Background: Lysosomal storage disorders (LSDs) are rare inherited metabolic diseases caused by deficiencies of specific lysosomal enzymes, leading to progressive multi-organ damage. This review focuses on Pompe disease and mucopolysaccharidoses (MPS) I, II, and IVA. Enzyme replacement therapies (ERTs) aim to provide the deficient enzymes and to slow disease progression; however, the durability of clinical benefit remains uncertain. This systematic review aimed to evaluate and synthesise the available evidence on the long-term effectiveness and safety of ERTs for Pompe disease and MPS I, II, and IVA.

Methods: A two-step systematic approach was applied. First, systematic reviews addressing the predefined PICO (Population–Intervention–Comparator–Outcome) were identified and assessed using the ROBIS tool. Second, an updated search was conducted. Where no suitable reviews were identified de novo searches for primary prospective studies were conducted. Searches were performed in four electronic databases in May 2025 for English and German publications, supplemented by manual searching. Only prospective studies (randomised or observational) were included. The risk of bias for non-randomised comparative studies was assessed using ROBINS-I, and evidence certainty was evaluated through the GRADE framework. Two reviewers independently conducted screening, data extraction, and quality assessment.

Results: Eight Studies for alglucosidase alfa in infantile-onset Pompe disease (IOPD), 17 for late-onset Pompe disease (LOPD), three for avalglucosidase alfa, four for laronidase in MPS I, 11 for idursulfase in MPS II, and four studies for elosulfase alfa in MPS IVA met the inclusion criteria. All were prospective observational studies, mostly single-arm, with no randomised controlled trials identified. Overall, the certainty of evidence was judged to be very low, mainly due to small cohorts, short or variable follow-up, heterogeneous endpoints, and moderate-to-serious risk of bias. In IOPD, a survival benefit and improved ventilator-free survival for alglucosidase alfa was shown, particularly when treatment is initiated very early. Cardiac function, especially left ventricular mass, has been shown to improve, whereas other cardiac effects are less well substantiated. The evidence regarding motor function, cognition, and quality of life is inconsistent. For avalglucosidase alfa, only limited data from one small study are currently available. Evidence on ERT in LOPD suggests that alglucosidase alfa may improve walking ability during the first years of treatment, while motor function tends to stabilise or slightly decline in the long term. Respiratory function is generally stable in the short term but shows deterioration over longer follow-up. Due to very limited data, no valid conclusions can be drawn regarding survival or ventilator dependence. Effects on quality of life are heterogeneous, with predominantly stable rather than clearly improved outcomes; earlier treatment initiation may be associated with more favourable courses.
Avalglucosidase alfa shows a similar pattern, with short-term motor improvements; however, robust long-term data are lacking. Thus, early improvement in motor function remains the only consistently demonstrated benefit.For MPS I, robust long-term data on survival are lacking for laronidase. Earlier treatment initiation and milder disease phenotypes are associated with better outcomes. However, the generalisability of these findings to more severe disease courses is highly limited. In MPS II, shorter-term idursulfase treatment showed signals of improved survival and endurance, particularly in attenuated forms, however, data on cognition, respiratory function, and quality of life were limited and inconsistent. For MPS IVA, a controlled study and several single-arm extensions showed short-term functional improvements with elosulfase alfa, particularly in patients receiving standard-dose ERT. Evidence for long-term survival or cardiac outcomes was lacking. Across all conditions, the rarity and phenotypic variability of these diseases constrain the feasibility of controlled trials and the generalisability of findings. ERTs were generally well tolerated across indications. Most adverse events (AEs) were mild or moderate infusion-related reactions. Serious treatment-related events were rare, and discontinuation rates due to AEs were below 10%. Mortality reported in long-term studies was not attributed to ERT.

Conclusion: In conclusion, based on the currently available evidence, a reliable and definitive assessment of the long-term effectiveness and safety of the evaluated ERTs is not possible. The overall certainty of evidence is very low, precluding firm conclusions on sustained clinical benefit. Therefore, the use of ERT should be guided by careful patient selection and embedded within structured monitoring and documentation frameworks, including the systematic collection of standardised endpoints and clearly predefined criteria for continuation or discontinuation of therapy.