Biomarkers for predicting disease course in Sanfilippo syndrome: An urgent unmet need in childhood-onset dementia

Abstract

Sanfilippo syndrome (MPS III) is an autosomal recessive inherited disorder causing dementia in children, following an essentially normal early developmental period. First symptoms typically include delayed language development, hyperactivity and/or insomnia from 2 years of age, followed by unremitting and overt loss of previously acquired skills. There are no approved treatments, and the median age of death is 18 years. Treatments under clinical trial demonstrate therapeutic benefit when applied pre-symptomatically in children diagnosed early through known familial inheritance risk. Newborn screening for Sanfilippo syndrome would enable pre-symptomatic diagnosis and optimal therapeutic benefit, however, many fold more patients with Sanfilippo syndrome are expected to be identified in the population than present with childhood dementia. Therefore, the capacity to stratify which Sanfilippo infants will need treatment in toddlerhood is necessary. While diagnostic methods have been developed, and continue to be refined, currently there are no tools or laboratory-based biomarkers available to provide pre-symptomatic prognosis. There is also a lack of progression and neurocognitive response-to-treatment biomarkers; disease stage and rate of progression are currently determined by age at symptom onset, loss of cerebral grey matter volume by magnetic resonance imaging and developmental quotient score for age. Robust blood-based biomarkers are an urgent unmet need. In this review, we discuss the development of biomarker assays for Sanfilippo based on the neuropathological pathways known to change leading into symptom onset and progression, and their performance as biomarkers in other neurodegenerative diseases. We propose that neural-derived exosomes extracted from blood may provide an ideal liquid biopsy to detect reductions in synaptic protein availability, and mitochondrial function. Furthermore, given the prominent role of neuroinflammation in symptom expression, glial fibrillary acidic protein detection in plasma/serum, alongside measurement of active brain atrophy by neurofilament light chain, warrant increased investigation for prognostic, progression and neurocognitive response-to-treatment biomarker potential in Sanfilippo syndrome and potentially other childhood dementias.

Keywords: MPS III; Sanfilippo; biomarker; childhood dementia; lysosomal storage disease; prognostic.