| Domain | Summary | Key ontology mappings | Quantitative details | Evidence source(s) |
|---|---|---|---|---|
| Definition / IDs | Infantile-onset Pompe disease (IOPD; classic/atypical infantile acid maltase deficiency) is the severe early-onset form of glycogen storage disease type II, a lysosomal storage disorder caused by acid alpha-glucosidase deficiency with glycogen accumulation, especially in cardiac and skeletal muscle. Disease-level information here is from aggregated literature/guidelines, not individual EHRs. | MONDO: glycogen storage disease II = **MONDO:0009290**; Orphanet: **365**; MeSH/ICD not confidently extracted here; UBERON: heart **UBERON:0000948**, skeletal muscle tissue **UBERON:0001134**, diaphragm **UBERON:0001103**, lysosome (GO CC) **GO:0005764** | MetabERN notes atypical infantile presentation may occur after 6 months but within first 2 years; untreated classic IOPD is typically fatal within the first year. | Parenti et al., 2024; Moschetti et al., 2024 (pqac-00000001, pqac-00000003) |
| Cause and inheritance | Primary cause is **biallelic pathogenic variants in GAA** causing markedly reduced/absent lysosomal acid alpha-glucosidase activity. Inheritance is **autosomal recessive**. CRIM status is a major treatment-response modifier; CRIM-negative patients lack endogenous GAA protein and are at higher risk of anti-ERT immune responses. Environmental causes are not established. | Gene: **GAA**; GO BP: glycogen catabolic process **GO:0005980**, autophagy **GO:0006914**; CL: skeletal muscle cell **CL:0000187**, cardiomyocyte **CL:0000746** | MetabERN cites **648** documented disease-associated variants (as of Dec 2020); a 2024 review reports **>911** disease-associated GAA variants; about **one-third** of infantile Pompe patients are CRIM-negative. | Parenti et al., 2024; Moschetti et al., 2024; Open Targets GAA-disease association (pqac-00000001, pqac-00000003, pqac-00000000) |
| Hallmark phenotypes | Core manifestations: hypertrophic cardiomyopathy, generalized hypotonia/floppy infant phenotype, respiratory insufficiency, feeding difficulty, motor delay/regression, macroglossia, hepatomegaly; long-term survivors may show persistent gross motor weakness, dysphagia/aspiration risk, motor speech deficits, hearing loss, osteopenia, and GERD. | HPO: cardiomyopathy **HP:0001638**, hypertrophic cardiomyopathy **HP:0001639**, hypotonia **HP:0001252**, respiratory insufficiency **HP:0002093**, hepatomegaly **HP:0002240**, macroglossia **HP:0000158**, dysphagia **HP:0002015**, hearing impairment **HP:0000365**, delayed gross motor development **HP:0002194** | In a long-term survivor series, **11** IOPD survivors had median age **8.0 y** (range **5.4–12.0**); **7/11** were independently ambulatory. | Prater et al., 2012; Parenti et al., 2024; Moschetti et al., 2024 (pqac-00000004, pqac-00000001, pqac-00000002) |
| Mechanism / pathophysiology | Upstream defect: GAA loss causes lysosomal glycogen accumulation. Downstream cascade: lysosomal enlargement, rupture/leakage of glycogen into cytoplasm, impaired autophagic flux, secondary accumulation of autophagic material, mitochondrial dysfunction and oxidative stress, culminating in cardiac, skeletal, smooth-muscle, and neural dysfunction. CNS involvement is increasingly recognized but incompletely corrected by standard ERT. | GO BP: lysosomal transport **GO:0007041** (broadly relevant), autophagy **GO:0006914**, response to oxidative stress **GO:0006979**; GO CC: lysosome **GO:0005764**; CL: motor neuron **CL:0000100**, endothelial cell **CL:0000115** | Gene-therapy review notes cross-correction may require only about **1–10%** of normal enzyme activity for effective substrate clearance in LSD paradigms. | Uribe-Carretero et al., 2024; Moschetti et al., 2024; Leon-Astudillo et al., 2023 (pqac-00000010, pqac-00000002, pqac-00000012) |
| Diagnosis | Typical workflow: first-line enzyme testing on dried blood spot (DBS), then confirmatory enzyme assay in leukocytes/fibroblasts and **GAA** sequencing; CRIM status assessment is important before/at ERT initiation. Supportive tests commonly include CK and disease biomarkers such as urinary/plasma glucose tetrasaccharide (Glc4/Hex4), plus ECG/echocardiography and respiratory evaluation. | HPO/lab-related: elevated creatine kinase not mapped here with confidence; UBERON: blood **UBERON:0000178**, skin fibroblast culture not ontologized here | In one older long-term cohort, diagnostic enzyme activity in fibroblasts/muscle was **<1%** of control mean; an Italian diagnostic cohort screened **2934** subjects and identified **39** symptomatic PD patients with two causative mutations plus **22** GVUS cases. | Moschetti et al., 2024; Prater et al., 2012 (pqac-00000005, pqac-00000004) |
| Epidemiology | Pompe disease frequency varies by population and ascertainment method; newborn screening (NBS) generally yields higher observed birth prevalence than historical clinical diagnosis. Certain founder/pseudodeficiency backgrounds complicate interpretation in some populations. | MONDO:0009290; no additional population ontology asserted | MetabERN: overall incidence about **1:40,000–1:146,000**; in NBS countries **1:8,684–1:23,596**; Taiwan about **1:17,000**; French Guiana about **1:2,000**. Population-genetic study: global **GAA** carrier frequency **1.3%**; common variant c.-32-13T>G AF **0.0033** globally (mostly relevant to LOPD/carrier screening, not specific to IOPD). | Parenti et al., 2024; Choi et al., 2024 (pqac-00000001, pqac-00000000) |
| Current treatment | Standard of care is **enzyme replacement therapy (ERT)** with alglucosidase alfa initiated as early as possible; prophylactic immune tolerance induction (ITI) is used particularly for CRIM-negative IOPD. Multidisciplinary supportive care includes cardiology, pulmonology/ventilation, nutrition/swallow management, PT/OT/speech therapy, and monitoring of antibody titers and biomarkers. Avalglucosidase alfa is an emerging/next-generation option under pediatric study rather than established universal standard for IOPD. | NCIT terms not asserted confidently; GO/CL/UBERON as above for affected systems | Long-term survivor cohort: biweekly ERT at cumulative doses **20–40 mg/kg**; all survivors had cardiac improvement and low/undetectable antibody titers. Avalglucosidase pediatric trial records: Mini-COMET **NCT03019406**, planned enrollment **22**; Baby-COMET **NCT04910776**, enrollment **17**. | Prater et al., 2012; Unnisa et al., 2022; ClinicalTrials.gov records (pqac-00000004, pqac-00000014, pqac-00000000) |
| Prognosis | Natural history is rapidly progressive and often lethal in infancy without therapy. ERT has markedly improved survival and ventilator-free survival, but residual disease remains common in long-term survivors, especially musculoskeletal, bulbar, auditory, and possibly CNS complications. Prognosis is modified by CRIM status, age at treatment start, antibody response, and likely residual enzyme activity/genotype. | HPO: progressive muscle weakness **HP:0003323** (broad), respiratory failure **HP:0002878** | Pre-ERT prognosis commonly death by age **<2 y**; Moschetti review states classic untreated fatality often within **1 year**. In the survivor cohort, **11** long-term survivors were alive at school age with persistent morbidity. | Moschetti et al., 2024; Prater et al., 2012; Kishnani et al., 2007 referenced in retrieved literature (pqac-00000003, pqac-00000004) |
| Screening / prevention | Secondary prevention is most important: **newborn screening** enables presymptomatic or very early treatment and CRIM-guided planning. Primary prevention of disease occurrence is not available; genetic counseling, carrier testing, cascade testing, prenatal diagnosis, and preimplantation testing are relevant for at-risk families. | No extra ontology confidently asserted | Northeast Italy screened about **250,000** neonates: **126** positives (**0.051%**), **51** confirmed affected, **40%** PPV, overall incidence **1:4,874** across 4 LSDs; **3 IOPD** infants were immediately treated. China NBGS cohort screened **22,687** newborns with **6.0%** carriers, **0.13%** initial positives, and **15** presymptomatic LSD diagnoses overall. | Gragnaniello et al., 2023; Wang et al., 2025 (pqac-00000009, pqac-00000008) |
| Emerging therapies / models | Experimental directions include next-generation ERT (avalglucosidase alfa), AAV- and lentiviral-based gene therapy, liver- and muscle-directed delivery, CNS-targeted/intrathecal approaches, substrate reduction (e.g., GYS1 inhibition), and even **in utero ERT** proof-of-concept. Key models include **Gaa−/− mouse**, naturally occurring Japanese quail disease, and large-animal models. | Model systems not ontology-mapped here; GO: glycogen biosynthetic process **GO:0005978** relevant to substrate reduction concept | In utero ERT case: single treated fetus with normal cardiac and age-appropriate motor function at **13 months**. Muscle-directed gene therapy review cites AAV8 liver-directed study in **4** LOPD subjects and ongoing pediatric avalglucosidase trial **NCT03019406**. Animal-model review summarized **42** GSD animal models total, including **26** genetically modified mouse models and **15** naturally occurring models; Pompe-relevant naturally occurring models include quail and large animals. | Cohen et al., 2022; Leon-Astudillo et al., 2023; Almodóvar-Payá et al., 2020; Ullman et al., 2024 (preclinical Pompe mouse substrate reduction) (pqac-00000011, pqac-00000012, pqac-00000014, pqac-00000000) |


*Table: This table condenses key disease-knowledge-base fields for infantile-onset Pompe disease, including identifiers, genetics, phenotypes, mechanisms, diagnostics, epidemiology, treatment, and emerging translational research. It is designed as a compact reference with ontology suggestions, quantitative details, and cited evidence sources.*