{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:48:30Z","timestamp":1790999310995,"version":"4.1.0"},"reference-count":85,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,18]],"date-time":"2021-10-18T00:00:00Z","timestamp":1634515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults. They share some similar clinical features and the accumulation of autofluorescent storage material. Since the discovery of the first causative genes, more than 530 mutations have been identified across 13 genes in cases diagnosed with NCL. These genes encode a variety of proteins whose functions have not been fully defined; most are lysosomal enzymes, or transmembrane proteins of the lysosome or other organelles. Many mutations in these genes are associated with a typical NCL disease phenotype. However, increasing numbers of variant disease phenotypes are being described, affecting age of onset, severity or progression, and including some distinct clinical phenotypes. This data is collated by the NCL Mutation Database which allows analysis from many perspectives. This article will summarise and interpret current knowledge and understanding of their genetic basis and phenotypic heterogeneity.<\/jats:p>","DOI":"10.3389\/fneur.2021.754045","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T18:44:35Z","timestamp":1634755475000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":71,"title":["The Genetic Basis of Phenotypic Heterogeneity in the Neuronal Ceroid Lipofuscinoses"],"prefix":"10.3389","volume":"12","author":[{"given":"Emily","family":"Gardner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara E.","family":"Mole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2237","DOI":"10.1016\/j.bbadis.2015.05.011","article-title":"Genetics of the neuronal ceroid lipofuscinoses (Batten disease)","volume":"1852","author":"Mole","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"B2","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1542\/peds.44.4.570","article-title":"Neuronal ceroid-lipofuscinosis (Batten's disease): relationship to amaurotic familial idiocy?","volume":"44","author":"Zeman","year":"1969","journal-title":"Pediatrics."},{"key":"B3","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.ajhg.2011.07.003","article-title":"Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis","volume":"89","author":"Noskova","year":"2011","journal-title":"Am J Hum Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1038\/376584a0","article-title":"Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis","volume":"376","author":"Vesa","year":"1995","journal-title":"Nature."},{"key":"B5","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1016\/0092-8674(95)90274-0","article-title":"Isolation of a novel gene underlying batten disease, CLN3","volume":"82","author":"Consortium","year":"1995","journal-title":"Cell."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1126\/science.277.5333.1802","article-title":"Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis","volume":"277","author":"Sleat","year":"1997","journal-title":"Science."},{"key":"B7","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1038\/975","article-title":"CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis","volume":"19","author":"Savukoski","year":"1998","journal-title":"Nat Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1086\/338708","article-title":"The gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel predicted transmembrane protein","volume":"70","author":"Wheeler","year":"2002","journal-title":"Am J Hum Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1086\/518902","article-title":"The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter","volume":"81","author":"Siintola","year":"2007","journal-title":"Am J Hum Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/13868","article-title":"The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8","volume":"23","author":"Ranta","year":"1999","journal-title":"Nat Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1438","DOI":"10.1093\/brain\/awl107","article-title":"Cathepsin D deficiency underlies congenital human neuronal ceroid lipofuscinosis","volume":"129","author":"Siintola","year":"2006","journal-title":"Brain."},{"key":"B12","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1086\/504159","article-title":"Cathepsin D deficiency is associated with a human neurodegenerative disorder","volume":"78","author":"Steinfeld","year":"2006","journal-title":"Am J Hum Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1016\/j.ajhg.2012.04.021","article-title":"Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage","volume":"90","author":"Smith","year":"2012","journal-title":"Am J Hum Genet"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2646","DOI":"10.1093\/hmg\/dds089","article-title":"Guerreiro RJ. 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