Abstract
Sanfilippo syndrome Type B or Mucopolysaccharidosis IIIB (MPS IIIB) is a neurodegenerative autosomal recessive lysosomal storage disorder in which patients suffer severe vision loss from associated retinopathy. Here we sought to study the underlying retinal functional and morphological changes associated with MPS IIIB disease progression using the established model of MPS IIIB, the B6.129S6-Naglu(tm1Efn)/J mouse line. Electroretinogram (ERG) was recorded from MPS IIIB and wild-type (WT) mice at the age of 28 and 46 weeks, and retinal tissues were subsequently collected for immunohistochemistry analysis. At the 28th week, rod a- and b-wave amplitudes were significantly diminished in MPS IIIB compared to WT mice. The cone a- and b-waves of MPS IIIB mice were not significantly different from those of the control at the 28th week but were significantly diminished at the 46th week, when MPS IIIB mice showed a major loss of rods and rod bipolar cells in both central and peripheral regions and a minor loss of cones in the periphery. Activation of microglia and neovascularization were also detected in the MPS IIIB retina. The new findings that cones and rod bipolar cells also undergo degeneration, and that retinal microglia are activated, will inform future development of therapeutic strategies.
Highlights
Mucopolysaccharidoses (MPS) are part of the lysosomal storage disease family, a large group of more than 50 clinically recognized conditions resulting from genetic defects of metabolism affecting lysosomes[1,2]
The differences between groups were significant at the 4 highest stimulus levels (Fig. 3a), indicating that rod function was adversely affected in the MPS IIIB mice
A-wave amplitudes in the MPS IIIB group decreased with time, while the same parameters in the WT group remained relatively stable over time
Summary
Mucopolysaccharidoses (MPS) are part of the lysosomal storage disease family, a large group of more than 50 clinically recognized conditions resulting from genetic defects of metabolism affecting lysosomes[1,2]. In MPS Type III (MPS III), or Sanfilippo syndrome, one of the four enzymes needed to degrade the GAG heparan sulfate (HS) is deficient. Complicated by the wide spectrum of clinical phenotypes, disease severity and numerous polymorphisms[14,15], the four MPS III subtypes display extensive overlaps from a clinical standpoint[16], except that type A has earlier onset, faster progression and shorter lifespan[17]. Visual impairment is common in most types of MPS, including MPS III20. In contrast to MPS I, changes in the anterior eye usually do not impair vision in MPS III21. The natural time course of visual impairment for MPS III is largely unknown because visual testing is extremely difficult in young patients due to behavior problems and cognitive impairment. Available data are limited and are usually in the form of isolated case studies or series
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