Cognitive Abilities of Dogs with Mucopolysaccharidosis I: Learning and Memory

Provoost, Lena; Siracusa, Carlo; Stefanovski, Darko; Che, Yan; Li, Mingyao; Casal, Margret L.

doi:10.3390/ani10030397

Cited by 3 publications

(4 citation statements)

References 112 publications

(153 reference statements)

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“…Behavioral and cognitive defects have been observed in MPS I mice [137][138][139][140] but skeletal abnormalities and sensatory deficiencies need to be considered when analyzing the results [141]. No cognitive deficits were found in MPS I dogs [142].…”

Section: Cognitive Impairmentmentioning

confidence: 99%

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology

Hampe

Eisengart

Lund

et al. 2020

Cells

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Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues. If untreated, patients with the severe phenotype die within the first decade of life. Early diagnosis is crucial to prevent the development of fatal disease manifestations, prominently cardiac and respiratory disease, as well as cognitive impairment. However, the initial symptoms are nonspecific and impede early diagnosis. This review discusses common phenotypic manifestations in the order in which they develop. Similarities and differences in the three animal models for MPS I are highlighted. Earliest symptoms, which present during the first 6 months of life, include hernias, coarse facial features, recurrent rhinitis and/or upper airway obstructions in the absence of infection, and thoracolumbar kyphosis. During the next 6 months, loss of hearing, corneal clouding, and further musculoskeletal dysplasias develop. Finally, late manifestations including lower airway obstructions and cognitive decline emerge. Cardiac symptoms are common in MPS I and can develop in infancy. The underlying pathogenesis is in the intra- and extracellular accumulation of partially degraded GAGs and infiltration of cells with enlarged lysosomes causing tissue expansion and bone deformities. These interfere with the proper arrangement of collagen fibrils, disrupt nerve fibers, and cause devastating secondary pathophysiological cascades including inflammation, oxidative stress, and other disruptions to intracellular and extracellular homeostasis. A greater understanding of the natural history of MPS I will allow early diagnosis and timely management of the disease facilitating better treatment outcomes.

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Section: Cognitive Impairmentmentioning

confidence: 99%

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology

Hampe

Eisengart

Lund

et al. 2020

Cells

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“…However, species-specific disease manifestations need to be considered. Canine animal models for MPS I tend to show milder manifestations compared to humans afflicted by the disease [170][171][172]. The introduction of exact mutations in mouse models provides insights into the genetics of the disease [173,174].…”

Section: Animal Modelsmentioning

confidence: 99%

Differences in MPS I and MPS II Disease Manifestations

Hampe

Yund

Orchard

et al. 2021

IJMS

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Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood–brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.

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“…The natural disease course observed in these animals is such that limb and joint abnormalities as well as liver and cardiac disease develop first at approximately 3-6 months of age, with ocular and neurologic abnormalities developing at approximately 10 months of age. 17,18 After approximately 1 year of age these dogs develop progressive corneal opacity and succumb to their somatic disease at approximately 3 years of age. 7,9,17,18 Dogs were euthanized by intravenous sodium pentobarbital overdose.…”

Section: Animalsmentioning

confidence: 99%

“…17,18 After approximately 1 year of age these dogs develop progressive corneal opacity and succumb to their somatic disease at approximately 3 years of age. 7,9,17,18 Dogs were euthanized by intravenous sodium pentobarbital overdose. Ages and disease status of dogs examined clinically and/or histologically are as follows; S1).…”

Section: Animalsmentioning

confidence: 99%

Clinical and pathological characterization of ophthalmic disease in a canine model of mucopolysaccharidosis type I

Nenninger

Ben‐Shlomo

Allbaugh

et al. 2023

J of Inher Metab Disea

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Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disease caused by α-L-iduronidase enzyme deficiency, resulting in glycosaminoglycan (GAG) accumulation in various cell types, including ocular tissues. Ocular manifestations in humans are common with significant pathological changes including corneal opacification, retinopathy, optic nerve swelling and atrophy, and glaucoma. Available treatments for MPS I are suboptimal and there is limited to no effect in treating the ocular disease. The goal of this study was to characterize the clinical and pathological features of ocular disease in a line of MPS I affected dogs, including changes not previously reported. A total of 22 dogs were studied; 12 MPS I were affected and 10 were unaffected. A subset of each underwent complete ophthalmic examination including slit lamp biomicroscopy, indirect ophthalmoscopy, rebound tonometry, and ultrasonic pachymetry. Globes were evaluated microscopically for morphological changes and GAG accumulation. Clinical corneal abnormalities in affected dogs included edema, neovascularization, fibrosis, and marked stromal thickening. Intraocular pressures were within reference interval for affected and unaffected dogs. Microscopically, vacuolated cells containing alcian blue positive inclusions were detected within the corneal stroma, iris, ciliary body, sclera, and optic nerve meninges of affected dogs. Ganglioside accumulation was identified by luxol fast blue staining in rare retinal ganglion cells. Increased lysosomal integral membrane protein-2 expression was demonstrated within the retina of affected animals when compared to unaffected controls. Results of this study further characterize ocular pathology in the canine model of MPS I and provide foundational data for future therapeutic efficacy studies.

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Cognitive Abilities of Dogs with Mucopolysaccharidosis I: Learning and Memory

Cited by 3 publications

References 112 publications

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology

Differences in MPS I and MPS II Disease Manifestations

Clinical and pathological characterization of ophthalmic disease in a canine model of mucopolysaccharidosis type I

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