(18) Morquio a Disease: Understanding the Eye Pathology Through Morphological, Genomic, and Functional Studies

Background: Mucopolysaccharidosis (MPS) IVA, also known as Morquio A disease, is an autosomal recessive lysosomal storage disease (LSD). Morquio A is characterized by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Without GALNS, lysosomes are unable to break down the glycosaminoglycans (GAGs) chondroitin-6-sulfate (C6S) and keratan sulfate (KS), leading to skeletal manifestations, valvular heart disease, hearing loss, corneal clouding, etc. One current treatment is enzyme replacement therapy (ERT), but ERT faces challenges, particularly in addressing cardiovascular and skeletal disease and improving corneal clouding.

Objectives: To explore the pathology of Morquio A disease in the eye, we conducted morphological, genomic, and functional studies in wild-type (WT) mice and Galns-/- (MKC) mice at different ages, relating to young adult, mature adult, and middle-aged time frames.

Design/Methods: Cross sections of mice eyes were stained with antibodies, allowing for the relative abundance of GAGs and GAG-associated molecules to be seen under an immunofluorescent microscope. Live mice were dark adapted and then shown white light flashes under scotopic and photopic conditions, data was recorded using an electroretinograph. Whole mouse eyes were collected, lysed, and RNA extracted. Data was compared between groups to show up and down regulation for genes.

Results: Immunofluorescence studies revealed statistically significant decreases in corneal and retinal levels of lumican, a reduction in corneal levels of decorin, and an increase in retinal levels of mimecan in MKC mice compared to their WT counterparts. Electroretinography studies showed that at 2, 3, and 6 months of age, the scotopic a-wave and b-wave responses in MKC mice were not significantly different from controls. However, by 12 months of age, a clear and reproducible decline in both scotopic a-wave and b-wave responses was observed in MKC mice compared to WT. Bulk transcriptomic studies identified 74 upregulated genes in MKC mice at 6 months of age compared to WT.

Conclusions: Morphological findings suggest that alterations in lumican, decorin, and mimecan are associated with corneal clouding. Functional findings suggest a slow, progressive decline in visual function in MKC mice. Taken together, our findings indicate that eye pathology in Morquio A disease is not limited to the cornea but affects other parts of the eye as well, which can pave the way for the development of novel treatments for this patient population.