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Dewsbury et al. J Transl Genet Genom 2024;8:85-101 Journal of Translational
DOI: 10.20517/jtgg.2023.58
Genetics and Genomics

Review Open Access

Molecular basis of neurocognitive dysfunction and
psychosis in Alpha-Mannosidosis

1,2
1
3
Mollie R. Dewsbury , Iain P. Hargreaves , Heather M. Morgan , Karolina M. Stepien 4,5
1
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK.
2
Neurometabolic Unit, National Hospital, London WC1N 3BG, UK.
3
Chiesi USA, Inc., One Boston Place, Boston, MA 02108, USA.
4
Adult Inherited Metabolic Disorders, Salford Royal Organisation, Northern Care Alliance NHS Foundation Trust, Salford
M6 8HD, UK.
5
Division of Cardiovascular Sciences, University of Manchester, Manchester M13 9PL, UK.
Correspondence to: Dr. Karolina M. Stepien, Adult Inherited Metabolic Disorders, Salford Royal Organisation, Northern Care
Alliance NHS Foundation Trust, Salford M6 8HD, UK. E-mail: Karolina.Stepien@nca.nhs.uk; Mollie R. Dewsbury, School of
Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK. E-mail:
molliedewsbury@gmail.com
How to cite this article: Dewsbury MR, Hargreaves IP, Morgan HM, Stepien KM. Molecular basis of neurocognitive dysfunction
and psychosis in Alpha-Mannosidosis. J Transl Genet Genom 2024;8:85-101. https://dx.doi.org/10.20517/jtgg.2023.58
Received: 18 Dec 2023 First Decision: 31 Jan 2024 Revised: 18 Feb 2024 Accepted: 27 Feb 2024 Published: 20 Mar 2024

Academic Editor: Sanjay Gupta Copy Editor: Fangyuan Liu Production Editor: Fangyuan Liu

Abstract
A significant portion of patients who are afflicted with lysosomal storage diseases (LSDs) encounter neurological
manifestations, including cognitive issues and developmental delay, seizures, psychiatric issues, and an overall
neurodegenerative decline. In order to enhance the development of effective therapies for these symptoms, it is
imperative that we allude to the neuropathophysiology that underlies these manifestations. These distinct
neurological and developmental features are particularly evident in patients with Alpha-Mannosidosis (AM), a type
of LSD. However, there is limited published information regarding the mechanisms and pathophysiology of these
presentations in patients with this condition. Although the precise impact of lysosomal storage on the biogenesis
and functioning of neuronal cells has not been clearly defined, recent studies have placed emphasis on the
significance of synaptic defects influencing this dysfunction. These defects encompass changes in synaptic spines,
proteins, and vesicles, as well as postsynaptic densities that potentially precipitate functional disruptions in
synaptic transmission and neurodegeneration. Ultimately, this cascade is thought to result in extensive neuronal
loss and, consequently, the onset of cognitive manifestations. Uncovering the effects on synaptic components in
LSDs with neurological symptoms like AM will enable a better understanding of disease progression. It will also
allow us to identify critical targets for therapeutic intervention and the determination of optimal time frames for

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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