{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T03:54:25Z","timestamp":1783569265095,"version":"3.55.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T00:00:00Z","timestamp":1660262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006668","name":"Fondo para la Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006668","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010442","name":"Universidad Nacional de C\u00f3rdoba","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010442","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005468","name":"Batten Disease Support and Research Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005468","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Neuronal ceroid lipofuscinoses (NCLs) comprise 13 hereditary neurodegenerative pathologies of very low frequency that affect individuals of all ages around the world. All NCLs share a set of symptoms that are similar to other diseases. The exhaustive collection of data from diverse sources (clinical, genetic, neurology, ophthalmology, etc.) would allow being able in the future to define this group with greater precision for a more efficient diagnostic and therapeutic approach. Despite the large amount of information worldwide, a detailed study of the characteristics of the NCLs in South America and the Caribbean region (SA&amp;amp;C) has not yet been done. Here, we aim to present and analyse the multidisciplinary evidence from all the SA&amp;amp;C with qualitative weighting and biostatistical evaluation of the casuistry. Seventy-one publications from seven countries were reviewed, and data from 261 individuals (including 44 individuals from the Cordoba cohort) were collected. Each NCL disease, as well as phenotypical and genetic data were described and discussed in the whole group. The CLN2, CLN6, and CLN3 disorders are the most frequent in the region. Eighty-seven percent of the individuals were 10 years old or less at the onset of symptoms. Seizures were the most common symptom, both at onset (51%) and throughout the disease course, followed by language (16%), motor (15%), and visual impairments (11%). Although symptoms were similar in all NCLs, some chronological differences could be observed. Sixty DNA variants were described, ranging from single nucleotide variants to large chromosomal deletions. The diagnostic odyssey was probably substantially decreased after medical education activities promoted by the pharmaceutical industry and parent organizations in some SA&amp;amp;C countries. There is a statistical deviation in the data probably due to the approval of the enzyme replacement therapy for CLN2 disease, which has led to a greater interest among the medical community for the early description of this pathology. As a general conclusion, it became clear in this work that the combined bibliographical\/retrospective evaluation approach allowed a general overview of the multidisciplinary components and the epidemiological tendencies of NCLs in the SA&amp;amp;C region.<\/jats:p>","DOI":"10.3389\/fneur.2022.920421","type":"journal-article","created":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T07:15:40Z","timestamp":1660288540000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Neuronal ceroid lipofuscinosis in the South American-Caribbean region: An epidemiological overview"],"prefix":"10.3389","volume":"13","author":[{"given":"Guillermo","family":"Guelbert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Clara","family":"Venier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines Adriana","family":"Cismondi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Becerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Vazquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elmer Andr\u00e9s","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Luc\u00eda","family":"De Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norberto","family":"Guelbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Noher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Favio","family":"Pesaola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jnen\/62.1.1","article-title":"The neuronal ceroid-lipofuscinoses","volume":"62","author":"Haltia","year":"2003","journal-title":"J Neuropathol Exp Neurol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1212\/WNL.0000000000002943","article-title":"Diagnosis and misdiagnosis of adult neuronal ceroid lipofuscinosis (Kufs disease)","volume":"87","author":"Berkovic","year":"2016","journal-title":"Neurology."},{"key":"B3","doi-asserted-by":"publisher","first-page":"754045","DOI":"10.3389\/fneur.2021.754045","article-title":"The genetic basis of phenotypic heterogeneity in the neuronal ceroid lipofuscinoses","volume":"12","author":"Gardner","year":"2021","journal-title":"Front Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1136\/jmg.31.3.177","article-title":"Northern epilepsy syndrome: an inherited childhood onset epilepsy with associated mental deterioration","volume":"31","author":"Hirvasniemi","year":"1994","journal-title":"J Med Genet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1006\/GENO.1994.1168","article-title":"A variant form of late infantile neuronal ceroid lipofuscinosis (CLN5) is not an allelic form of batten (Spielmeyer-Vogt-Sj\u00f6gren, CLN3) disease: exclusion of linkage to the CLN3 region of chromosome 16","volume":"20","author":"Williams","year":"1994","journal-title":"Genomics."},{"key":"B6","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/0022-510X(78)90087-4","article-title":"Early-juvenile batten's disease\u2013a recognisable sub-group distinct from other forms of Batten's disease. Analysis of 5 patients","volume":"36","author":"Lake","year":"1978","journal-title":"J Neurol Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/S0887-8994(01)00284-3","article-title":"Serial MRI findings in the costa rican variant of neuronal ceroid-lipofuscinosis","volume":"25","author":"Pe\u00f1a","year":"2001","journal-title":"Pediatric Neurol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1002\/humu.10227","article-title":"Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis","volume":"22","author":"Sharp","year":"2003","journal-title":"Hum Mutat."},{"key":"B9","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/S1090-3798(97)80041-4","article-title":"Neuronal ceroid lipofuscinosis in the Czech Republic: analysis of 57 cases","volume":"1","author":"Elleder","year":"1997"},{"key":"B10","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1006\/mgme.1999.2804","article-title":"A new locus for variant late infantile neuronal ceroid lipofuscinosis-CLN7","volume":"66","author":"Wheeler","year":"1999","journal-title":"Mol Genet Metab."},{"key":"B11","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1111\/jpc.15250","article-title":"Revealing the clinical phenotype of atypical neuronal ceroid lipofuscinosis type 2 disease: Insights from the largest cohort in the world","volume":"57","author":"Louren\u00e7o","year":"2020","journal-title":"J Paediatr Child Health"},{"key":"B12","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/S2352-4642(18)30179-2","article-title":"Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study","volume":"2","author":"Nickel","year":"2018","journal-title":"Lancet Child Adol Health."},{"key":"B13","doi-asserted-by":"publisher","first-page":"785841","DOI":"10.3389\/FNEUR.2022.785841","article-title":"Natural history studies in NCL and their expanding role in drug development: experiences from CLN2 disease and relevance for clinical trials","volume":"13","author":"Nickel","year":"2022","journal-title":"Front Neurol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2316","DOI":"10.1016\/j.bbadis.2015.06.018","article-title":"Guidelines for incorporating scientific knowledge and practice on rare diseases into higher education: neuronal ceroid lipofuscinoses as a model disorder","volume":"1852","author":"Cismondi","year":"2015","journal-title":"Biochim Biophys Acta."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e20210009","DOI":"10.1590\/2326-4594-jiems-2021-0009","article-title":"\u201cAtypical\u201d phenotypes of neuronal ceroid lipofuscinosis: the argentine experience in the genomic era","volume":"9","author":"Pesaola","year":"2021","journal-title":"J Inborn Errors Metab Screen."},{"key":"B16","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1002\/ajmg.1320570207","article-title":"Childhood neuronal ceroid-lipofuscinoses in Argentina","volume":"57","author":"Taratuto","year":"1995","journal-title":"Am J Med Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1590\/S0004-282X1997000500016","article-title":"Estudo por microscopia eletr\u00f4nica em doen\u00e7as neurodegenerativas na inf\u00e2ncia","volume":"55","author":"Torres","year":"1997","journal-title":"Arquiv Neuro Psiquiatria."},{"key":"B18","doi-asserted-by":"publisher","first-page":"42","DOI":"10.33588\/rn.3801.2003300","article-title":"Characterization of neuronal ceroid lipofuscinosis in venezuelan children","volume":"38","author":"Pe\u00f1a","year":"2004","journal-title":"Rev Neurol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1590\/S0004-282X2000000400001","article-title":"Neuronal ceroid lipofuscinoses: a clinical and morphological study of 17 patients from Southern Brazil","volume":"58","author":"Puga","year":"2000","journal-title":"Arquiv Neuro Psiquiatria."},{"key":"B20","doi-asserted-by":"publisher","first-page":"215","DOI":"10.5935\/0004-2749.20170053","article-title":"Retinal function in patients with the neuronal ceroid lipofuscinosis phenotype","volume":"80","author":"Quagliato","year":"2017","journal-title":"Arquiv Brasil Oftalmol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1590\/s0004-282x1998000300013","article-title":"Diagnosis of metabolic diseases of the nervous system in children through ultrastructural analysis of non cerebral tissue","volume":"56","author":"Rosemberg","year":"1998","journal-title":"Arquiv Neuro Psiquiatria."},{"key":"B22","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1590\/s0004-282x2005000100017","article-title":"Pitfalls in the clinical and electroencephalographic diagnosis of ceroid lipofuscinosis","volume":"63","author":"Vasques","year":"2005","journal-title":"Arquiv Neuro Psiquiatr."},{"key":"B23","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1590\/s0004-282x2007000200025","article-title":"Neuronal ceroid lipofuscinosis: clinical and neuroradiological findings","volume":"65","author":"Gama","year":"2007","journal-title":"Arquiv Neuro Psiquiatr."},{"key":"B24","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1212\/WNL.0b013e31825f0547","article-title":"New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses","volume":"79","author":"Williams","year":"2012","journal-title":"Neurology."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1002\/MDS.22996","article-title":"Clinical spectrum of Kufor-Rakeb syndrome in the chilean kindred with ATP13A2 mutations","volume":"25","author":"Behrens","year":"2010","journal-title":"Mov Disord."},{"key":"B26","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/S13023-021-02162-Z","article-title":"Neuronal ceroid lipofuscinosis type 6 (CLN6) clinical findings and molecular diagnosis: costa rica's experience","volume":"17","author":"Badilla-Porras","year":"2022","journal-title":"Orphanet J Rare Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"155","DOI":"10.33588\/rn.6804.2018217","article-title":"Congenital CLN8 disease of neuronal ceroid lipofuscinosis: a novel phenotype","volume":"68","author":"Pesaola","year":"2019","journal-title":"Rev Neurol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1002\/mgg3.263","article-title":"CLN8 disease caused by large genomic deletions","volume":"5","author":"Beesley","year":"2017","journal-title":"Mol Genet Genomic Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e3","DOI":"10.1111\/ene.13194","article-title":"A new phenotype associated with homozygous GRN mutations: complicated spastic paraplegia","volume":"24","author":"Faber","year":"2017","journal-title":"Eur J Neurol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1212\/01.WNL.0000260963.08711.08","article-title":"ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease","volume":"68","author":"di Fonzo","year":"2007","journal-title":"Neurology."},{"key":"B31","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/J.PARKRELDIS.2020.10.004","article-title":"Intermediate phenotype of ATP13A2 mutation in two chilean siblings: towards a continuum between parkinsonism and hereditary spastic paraplegia","volume":"81","author":"Miranda","year":"2020","journal-title":"Parkinsonism Relat Disord."},{"key":"B32","doi-asserted-by":"publisher","first-page":"811686","DOI":"10.3389\/FNEUR.2022.811686","article-title":"Neuronal ceroid lipofuscinosis: the multifaceted approach to the clinical issues, an overview","volume":"13","author":"Simonati","year":"2022","journal-title":"Front Neurol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"100718","DOI":"10.1016\/J.YMGMR.2021.100718","article-title":"Real world effectiveness of cerliponase alfa in classical and atypical patients. A case series","volume":"27","author":"Espitia Segura","year":"2021","journal-title":"Mol Genet Metab Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ymgme.2019.11.094","article-title":"Atypical neuronal ceroid lipofuscinosis type 2 (CLN2 disease): a case report. WORLD SymposiumTM 2020","volume":"129","author":"Curiati Mendes","year":"2020","journal-title":"Mol Genet Metab."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e20200010","DOI":"10.1590\/2326-4594-jiems-2020-0010","article-title":"A case report on the challenging diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2)","volume":"8","author":"Nunes","year":"2020","journal-title":"J Inborn Errors Metab Screen."},{"key":"B36","first-page":"33","article-title":"Lipofuscinosis ceroidea neuronal infantil tard\u00eda (Jansky- Bielchowsky). Estudio de casos","volume":"41","author":"Ortiz","year":"2014","journal-title":"Pediatr"},{"key":"B37","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1212\/01.WNL.0000151974.44980.F1","article-title":"A CLN5 mutation causing an atypical neuronal ceroid lipofuscinosis of juvenile onset","volume":"64","author":"Pineda-Trujillo","year":"2005","journal-title":"Neurology."},{"key":"B38","doi-asserted-by":"publisher","first-page":"368","DOI":"10.33588\/RN.7310.2021174","article-title":"Neuronal ceroid lipofuscinosis. Type 6 late infantile variant in two compound heterozygous siblings with novel mutations","volume":"73","author":"Bravo Oro","year":"2021","journal-title":"Rev Neurol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"197","DOI":"10.22379\/24224022388","article-title":"Lipofuscinosis ceroidea neuronal 6 (enfermedad Kufs tipo A): Reporte de caso en Colombia","volume":"37","author":"Gonz\u00e1lez Pab\u00f3n","year":"2021","journal-title":"Acta Neurol Colomb."},{"key":"B40","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.ymgme.2007.08.124","article-title":"CLN2\/TPP1 deficiency: the novel mutation IVS7-10A>G causes intron retention and is associated with a mild disease phenotype","volume":"93","author":"Bessa","year":"2008","journal-title":"Mol Genet Metab."},{"key":"B41","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1590\/s0004-282x2011000100004","article-title":"Juvenile neuronal ceroid-lipofuscinosis: clinical and molecular investigation in a large family in Brazil","volume":"69","author":"Valadares","year":"2011","journal-title":"Arq Neuropsiquiatr."},{"key":"B42","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/j.clinbiochem.2004.12.007","article-title":"Palmitoyl protein thioesterase1 (PPT1) and tripeptidyl peptidase-I (TPP-I) are expressed in the human saliva. A reliable and non-invasive source for the diagnosis of infantile (CLN1) and late infantile (CLN2) neuronal ceroid lipofuscinoses","volume":"38","author":"Kohan","year":"2005","journal-title":"Clin Biochem."},{"key":"B44","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1373\/49.3.509","article-title":"Rapid and simple assay for the determination of tripeptidyl peptidase and palmitoyl protein thioesterase activities in dried blood spots","volume":"49","author":"Lukacs","year":"2003","journal-title":"Clin Chem."},{"key":"B45","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1053\/ejpn.2001.0509","article-title":"Pre- and postnatal enzyme analysis for infantile, late infantile and adult neuronal ceroid lipofuscinosis (CLN1 and CLN2)","volume":"5","author":"van Diggelen","year":"2001","journal-title":"Eur J Paediatr Neurol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1038\/s41556-018-0228-7","article-title":"CLN8 is an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis","volume":"20","author":"di Ronza","year":"2018","journal-title":"Nat Cell Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"930235","DOI":"10.3389\/FCELL.2022.930235","article-title":"Mfsd8 modulates growth and the early stages of multicellular development in dictyostelium discoideum","volume":"10","author":"Yap","year":"2022","journal-title":"Front Cell Dev Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.3390\/BIOM11101412","article-title":"Deficiency of the lysosomal protein CLN5 alters lysosomal function and movement","volume":"11","author":"Basak","year":"2021","journal-title":"Biomolecules."},{"key":"B49","doi-asserted-by":"publisher","first-page":"4118","DOI":"10.1172\/jci130955","article-title":"A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for golgi transfer","volume":"130","author":"Bajaj","year":"2020","journal-title":"J Clin Invest"},{"key":"B50","doi-asserted-by":"publisher","first-page":"2300","DOI":"10.1016\/j.bbadis.2015.05.003","article-title":"The neuronal ceroid lipofuscinoses program: a translational research experience in Argentina","volume":"1852","author":"Kohan","year":"2015","journal-title":"Biochim Biophys Acta."},{"key":"B51","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.gene.2012.12.058","article-title":"Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America","volume":"516","author":"Kohan","year":"2013","journal-title":"Gene."},{"key":"B52","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1086\/338190","article-title":"Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse","volume":"70","author":"Gao","year":"2002","journal-title":"Am J Hum Genet."},{"key":"B53","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 Human Genet."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.920421\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T07:15:47Z","timestamp":1660288547000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.920421\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,12]]},"references-count":53,"alternative-id":["10.3389\/fneur.2022.920421"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2022.920421","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,12]]},"article-number":"920421"}}