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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 by the authors.Background: Lysosomal storage diseases (LSDs) are a genetically and clinically heterogeneous group of inborn errors of metabolism caused by variants in genes encoding lysosomal hydrolases, membrane proteins, activator proteins, or transporters. These disease-causing variants lead to enzymatic deficiencies and the progressive accumulation of undegraded substrates within lysosomes, disrupting cellular function across multiple organ systems. While classical phenotypes typically manifest in infancy or early childhood with severe multisystem involvement, a combination of advances in molecular diagnostics [particularly next-generation sequencing (NGS)] and improved understanding of disease heterogeneity have enabled the identification of attenuated forms characterised by residual enzyme activity and later-onset presentations. These milder phenotypes often evade early recognition due to nonspecific or isolated symptoms, resulting in significant diagnostic delays and missed therapeutic opportunities. Objectives/Methods: This study characterises the clinical, biochemical, and molecular profiles of 10 adult patients diagnosed with LSDs, all representing attenuated forms, and discusses them alongside a narrative review. Results: Enzyme activity, molecular data, and phenotypic assessments are described to explore genotype–phenotype correlations and identify diagnostic challenges. Conclusions: These findings highlight the variable expressivity and organ involvement of attenuated LSDs and reinforce the importance of maintaining clinical suspicion in adults presenting with unexplained cardiovascular, neurological, ophthalmological, or musculoskeletal findings. Enhanced recognition of atypical presentations is critical to facilitate earlier diagnosis, guide management, and enable cascade testing for at-risk family members.
Author(s): Urizar E, McCarron EP, Gadepalli C, Bentley A, Woolfson P, Lin S, Iosifidis C, Browning AC, Bassett J, Senarathne UD, Indika N-LR, Church HJ, Cooper JA, Menendez Lorenzo J, Farrugia ME, Jones SA, Black GC, Stepien KM
Publication type: Article
Publication status: Published
Journal: Genes
Year: 2025
Volume: 16
Issue: 8
Print publication date: 01/08/2025
Online publication date: 30/07/2025
Acceptance date: 28/07/2025
Date deposited: 09/09/2025
ISSN (electronic): 2073-4425
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
URL: https://doi.org/10.3390/genes16080915
DOI: 10.3390/genes16080915
Data Access Statement: No new data were created or analysed in this study. Data sharing is not applicable to this article.
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