Pompe disease, or glycogen storage disease type II (GSDII), is caused by mutations in the acid alpha-glucosidase (GAA) gene leading to deficient acid alpha-glucosidase activity, impairing lysosomal glycogen breakdown (1, 2). This enzymatic defect leads to pathological glycogen accumulation primarily in skeletal, cardiac, and smooth muscles. The disease spectrum ranges from severe infantile-onset Pompe disease (IOPD), characterized by cardiomyopathy and rapid progression, to more heterogenous late-onset Pompe disease (LOPD) with predominant skeletal and respiratory muscle involvement (3, 4). Beyond lysosomal pathology, mitochondrial dysfunction is increasingly recognized as a central mechanism in disease complications. Glycogen accumulation disrupts autophagic flux, impairing the clearance of damaged mitochondria (mitophagy), leading to oxidative stress and bioenergetic failure. This contributes to disease severity and explains why current ERTs, which do not cross the blood-brain barrier (BBB), fail to address neurological decline (5).

The introduction of firstgeneration enzyme replacement therapy (ERT) with alglucosidase alfa (ALG, Myozyme^® in 2006/Lumizyme^® in 2010) transformed management, especially for IOPD (6, 7). The second-generation of ERT was avalglucosidase alfa (AVA, Nexviazyme^®/Nexviadyme^®), which was approved in 2021. AVA showed enhanced M6P targeting for better muscle uptake superior respiratory function improvements compared to 1st generation. The third-generation ERT was Cipaglucosidase alfa + Miglustat (Cipa+mig, Pombiliti^® + Opfolda^®), which was a combination therapy approved in 2023 with enzyme stabilization technology, offering an alternative for antibody-positive LOPD patients (8, 9). However, challenges like gradual functional decline, treatment resistance, high costs, and untreated CNS manifestations persist.

This review consolidates recent evidence on the natural history, economic impact, novel biomarkers, evolving treatments, animal model, induced stem cell, and the roles of NBS and DHTs. We integrate three critical emerging areas: (1) the application of DHTs for pre-symptomatic motor impairment detection, (2) the potential of transferrin receptor-mediated ERT to address CNS disease, and (3) a critical appraisal of cost-effectiveness modeling challenges when standard care is itself cost-ineffective. These perspectives provide a forward-looking framework for research and policy.

Early diagnosis is crucial for initiating ERT before irreversible muscle damage occurs. Traditional newborn screening (NBS) utilizing heel-prick dried blood spots (DBS) faces logistical challenges, particularly with early hospital discharge. Cheah et al. (10) validated umbilical cord blood (UCB) as a viable alternative.

In their analysis of 4,091 UCB samples, mean GAA activity was comparable to Day 3 heel-prick samples from a Taiwanese cohort in Malaysia. Applying a cutoff of 1.54 μM/h (0.1% of the population), one confirmed Pompe case was identified(prevalence of 1 in 4,091, or 0.024%) suggesting possible regional variations or underdiagnosis. The identified infant, compound heterozygous for a novel deletion (c.2005_2010del) and a known likely pathogenic variant (c.1123C>T), was clinically asymptomatic at 3 months, consistent with LOPD (10).

UCB GAA activity remained stable for 72 h at 4 °C. Pseudodeficiency alleles posed a challenge, with 12 of 13 initially flagged infants carrying benign variants (e.g., c.1726G>A) that reduce GAA activity without causing disease. This underscores the need for a two-tiered strategy (enzyme activity followed by genetic confirmation). UCB sampling is particularly useful for regions with high hospital turnover or limited community infrastructure. These advances in early diagnosis set the stage for understanding how treatment timing influences long-term outcomes (10).

Corbett et al. (11) conducted a systematic review and network meta-analysis (NMA) evaluating ALG, AVA, and Cipa+mig vs. each other and best supportive care (BSC).

The review included 38 studies (3 RCTs, 3 extension studies, 7 registry studies, 25 single-group prospective studies). For ERT-naïve patients at ~1 year, both ALG and AVA showed statistically significant 6MWT improvements vs. BSC (mean differences ≈25m and ≈54m, respectively). Cipa+mig showed numerical superiority not reaching statistical significance, likely due to small ERT-naïve patient numbers in PROPEL. For FVC % predicted, all three ERTs showed numerical superiority over BSC without reaching statistical significance.

Direct and indirect comparisons suggested potential AVA advantage over ALG in 6MWT, statistically significant in primary analysis but attenuated to non-significant in sensitivity analysis adjusting for COMET trial data skewness (11). The review highlighted evidence limitations: high risk of bias in two pivotal RCTs (LOTS and PROPEL) due to selective outcome reporting, inability to access individual participant data, and scarce long-term comparative evidence (Table 1).

While ERT has improved survival, long-term real-world data show many LOPD patients experience gradual motor and respiratory decline after several years (12). This has driven the development of next-generation ERTs. Cipa+mig is a novel two-component therapy designed for enhanced cellular uptake and enzyme stabilization (13).

The American College of Medical Genetics and Genomics (ACMG) recently published a therapeutics bulletin on Cipa+mig for adult LOPD patients. Cipaglucosidase alfa is distinguished by a cell-line selected N-glycan profile rich in bis-mannose-6-phosphate (bis-M6P), enhancing receptor binding affinity and glycogen clearance. Miglustat, an iminosugar, stabilizes cipaglucosidase alfa during circulation (14). Approval was based on the PROPEL trial and its extension. While the primary endpoint (6MWT improvement at 52 weeks) did not achieve statistical superiority, clinically meaningful improvement was observed in sitting FVC, with statistically significant reductions in creatine kinase and Hex4 compared to AVG (14, 15). Extension data indicated maintained walking distance and stabilized pulmonary function through 104 weeks (14, 16). Evidence is emerging from more severely affected populations previously excluded from pivotal trials. Case series show that non-ambulatory patients transitioning from high-dose ALG can achieve sustained improvements in upper limb strength and biomarkers over 54 months with Cipa+mig, highlighting its potential in advanced disease (17).

In ERT-naïve patients (n = 123), AVA demonstrated numerically superior efficacy at 49–52 weeks: differences favored AVA by 4.69–5.49% for predicted forced vital capacity (FVC) and 41.88–57.08 meters for the 6-min walk test (6MWT). The 6MWT difference (57.08 m) reached statistical significance (P < 0.02) and is considered clinically meaningful (8, 9, 18). In ERT-experienced patients, AVA showed numerical superiority across outcomes, with maximal expiratory pressure (MEP) improvement (8.62%) reaching significance (18).

Long-term efficacy and safety of AVA are supported by COMET trial 145-week extension data. In this Phase 3 trial, 100 ERT-naïve LOPD patients were randomized to AVA or ALG for 49 weeks, followed by open-label AVA through week 145. 88 patients completed ≥145 weeks. Patients on continuous AVA maintained or improved least squares mean FVC % predicted (+1.38) and 6MWT distance (+20.65 m). Patients switching from ALG to AVA showed further improvement in respiratory and some physical function measures from week 49 to 145. Safety analysis revealed no new concerns, with decreasing anti-drug antibody titers over time. These data support AVA as a first-line treatment and demonstrate the safety and efficacy of switching from ALG to AVA (Table 2) (19).

Safety requires particular attention: a Boxed Warning for hypersensitivity reactions (incidence 27%, 3% severe), infusion-associated reactions (32%), and risk of acute cardiorespiratory failure (14). It is contraindicated in pregnancy due to embryo-fetal toxicity. The ACMG bulletin positions this therapy for adult LOPD patients not improving on current ERT (14). This guidance is complemented by recent perspectives on next-generation therapies, including Singh et al.'s (20) analysis of cipaglucosidase alfa-atga, which unveiled new horizons in Pompe disease therapy.

A post hoc analysis of the COMET trial provides further evidence supporting the switch from ALG to AVA, regardless of prior response to ALG (21). This analysis, while valuable, carries inherent limitations of retrospective subgroup analyses. It focused on 44 participants who switched from ALG to AVA after week 49. Participants were stratified by their change in upright FVC % predicted (ΔFVC) at Week 49 (thresholds >0% and ≥3%).

Among those who improved on ALG (ΔFVC > 0%, n = 20), FVC was maintained after switching to AVA (slope 0.1 %/year, P = 0.86). Among those who declined on ALG (ΔFVC ≤ 0%, n = 24), FVC stabilized after switching (slope 0.3 %/year, P = 0.70), halting the progressive decline observed earlier (slope−3.4 %/year, P < 0.01). Similar patterns were observed for FEV1, maximal inspiratory pressure (MIP), and MEP. A sustained reduction in urinary hexose tetrasaccharide (Hex4), a glycogen-derived biomarker, followed the switch, supporting AVA's enhanced cellular uptake (14). These findings indicate switching to AVA can provide meaningful respiratory stabilization for at least 2 years, irrespective of prior ALG response (21).

Beyond next-generation ERTs, small-molecule pharmacological chaperones and stabilizers represent a complementary therapeutic strategy. These compounds bind directly to GAA, enhancing stability, cellular uptake, and lysosomal delivery.

Li et al. (22) designed and synthesized novel polyhydroxylated azabicyclo [3.3.1] nonane derivatives (bridged bicyclic iminosugars). The lead candidate, iminosugar 15, demonstrated potent a competitive GAA inhibition (Ki = 0.7 μM) with high selectivity over other glycosidases. As an enzyme stabilizer, it increased GAA melting temperature by 13.3 °C and prevented heat-induced enzyme inactivation, preserving approximately 80% of GAA activity. In Pompe fibroblasts, co-treatment with iminosugar 15 and recombinant GAA resulted in a 3.7-fold increase in intracellular GAA activity, significantly outperforming other derivatives and demonstrating efficacy comparable to N-butyl-deoxynojirimycin (NB-DNJ) (22). This enhancement was mediated through the Mannose-6-Phosphate Receptor pathway, confirming legitimate lysosomal delivery. Bridged bicyclic iminosugars thus represent a promising class of stabilizers for adjunct use with ERT or as standalone chaperones for specific GAA mutations.

Gene therapy represents a promising one-time curative approach. Systemic delivery of adeno-associated virus (AAV) delivery has been limited by the high doses required for effective skeletal muscle targeting, causing liver toxicity and immune responses.

Sellier et al. (23) combined engineered myotropic AAV capsids with a muscle-specific expression cassette. This approach demonstrated superior skeletal muscle targeting and robust liver detargeting (>300-fold reduction vs. AAV9) in Gaa⁻/⁻ mice. Enhanced GAA expression and glycogen clearance were achieved at doses 10-fold lower than typical AAV9 clinical doses. However, this highly specific muscle targeting elicited a robust and sustained anti-hGAA antibody response in immunocompetent mice, highlighting that GAA hepatic expression promotes immune tolerance (23). Future optimized muscle-directed gene therapies may require balancing high muscle specificity with immunogenicity management strategies, potentially via transient immunomodulation or minimal residual liver expression.

A fundamental limitation of current ERTs is their inability to cross the blood-brain barrier (BBB), leaving central nervous system (CNS) manifestations untreated.

George et al. (5) developed a strategy leveraging transferrin receptor (TfR) for enzyme delivery. Fusion proteins combining anti-TfR antibody with recombinant human GAA (anti-TfR-GAA) were evaluated in humanized TfR Pompe mice. A single dose of the lead candidate (FabFc-GAA2) resulted in a 68% reduction in brain glycogen and significant spinal cord clearance—unattainable by standard ERTs. 4 weekly doses normalized CNS glycogen, reduced neuroinflammation, and cleared muscle glycogen more effectively than AVA.

The mechanism involves TfR-mediated transcytosis across the BBB and enhanced muscle uptake, bypassing the CI-MPR pathway. The study also introduced cerebrospinal fluid Hex4 as a potential CNS biomarker and Glyco-CEST/NOE MRI for non-invasive brain glycogen quantification (22). This TfR-mediated approach represents a paradigm shift, potentially addressing both neurogenic and myogenic disease aspects (5).

Extensive preclinical research utilizing GAA-knockout mice and patient-derived induced pluripotent stem cells (iPSCs) has been instrumental in elucidating disease mechanisms and testing therapies. A comprehensive summary of key models, their genetic backgrounds, and main findings regarding systemic and tissue-specific pathology (including cardiac, skeletal muscle, nervous system, and smooth muscle involvement), therapeutic responses (to ERT, gene therapy, small molecules), and emerging aspects like mitochondrial dysfunction and autophagy defects is provided in Tables 3, 4. These models consistently replicate core disease features—lysosomal glycogen accumulation, autophagic buildup, mitochondrial abnormalities, and tissue dysfunction—providing validated platforms for mechanistic studies and therapeutic screening. Notably, they highlight challenges like the resistance of type II muscle fibers to ERT, the critical role of immune tolerance in gene therapy, and the involvement of CNS and smooth muscle pathology.

Pompe disease management imposes substantial economic burden, predominantly driven by ERT costs. Analysis of the French national healthcare database revealed mean annual healthcare costs of €232,117 for IOPD and €358,768 for LOPD in 2022 (24). Over 90% of LOPD costs were hospital-incurred, with ALG acquisition comprising approximately 75% of total expenses. Ventilator dependence and female sex were independent cost drivers. Patients averaged 81.9 medical/paramedical consultations and 49 hospitalization days annually (24).

Steiner et al. (25) analyzed US. data (MarketScan Databases). Among 105 ERT-treated patients, mean total all-cause costs over 2.5–2.7 years were $950,380 for IOPD and $1,857,823 for LOPD. Outpatient and ERT-related costs were primary drivers, with mean all-cause outpatient ERT costs of $308,421 (IOPD) and $778,190 (LOPD). IOPD patients had higher inpatient and supportive care utilization, while LOPD patients had higher outpatient service costs (25).

This high-cost background raises cost-effectiveness questions. A modeling study examining the UK's NICE framework highlighted a fundamental challenge: when standard care (ALG) is profoundly cost-ineffective, it distorts valuation of new technologies. A hypothetical curative gene therapy was valued at over £4 million vs. current ERT, but only £629,392 when appropriately “re-anchored” against best supportive care, indicating perceived value derives from displacing costly chronic treatment rather than intrinsic health gains (26).

A French Pompe Registry study of 60 deceased LOPD patients provided cause-of-death insights. Disease-related causes accounted for 46.7% of deaths, primarily respiratory failure (50%) and pulmonary infections (25%). Malignant neoplasms were the most common non-disease-related cause (28.3%). Patients dying from disease-related causes had significantly lower FVC (38% vs. 54.7%) and longer median delay in ERT initiation (8 vs. 1 year). The study documented high comorbidity prevalence: hypertension (42.6%), chronic constipation (24.1%), and dysphagia (22.2%) (27).

Understanding mortality patterns is crucial for improving patient management. A French Pompe Registry retrospective study analyzing 60 deceased LOPD patients provided detailed cause-of-death insights (27). Disease-related causes accounted for 46.7% of deaths, primarily respiratory failure (50% of disease-related deaths) and pulmonary infections (25%). Malignant neoplasms were the most common non-disease-related cause (28.3% of all deaths). Patients dying from disease-related causes had significantly lower FVC (38% vs. 54.7%) and longer median delay in ERT initiation after diagnosis (8 vs. 1 year) compared to those dying from unrelated causes (27). Respiratory function is thus a key prognostic factor, emphasizing early treatment importance. The study documented high comorbidity prevalence: hypertension (42.6%), chronic constipation (24.1%), and dysphagia (22.2%) (27).

As ERT significantly extends the lifespan of IOPD patients, previously unrecognized or rare long-term complications are emerging. A critical case report by Akagi et al. (28) highlights complete atrioventricular block (cAVB) as a life-threatening arrhythmic event in a long-term survivor.

The report describes an 18-year-old male with IOPD, diagnosed at 6 months of age and successfully treated with ERT since 8 months of age, leading to remarkable improvement of his initial severe cardiomyopathy. Despite chronic ERT, he presented acutely with extreme bradycardia and cAVB, necessitating emergency temporary pacing and subsequent permanent biventricular pacemaker implantation (28). This case underscores that ERT, while life-saving for cardiomyopathy, may not fully protect against the progression of conduction system disease. This cardiac phenotype is particularly concerning given that mitochondrial structural and functional damage is increasingly recognized as a key pathogenic mechanism in PD complications.

The pathophysiology of conduction abnormalities in Pompe disease is attributed to glycogen accumulation within cardiac conduction cells, leading to cellular enlargement which can initially accelerate conduction (manifesting as a shortened PR interval, a classic ECG finding in Pompe disease) but ultimately progress to fibrosis and block (28). This aligns with previous findings in LOPD cohorts, where a small but significant proportion of patients developed high-grade AV block requiring pacemaker implantation, irrespective of ERT status (29).

This case emphasizes the critical need for lifelong, comprehensive cardiac surveillance in all Pompe disease patients, extending beyond the assessment of ventricular hypertrophy and systolic function. Regular rhythm monitoring, including Holter ECG, is essential for the early detection of progressive conduction disease, enabling timely intervention to prevent catastrophic bradyarrhythmic events (28).

Conventional functional tests may be insensitive to early biological changes preceding irreversible muscle damage. Mitochondrial structural and functional impairment is increasingly recognized as an important mechanism in PD pathogenesis.

Beha et al. (30) utilized 7 Tesla ¹³C nuclear magnetic resonance (NMR) spectroscopy to non-invasively quantify muscle glycogen in vivo. Young, minimally affected LOPD patients had significantly elevated glycogen levels in early-degenerating muscles—lumbar paraspinals (2.2x higher) and hamstrings (1.8x higher)—while glycogen in more resilient calf muscles was normal. This suggests glycogen accumulation precedes fat replacement and clinical weakness (30). Muscle glycogen concentration thus represents a promising quantitative biomarker for assessing treatment efficacy at the molecular level, potentially enabling intervention before functional decline.

Additionally, lysosome-mediated autophagy and mitophagy dysregulation are regarded as important mechanisms in PD development, contributing to the observed increase in glial cell proportions (30). Future studies should examine relevant autophagy pathways using Western blot analysis to elucidate these mechanisms further.

Conventional clinical scales and timed functional tests may lack sensitivity for detecting subtle motor changes, particularly in mild or asymptomatic Pompe disease. Digital health technologies (DHTs) offer potential for detecting minute mobility alterations.

Pilotto et al. (31) conducted a case-control study evaluating DHT for detecting and quantifying mobility impairment in LOPD. Eight LOPD patients (including three young, mildly affected/asymptomatic subjects) and 52 matched controls underwent comprehensive mobility assessment using the RehaGait inertial sensor system. Compared to controls, patients showed significant alterations in walking (reduced speed, increased step time variability, shorter step length), turning (reduced angular and peak velocities), and postural transitions (prolonged standing duration, reduced maximal extension velocity) (31).

Critically, the three mildly affected/asymptomatic patients with normal clinical scale scores showed significantly increased step time variability and reduced step length compared to younger matched controls (31). This suggests digital motor metrics can detect subtle impairment before clinical manifestation (Table 5).

DHT provides richer, more objective motor function readouts than conventional assessment. In conditions like Pompe disease where early intervention modifies disease course, digital health assessment could facilitate more timely, personalized treatment decisions and enable reliable remote monitoring, potentially improving care and reducing healthcare burden (31). Longitudinal studies are needed to validate prognostic value, sensitivity to change, and role in guiding treatment decisions (Table 6).

A critical appraisal of the available evidence reveals several limitations and biases across key studies. For newborn screening, while umbilical cord blood shows promise, most validation studies are single-center with limited sample sizes (< 5,000), and false-positive rates due to pseudodeficiency alleles remain a challenge (10). In the ERT domain, the PROPEL trial excluded severely affected non-ambulatory patients, limiting generalizability to advanced disease stages (8, 9, 18). Variability in Hex4 reporting methods across studies complicates biomarker comparisons. Digital health studies, while innovative, often involve small sample sizes and lack longitudinal validation. Gene therapy studies remain preclinical, with immunogenicity and long-term safety yet to be established in humans. These limitations underscore the need for larger, more representative trials and standardized outcome measures.

While this review highlights significant advances, several critical gaps remain. First, there is a lack of head-to-head randomized controlled trials comparing next-generation ERTs (e.g., AVA vs. Cipa+mig), forcing reliance on indirect comparisons with inherent limitations. Second, long-term data on CNS involvement in both IOPD and LOPD are inadequate, especially regarding cognitive and neurodevelopmental outcomes. Third, ethical and regulatory issues surrounding gene therapy dosing, especially in pediatric populations, require careful navigation. Fourth, barriers to implementing digital health tools—including cost, accessibility, data standardization, and clinician training—must be addressed before widespread adoption. Future research should prioritize direct comparative trials, longitudinal CNS studies, ethical frameworks for gene therapy, and pragmatic implementation studies for digital monitoring. Additionally, the consistent observation of increased glial cell proportions requires mechanistic investigation to determine whether this represents reactive gliosis, inflammatory activation, or compensatory responses to neuronal loss.

The Pompe disease landscape is rapidly evolving, creating a more comprehensive patient journey from birth through adulthood. Umbilical cord blood validation for NBS offers a practical solution to logistical barriers, enabling earlier diagnosis, particularly of LOPD variants (10). Upon diagnosis, patients now have broader therapeutic options. Next-generation enzyme replacement therapies offer new hope, with indirect treatment comparison evidence suggesting potential AVA advantages over Cipa+mig (18), supported by COMET trial 145-week extension data confirming sustained efficacy and safety (19). Critically, a post hoc analysis of the COMET trial demonstrates that switching from ALG to AVA provides sustained respiratory benefit for at least 2 years, regardless of a patient's prior response to ALG, reinforcing the value of AVA in the long-term management of LOPD (21).

Concurrently, gene therapy approaches are maturing. Sellier et al. shows muscle-directed AAV vectors demonstrate efficient, low-dose treatment potential (23), with critical insights regarding anti-transgene immunogenicity management in highly specific targeting strategies.

Most notably, therapeutic frontiers are expanding to address previously untreatable CNS disease. George et al.'s (5) pioneering work on TfR-mediated ERT demonstrates, in preclinical models, effective simultaneous clearance of brain and skeletal muscle glycogen with a single biologic. This approach, coupled with novel biomarkers (e.g., CSF Hex4) and advanced imaging (Glyco-CEST/NOE MRI), opens new therapeutic possibilities.

As patient survival extends, new long-term challenges are recognized. The emergence of life-threatening cardiac conduction abnormalities, such as complete atrioventricular block in long-term IOPD survivors, underscores the necessity of lifelong, multi-system surveillance that includes arrhythmia monitoring, even in patients with stable ventricular function on ERT (28).

Amid these exciting developments, Corbett et al.'s (11) systematic review and network meta-analysis provide crucial reality checks on the current evidence base for approved ERTs. While confirming modest short-term benefits of ERTs like ALG and AVA over best supportive care in ERT-naïve patients, limited reliable evidence supports clinically meaningful outcome differences between available ERTs. The review critically highlights long-term comparative data scarcity, high bias risk in key trials, and independent research data access challenges.

Real-world evidence has clarified Pompe disease's substantial economic burden and specific mortality causes, reinforcing the critical importance of early diagnosis pathways provided by newborn screening. For disease monitoring, non-invasive biomarkers like 7T NMR spectroscopy and wearable sensor-based DHT show significant potential for early, sensitive disease activity detection at molecular and functional levels, providing earlier intervention windows (30, 31).

Looking forward, the development pipeline shows considerable promise. The prospects of curative gene therapies, highly selective oral stabilizers, advanced delivery systems (e.g., TfR-ERT), and expanded screening must be accompanied by synchronized health technology assessment and policy reform. This ensures these innovations are fairly evaluated and sustainable, equitable access models are established. The future of Pompe disease management lies in a fully integrated strategy: robust and accessible NBS, next-generation biologics and delivery systems, smart small-molecule adjuncts, advanced gene therapies with immunogenicity management, sensitive biomarkers, more robust and transparent comparative evidence bases for existing therapies, comprehensive long-term surveillance protocols for emerging complications, and supportive policy reforms—all working collectively to comprehensively improve patient outcomes from the earliest possible moment.