2026-04-29 | Short-Term Oral Spermidine Supplementation Modifies Aspects of Neurodegenerative Disease in Flies and Mice With MPS III.
Mucopolysaccharidosis type III (MPS III) is a group of autosomal recessive neurodegenerative lysosomal storage disorders that causes progressive cognitive and physical impairment, predominantly in child/early adulthood. The median age of death is 17 years as there is no safe, effective treatment approved. Using faithful Drosophila and murine models of MPS III, we have characterised the MPS IIIA and MPS IIIC fly metabolome, explored the ability of oral spermidine supplementation to ameliorate clinical disease in the fly models and explored its mechanism of action in MPS IIIA mice. Spermidine is a polyamine naturally synthesised by the body. Its manufacture decreases with age. Supplementation has been reported to stimulate autophagy, reduce cell senescence and increase health/lifespan. The metabolomic evaluation confirmed that whole MPS IIIA and MPS IIIC flies exhibit a progressively deranged metabolome. Significantly up-regulated metabolites were those involved in nucleotide and purine metabolism. The most significantly down-regulated metabolites were those involved in ascorbate and aldarate metabolism. Further, spermidine levels decreased significantly in all fly genotypes with age. In short-term studies, food enriched with 5 mM spermidine improved overall fly activity and climbing ability. A 4-week study in pre-symptomatic MPS IIIA mice (3- or 6-mM spermidine, supplemented in drinking water) revealed no improvement in microgliosis or lysosomal compartment size; however, we observed a significant reduction in the astroglial response in the brain, which is believed to drive disease progression. Longer-term confirmatory studies in larger cohorts of MPS III animals are now warranted to determine whether spermidine supplementation is of benefit in preventing or slowing clinical disease in this and other childhood dementias.
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2026-03-12 | Retinal Phenotype in Mucopolysaccharidosis Type III.
Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a group of rare, hereditary, autosomal recessive, lysosomal storage disorders characterized by neurocognitive decline and early mortality. Pronounced visual impairment is frequent and retinal disease is more common in MPS III than in other MPS subtypes. The aim of this study was to characterize the retinal phenotype in MPS III and to provide insights into the disease course. Retrospective monocenter case series. In this study, 27 patients with genetically confirmed MPS III (n = 16 MPS IIIA; n = 9 MPS IIIB; n = 2 MPS IIIC) were included. The disease phenotype was classified as rapid or slowly progressive. All patients underwent spectral-domain optical coherence tomography (OCT) imaging to analyze central retinal thickness, peripapillary retinal nerve fiber layer thickness (RNFL), and configuration of retinal layers. Depending on neurocognitive status and compliance, best-corrected visual acuity (BCVA), slitlamp microscopy, and fundoscopy were performed. The median age at the ophthalmological examination was 6.5 years (range, 1-16 years). Slitlamp examination findings were usually unremarkable. BCVA was assessable in 6 of 27 patients and was within the normal age-adjusted range. Parafoveal degeneration of the outer retinal layers was observed in 59% of patients, whereas foveal thickening of the external limiting membrane was noted in 67%. One MPS IIIA patient showed severe foveal atrophy, and another presented with foveal intraretinal fluid accumulation. Quantitative retinal thickness analysis of all patients showed median values at the lower end of the reference spectrum in the inner perifoveal ring and below the normal range in the outer perifoveal ring, with no distinct pattern that distinguishes the subtypes or phenotypes. RNFL thickness was unremarkable in all patients. This study reveals a pattern of parafoveal degeneration of outer retinal layers in patients with all 3 MPS III subtypes, of whom MPS IIIA patients, known to have a more rapidly progressive neurocognitive disease, show the most severe retinal involvement. We provide natural history data that may contribute to planning and conducting future clinical trials, and we recommend further systematic ophthalmological examinations of MPS III patients to evaluate ocular involvement.
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