000010, pqac-00000012, pqac-00000013) | NCIT-style interventions: noninvasive ventilation; physical therapy; occupational therapy; nutritional support; speech/swallow therapy |
| Experimental / active trials | **RESOLUTE (NCT04093349)**: AAV gene transfer (**SPK-3006**), phase 1/2, active-not-recruiting, adults on prior ERT; additional interventional studies include **S-606001** add-on therapy (**NCT07123155**) and extension (**NCT07750990**) (pqac-00000028, pqac-00000029, pqac-00000030) | NCIT-style intervention: **Gene Therapy**; AAV vector gene transfer; small-molecule add-on therapy |
| Prevention / screening | No primary environmental prevention. Secondary prevention centers on newborn screening where available, early recognition of asymptomatic/presymptomatic cases, carrier testing, cascade family testing, reproductive counseling, and early treatment before fixed muscle damage (pqac-00000009, pqac-00000012) | NCIT-style interventions: newborn screening; carrier screening; genetic counseling; cascade screening |
| Environmental / infectious factors | No established infectious cause. No convincing environmental toxin/lifestyle cause for disease occurrence; non-genetic factors mainly influence complications and management rather than primary causation (pqac-00000012, pqac-00000015) | Not applicable / no established environmental etiologic ontology term |
| Model organisms / natural disease | Key preclinical systems include **Gaa knockout mouse**, murine GAA-KO muscle cell lines, and naturally occurring animal models including **Japanese quail**; models recapitulate lysosomal glycogen storage and autophagic pathology and are used for ERT/gene-therapy development (pqac-00000005, pqac-00000024) | NCBI Taxon: **Mus musculus**; **Coturnix japonica**; model types: knockout mouse, muscle cell line, natural animal model |


*Table: This compact table summarizes the most actionable disease-knowledge fields for late-onset Pompe disease, including genetics, core phenotypes, mechanisms, diagnostics, therapies, epidemiology, and models. It is designed for rapid knowledge-base curation with conservative ontology suggestions and evidence-linked claims.*