Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Abstract

The mucopolysaccharidoses (MPS) are a group of diseases caused by the lysosomal accumulation of glycosaminoglycans, due to genetic deficiencies of enzymes involved in their degradation. MPS III or Sanfilippo disease, in particular, is characterized by early-onset severe, progressive neurodegeneration but mild somatic involvement, with patients losing milestones and previously acquired skills as the disease progresses. Despite being the focus of extensive research over the past years, the links between accumulation of the primary molecule, the glycosaminoglycan heparan sulfate, and the neurodegeneration seen in patients have yet to be fully elucidated. This review summarizes the current knowledge on the molecular bases of neurological decline in Sanfilippo disease. It emerges that this deterioration results from the dysregulation of multiple cellular pathways, leading to neuroinflammation, oxidative stress, impaired autophagy and defects in cellular signaling. However, many important questions about the neuropathological mechanisms of the disease remain unanswered, highlighting the need for further research in this area.

Keywords: Sanfilippo syndrome; molecular bases; mucopolysaccharidosis III; neurodegeneration.

Figure 1

Association of grey matter volume and developmental quotient (DQ). A, Change in gray matter volume for the rapid progressing (RP) and slow progressing (SP) groups of MPS IIIA patients by age. B, Association of decline in developmental quotient and gray matter volume for the RP and SP groups. Open circles indicate the imputed values, which are connected with dotted lines (values imputed from slope of previous visits) for 4 patients at the 24-month visit only and for 1 patient at both the 12-month and 24-month visits (figure reproduced from Shapiro et al., 2016 [37], with permission from Elsevier).