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First symptoms typically include delayed language development, hyperactivity and\/or insomnia from 2\u2009years 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\u2009years. Treatments under clinical trial demonstrate therapeutic benefit when applied pre\u2010symptomatically in children diagnosed early through known familial inheritance risk. Newborn screening for Sanfilippo syndrome would enable pre\u2010symptomatic 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\u2010based biomarkers available to provide pre\u2010symptomatic prognosis. There is also a lack of progression and neurocognitive response\u2010to\u2010treatment 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\u2010based 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\u2010derived 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\u2010to\u2010treatment biomarker potential in Sanfilippo syndrome and potentially other childhood dementias.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15891-fig-0002-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15891","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T10:37:17Z","timestamp":1687775837000},"page":"481-496","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Biomarkers for predicting disease course in Sanfilippo syndrome: An urgent unmet need in childhood\u2010onset dementia"],"prefix":"10.1111","volume":"166","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5175-4839","authenticated-orcid":false,"given":"Leanne K.","family":"Winner","sequence":"first","affiliation":[{"name":"Childhood Dementia Research Group, FHMRI Flinders University  Bedford Park South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3482-8741","authenticated-orcid":false,"given":"Mary\u2010Louise","family":"Rogers","sequence":"additional","affiliation":[{"name":"Motor Neurone Disease and Neurotrophic Research Lab, FHMRI Flinders University  Bedford Park South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8502-7274","authenticated-orcid":false,"given":"Marten F.","family":"Snel","sequence":"additional","affiliation":[{"name":"Proteomics, Metabolomics and MS\u2010Imaging Facility, SAHMRI  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-9884","authenticated-orcid":false,"given":"Kim M.","family":"Hemsley","sequence":"additional","affiliation":[{"name":"Childhood Dementia Research Group, FHMRI Flinders University  Bedford Park South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,6,26]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002296"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51234"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478\u2010020\u201001070\u2010w"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2017.06.010"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac394"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010004\u20100368\u20105"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21155188"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2018.08.003"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12816"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2022.08.017"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399\u20100004.2010.01525.x"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195\u2010021\u201000804\u20109"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2022.01.005"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.05.079"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3558\u201004.2004"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep46576"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2016.05.015"},{"key":"e_1_2_13_19_1","unstructured":"ESTEVE. 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