{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:36:28Z","timestamp":1785152188451,"version":"3.55.0"},"reference-count":30,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T00:00:00Z","timestamp":1659657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Triangle Research and Development Center (TRDC)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The CLN8 disease type refers to one of the neuronal ceroid lipofuscinoses (NCLs) which are the most common group of neurodegenerative diseases in childhood. The clinical phenotypes of this disease are progressive neurological deterioration that could lead to seizures, dementia, ataxia, visual failure, and various forms of abnormal movement. In the current study, we describe two patients who presented with atypical phenotypic manifestation and protracted clinical course of CLN8 carrying a novel compound heterozygous variant at the CLN8 gene. Our patients developed a mild phenotype of CLN8 disease: as they presented mild epilepsy, cognitive decline, mild learning disability, attention-deficit\/hyperactivity disorder (ADHD), they developed a markedly protracted course of motor decline. Bioinformatic analyses of the compound heterozygous CLN8 gene variants were carried out. Most of the variants seem likely to act by compromising the structural integrity of regions within the protein. This in turn is expected to reduce the overall stability of the protein and render the protein less active to various degrees. The cases in our study confirmed and expanded the effect of compound heterozygous variants in CLN8 disease.<\/jats:p>","DOI":"10.3390\/genes13081393","type":"journal-article","created":{"date-parts":[[2022,8,7]],"date-time":"2022-08-07T22:51:46Z","timestamp":1659912706000},"page":"1393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["CLN8 Gene Compound Heterozygous Variants: A New Case and Protein Bioinformatics Analyses"],"prefix":"10.3390","volume":"13","author":[{"given":"Rajech","family":"Sharkia","sequence":"first","affiliation":[{"name":"Unit of Human Biology and Genetics, The Triangle Regional Research and Development Center, Kafr Qara 30075, Israel"},{"name":"Beit-Berl Academic College, Beit-Berl 4490500, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4776-0675","authenticated-orcid":false,"given":"Abdelnaser","family":"Zalan","sequence":"additional","affiliation":[{"name":"Unit of Human Biology and Genetics, The Triangle Regional Research and Development Center, Kafr Qara 30075, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazar","family":"Zahalka","sequence":"additional","affiliation":[{"name":"Child Neurology and Development Center, Hillel-Yaffe Medical Center, Hadera 38100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0227-0226","authenticated-orcid":false,"given":"Amit","family":"Kessel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8868-2752","authenticated-orcid":false,"given":"Ayman","family":"Asaly","sequence":"additional","affiliation":[{"name":"Pediatrics Department, Hillel-Yaffe Medical Center, Hadera 38100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wasif","family":"Al-Shareef","sequence":"additional","affiliation":[{"name":"Unit of Human Biology and Genetics, The Triangle Regional Research and Development Center, Kafr Qara 30075, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Mahajnah","sequence":"additional","affiliation":[{"name":"Child Neurology and Development Center, Hillel-Yaffe Medical Center, Hadera 38100, Israel"},{"name":"Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"812728","DOI":"10.3389\/fcell.2022.812728","article-title":"Autophagy in the Neuronal Ceroid Lipofuscinoses (Batten Disease)","volume":"10","author":"Kim","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1002\/ajmg.10660","article-title":"Late Infantile Neuronal Ceroid Lipofuscinosis: Quantitative Description of the Clinical Course in Patients with CLN2 Mutations","volume":"112","author":"Steinfeld","year":"2002","journal-title":"Am. J. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1016\/j.bbadis.2013.03.017","article-title":"Genetic Basis and Phenotypic Correlations of the Neuronal Ceroid Lipofusinoses","volume":"1832","author":"Warrier","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s10048-010-0258-1","article-title":"A Novel CLN2\/TPP1 Mutation in a Chinese Patient with Late Infantile Neuronal Ceroid Lipofuscinosis","volume":"12","author":"Wang","year":"2011","journal-title":"Neurogenetics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.braindev.2011.12.005","article-title":"Clinical Study in Chinese Patients with Late-Infantile Form Neuronal Ceroid Lipofuscinoses","volume":"34","author":"Chang","year":"2012","journal-title":"Brain Dev."},{"key":"ref_6","doi-asserted-by":"crossref","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":"ref_7","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1080\/21678707.2019.1684258","article-title":"Advances in the Treatment of Neuronal Ceroid Lipofuscinosis","volume":"7","author":"Rosenberg","year":"2019","journal-title":"Expert Opin. Orphan Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s40263-019-00620-8","article-title":"Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses","volume":"33","author":"Schulz","year":"2019","journal-title":"CNS Drugs"},{"key":"ref_9","doi-asserted-by":"crossref","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":"ref_10","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.pediatrneurol.2007.01.008","article-title":"A Novel Mutation of the CLN8 Gene: Is There a Mediterranean Phenotype?","volume":"36","author":"Zelnik","year":"2007","journal-title":"Pediatr. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1002\/humu.21012","article-title":"A Novel CLN8 Mutation in Late-Infantile-Onset Neuronal Ceroid Lipofuscinosis (LINCL) Reveals Aspects of CLN8 Neurobiological Function","volume":"30","author":"Vantaggiato","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Badura-Stronka, M., Winczewska-Wiktor, A., Pietrzak, A., Hirschfeld, A.S., Zemojtel, T., Wo\u0142y\u0144ska, K., Bednarek-Rajewska, K., Seget-Dubaniewicz, M., Matheisel, A., and Latos-Bielenska, A. (2021). CLN8 Mutations Presenting with a Phenotypic Continuum of Neuronal Ceroid Lipofuscinosis-Literature Review and Case Report. Genes, 12.","DOI":"10.3390\/genes12070956"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/humu.21624","article-title":"Update of the Mutation Spectrum and Clinical Correlations of over 360 Mutations in Eight Genes That Underlie the Neuronal Ceroid Lipofuscinoses","volume":"33","author":"Kousi","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.bbamcr.2008.11.004","article-title":"Neuronal Ceroid Lipofuscinoses","volume":"1793","author":"Jalanko","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S0968-0004(02)02154-0","article-title":"TRAM, LAG1 and CLN8: Members of a Novel Family of Lipid-Sensing Domains?","volume":"27","author":"Winter","year":"2002","journal-title":"Trends Biochem. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.pediatrneurol.2012.05.016","article-title":"Phenotypic Heterogeneity in Consanguineous Patients with a Common CLN8 Mutation","volume":"47","author":"Mahajnah","year":"2012","journal-title":"Pediatr. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly Accurate Protein Structure Prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41586-021-03828-1","article-title":"Highly Accurate Protein Structure Prediction for the Human Proteome","volume":"596","author":"Tunyasuvunakool","year":"2021","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"W314","DOI":"10.1093\/nar\/gku411","article-title":"DUET: A Server for Predicting Effects of Mutations on Protein Stability Using an Integrated Computational Approach","volume":"42","author":"Pires","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"W344","DOI":"10.1093\/nar\/gkw408","article-title":"ConSurf 2016: An Improved Methodology to Estimate and Visualize Evolutionary Conservation in Macromolecules","volume":"44","author":"Ashkenazy","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1107\/S0907444998009378","article-title":"Protein Data Bank (PDB): Database of Three-Dimensional Structural Information of Biological Macromolecules","volume":"54","author":"Sussman","year":"1998","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/978-1-0716-0270-6_3","article-title":"Using Dali for Protein Structure Comparison","volume":"2112","author":"Holm","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1053\/ejpn.2000.0429","article-title":"Turkish Variant Late Infantile Neuronal Ceroid Lipofuscinosis (CLN7) May Be Allelic to CLN8","volume":"5","author":"Mitchell","year":"2001","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s10048-005-0024-y","article-title":"Novel Mutations in CLN8 in Italian Variant Late Infantile Neuronal Ceroid Lipofuscinosis: Another Genetic Hit in the Mediterranean","volume":"7","author":"Cannelli","year":"2006","journal-title":"Neurogenetics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1111\/j.1399-0004.2011.01777.x","article-title":"Variant Late-Infantile Neuronal Ceroid Lipofuscinosis Due to a Novel Heterozygous CLN8 Mutation and de Novo 8p23.3 Deletion","volume":"81","author":"Allen","year":"2012","journal-title":"Clin. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","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. Genom. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ajoc.2016.07.005","article-title":"Atypical Presentation of Neuronal Ceroid Lipofuscinosis Type 8 in a Sibling Pair and Review of the Eye Findings and Neurological Features","volume":"4","author":"Sanchez","year":"2016","journal-title":"Am. J. Ophthalmol. Case Rep."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gao, Z., Xie, H., Jiang, Q., Wu, N., Chen, X., and Chen, Q. (2018). Identification of Two Novel Null Variants in CLN8 by Targeted Next-Generation Sequencing: First Report of a Chinese Patient with Neuronal Ceroid Lipofuscinosis Due to CLN8 Variants. BMC Med. Genet., 19.","DOI":"10.1186\/s12881-018-0535-7"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Sharkia, R., Khatib, M., Sheikh-Muhammad, A., Mahajnah, M., and Zalan, A. (2021). The Prevailing Trend of Consanguinity in the Arab Society of Israel: Is It Still a Challenge?. J. Biosoc. Sci., 1\u20135.","DOI":"10.1017\/S0021932021000675"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"66","DOI":"10.34297\/AJBSR.2021.15.002071","article-title":"Consanguinity Status in the Arab Society of Israel: Is It Different?","volume":"15","author":"Zalan","year":"2021","journal-title":"AJBSR"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/8\/1393\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:04:33Z","timestamp":1760141073000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/8\/1393"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,5]]},"references-count":30,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["genes13081393"],"URL":"https:\/\/doi.org\/10.3390\/genes13081393","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,5]]}}}