{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T07:33:14Z","timestamp":1770967994208,"version":"3.50.1"},"reference-count":110,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T00:00:00Z","timestamp":1647043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P","award":["UIDB\/04293\/2020"],"award-info":[{"award-number":["UIDB\/04293\/2020"]}]},{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P","award":["FCT-ANR\/BEX-GMG\/0008\/2013"],"award-info":[{"award-number":["FCT-ANR\/BEX-GMG\/0008\/2013"]}]},{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P","award":["SFRH\/BPD\/116046\/2016"],"award-info":[{"award-number":["SFRH\/BPD\/116046\/2016"]}]},{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P","award":["DL 57\/2016 - Norma Transit\u00f3ria."],"award-info":[{"award-number":["DL 57\/2016 - Norma Transit\u00f3ria."]}]},{"name":"Norte Portugal Regional Operational Programme (NORTE 2020)","award":["Norte-01-0145-FEDER-000008"],"award-info":[{"award-number":["Norte-01-0145-FEDER-000008"]}]},{"name":"GenomePT","award":["POCI-01-0145-FEDER-022184"],"award-info":[{"award-number":["POCI-01-0145-FEDER-022184"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (SACS and KIF1C) and with ataxia and neuropathy or AOA (PNKP). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in KIF1A, CACNA1A, or ATP1A3, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.<\/jats:p>","DOI":"10.3390\/cells11060981","type":"journal-article","created":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T22:29:43Z","timestamp":1647210583000},"page":"981","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2343-2215","authenticated-orcid":false,"given":"Mariana","family":"Santos","sequence":"first","affiliation":[{"name":"UnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6539-6398","authenticated-orcid":false,"given":"Joana","family":"Dam\u00e1sio","sequence":"additional","affiliation":[{"name":"UnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Neurology Department, Centro Hospitalar Universit\u00e1rio do Porto, 4099-001 Porto, Portugal"},{"name":"CGPP-Centre for Predictive and Preventive Genetics, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susana","family":"Carmona","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0863-158X","authenticated-orcid":false,"given":"Jo\u00e3o Lu\u00eds","family":"Neto","sequence":"additional","affiliation":[{"name":"UnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Dehghani","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9846-1037","authenticated-orcid":false,"given":"Leonor Correia","family":"Guedes","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and Mental Health, Neurology, Hospital de Santa Maria, Centro Hospitalar Universit\u00e1rio Lisboa Norte, 1649-028 Lisbon, Portugal"},{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal"},{"name":"CNS-Campus Neurol\u00f3gico S\u00e9nior, 2560-280 Torres Vedras, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Barbot","sequence":"additional","affiliation":[{"name":"CGPP-Centre for Predictive and Preventive Genetics, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9","family":"Barros","sequence":"additional","affiliation":[{"name":"Neurology Department, Centro Hospitalar Universit\u00e1rio do Porto, 4099-001 Porto, Portugal"},{"name":"ICBAS-School of Medicine and Biomedical Sciences, Universidade do Porto, 4050-313 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9","family":"Br\u00e1s","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA"},{"name":"Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Sequeiros","sequence":"additional","affiliation":[{"name":"UnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"CGPP-Centre for Predictive and Preventive Genetics, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"ICBAS-School of Medicine and Biomedical Sciences, Universidade do Porto, 4050-313 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5879-3486","authenticated-orcid":false,"given":"Rita","family":"Guerreiro","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA"},{"name":"Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1056\/NEJMra1006610","article-title":"The autosomal recessive cerebellar ataxias","volume":"366","author":"Anheim","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1159\/000358801","article-title":"The global epidemiology of hereditary ataxia and spastic paraplegia: A systematic review of prevalence studies","volume":"42","author":"Ruano","year":"2014","journal-title":"Neuroepidemiology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/B978-0-444-51892-7.00014-0","article-title":"Epidemiology and population genetics of degenerative ataxias","volume":"103","author":"Sequeiros","year":"2012","journal-title":"Handb. Clin. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1001\/jamaneurol.2014.1944","article-title":"Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia","volume":"71","author":"Fogel","year":"2014","journal-title":"JAMA Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1038\/ejhg.2016.42","article-title":"Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders","volume":"24","author":"Schouten","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"707","DOI":"10.3389\/fnins.2020.00707","article-title":"Aberrant Cerebellar Circuitry in the Spinocerebellar Ataxias","volume":"14","author":"Robinson","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1136\/jmedgenet-2018-105703","article-title":"Integrative network and brain expression analysis reveals mechanistic modules in ataxia","volume":"56","author":"Eidhof","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1093\/brain\/awl081","article-title":"Molecular pathogenesis of spinocerebellar ataxias","volume":"129","author":"Duenas","year":"2006","journal-title":"Brain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/B978-0-444-63233-3.00013-0","article-title":"Autosomal-recessive cerebellar ataxias","volume":"147","author":"Fogel","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1001\/jamaneurol.2013.1707","article-title":"Hereditary Ataxia and Spastic Paraplegia in Portugal","volume":"70","author":"Coutinho","year":"2013","journal-title":"JAMA Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.ajhg.2015.01.005","article-title":"Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4","volume":"96","author":"Bras","year":"2015","journal-title":"Am. J. Hum. Genet"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Santos, M., Damasio, J., Kun-Rodrigues, C., Barbot, C., Sequeiros, J., Bras, J., Alonso, I., and Guerreiro, R. (2020). Novel MAG Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype. J. Clin. Med., 9.","DOI":"10.3390\/jcm9041212"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/s41588-019-0372-4","article-title":"Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia","volume":"51","author":"Cortese","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_15","first-page":"11.10.11","article-title":"From FastQ data to high confidence variant calls: The Genome Analysis Toolkit best practices pipeline","volume":"43","author":"Carneiro","year":"2013","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1093\/bioinformatics\/btu314","article-title":"SAMBLASTER: Fast duplicate marking and structural variant read extraction","volume":"30","author":"Faust","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"E2393","DOI":"10.1002\/humu.22376","article-title":"dbNSFP v2.0: A database of human non-synonymous SNVs and their functional predictions and annotations","volume":"34","author":"Liu","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1038\/nprot.2015.124","article-title":"Next-generation diagnostics and disease-gene discovery with the Exomiser","volume":"10","author":"Smedley","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: Predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e118","DOI":"10.1093\/nar\/gkr407","article-title":"Predicting the functional impact of protein mutations: Application to cancer genomics","volume":"39","author":"Reva","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/humu.22225","article-title":"Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models","volume":"34","author":"Shihab","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1002\/humu.22965","article-title":"UMD-Predictor: A High-Throughput Sequencing Compliant System for Pathogenicity Prediction of any Human cDNA Substitution","volume":"37","author":"Salgado","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7155","DOI":"10.1093\/nar\/15.17.7155","article-title":"RNA splice junctions of different classes of eukaryotes: Sequence statistics and functional implications in gene expression","volume":"15","author":"Shapiro","year":"1987","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1089\/1066527041410418","article-title":"Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals","volume":"11","author":"Yeo","year":"2004","journal-title":"J. Comput. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1089\/cmb.1997.4.311","article-title":"Improved splice site detection in Genie","volume":"4","author":"Reese","year":"1997","journal-title":"J. Comput. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1093\/nar\/29.5.1185","article-title":"GeneSplicer: A new computational method for splice site prediction","volume":"29","author":"Pertea","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1093\/nar\/gkp215","article-title":"Human Splicing Finder: An online bioinformatics tool to predict splicing signals","volume":"37","author":"Desmet","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","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":"ref_32","doi-asserted-by":"crossref","first-page":"391","DOI":"10.4049\/jimmunol.1400038","article-title":"T cell activation regulates CD6 alternative splicing by transcription dynamics and SRSF1","volume":"193","author":"Leal","year":"2014","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Luo, X., Rosenfeld, J.A., Yamamoto, S., Harel, T., Zuo, Z., Hall, M., Wierenga, K.J., Pastore, M.T., Bartholomew, D., and Delgado, M.R. (2017). Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1006905"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.ajhg.2017.06.007","article-title":"A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia","volume":"101","author":"Seixas","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1001\/jamaneurol.2017.5121","article-title":"Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes","volume":"75","author":"Coutelier","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e30","DOI":"10.1212\/NXG.0000000000000030","article-title":"Mutation in PNKP presenting initially as axonal Charcot-Marie-Tooth disease","volume":"1","author":"Pedroso","year":"2015","journal-title":"Neurol. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0960-8966(02)00216-X","article-title":"Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia","volume":"13","author":"Martin","year":"2003","journal-title":"Neuromuscul. Disord."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1093\/brain\/aww079","article-title":"SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: A large multi-centre study","volume":"139","author":"Synofzik","year":"2016","journal-title":"Brain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1136\/jmedgenet-2013-102012","article-title":"KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction","volume":"51","author":"Dor","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2688","DOI":"10.1093\/brain\/awp211","article-title":"Ataxia with oculomotor apraxia type 2: Clinical, biological and genotype\/phenotype correlation study of a cohort of 90 patients","volume":"132","author":"Anheim","year":"2009","journal-title":"Brain"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/jhg.2015.108","article-title":"De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance","volume":"60","author":"Ohba","year":"2015","journal-title":"J. Hum. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1038\/ejhg.2017.124","article-title":"Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias","volume":"25","author":"Morais","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/humu.22709","article-title":"De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy","volume":"36","author":"Lee","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1136\/jmedgenet-2020-107007","article-title":"Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders","volume":"58","author":"Nicita","year":"2021","journal-title":"J. Med. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"10893","DOI":"10.1074\/jbc.275.15.10893","article-title":"Spinocerebellar ataxia type 6 mutation alters P-type calcium channel function","volume":"275","author":"Toru","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6960","DOI":"10.1074\/jbc.M110948200","article-title":"Functional consequences of P\/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia","volume":"277","author":"Wappl","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1038\/ng.2358","article-title":"De novo mutations in ATP1A3 cause alternating hemiplegia of childhood","volume":"44","author":"Heinzen","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1750-1172-9-15","article-title":"A novel recurrent mutation in ATP1A3 causes CAPOS syndrome","volume":"9","author":"Demos","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41572-019-0074-3","article-title":"Spinocerebellar ataxia","volume":"5","author":"Klockgether","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_50","first-page":"144","article-title":"Clinical phenotypes of infantile onset CACNA1A-related disorder","volume":"30","author":"Berkowitz","year":"2021","journal-title":"Eur. J. Paediatr. Neurol. EJPN Off. J. Eur. Paediatr. Neurol. Soc."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"637890","DOI":"10.3389\/fneur.2021.637890","article-title":"ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum","volume":"12","author":"Salles","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1002\/mds.25396","article-title":"The multiple faces of the ATP1A3-related dystonic movement disorder","volume":"28","author":"Roubergue","year":"2013","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/B978-0-444-64189-2.00012-3","article-title":"Spastic ataxias","volume":"155","author":"Bereznyakova","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1212\/WNL.0b013e31826d5fb0","article-title":"Reviewing the genetic causes of spastic-ataxias","volume":"79","author":"Willemsen","year":"2012","journal-title":"Neurology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1093\/hmg\/ddp067","article-title":"The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1","volume":"18","author":"Parfitt","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1073\/pnas.1113166109","article-title":"Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)","volume":"109","author":"Girard","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1093\/hmg\/ddu491","article-title":"Sacs knockout mice present pathophysiological defects underlying autosomal recessive spastic ataxia of Charlevoix-Saguenay","volume":"24","author":"Lariviere","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13041-019-0438-3","article-title":"Sacs R272C missense homozygous mice develop an ataxia phenotype","volume":"12","author":"Lariviere","year":"2019","journal-title":"Mol. Brain"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e2315","DOI":"10.1212\/WNL.0000000000012962","article-title":"Assessment of Sacsin Turnover in Patients With ARSACS: Implications for Molecular Diagnosis and Pathogenesis","volume":"97","author":"Longo","year":"2021","journal-title":"Neurology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.parkreldis.2011.03.005","article-title":"Autosomal recessive spastic ataxia of Charlevoix-Saguenay: An overview","volume":"17","author":"Bouhlal","year":"2011","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3389\/fncel.2019.00419","article-title":"Going Too Far Is the Same as Falling Short(dagger): Kinesin-3 Family Members in Hereditary Spastic Paraplegia","volume":"13","author":"Gabrych","year":"2019","journal-title":"Front. Cell Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1212\/WNL.0000000000000479","article-title":"Motor protein mutations cause a new form of hereditary spastic paraplegia","volume":"82","author":"Battaloglu","year":"2014","journal-title":"Neurology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1007\/s00415-016-8254-5","article-title":"Severe axonal neuropathy is a late manifestation of SPG11","volume":"263","author":"Manole","year":"2016","journal-title":"J. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/acn3.64","article-title":"Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11","volume":"1","author":"Renvoise","year":"2014","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4859","DOI":"10.1093\/hmg\/ddu200","article-title":"Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia","volume":"23","author":"Mishra","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"31986","DOI":"10.1074\/jbc.M004775200","article-title":"Syne-1, a dystrophin- and Klarsicht-related protein associated with synaptic nuclei at the neuromuscular junction","volume":"275","author":"Apel","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/ng1927","article-title":"Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia","volume":"39","author":"Dupre","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"17052","DOI":"10.1038\/hgv.2017.52","article-title":"A novel frameshift mutation of SYNE1 in a Japanese family with autosomal recessive cerebellar ataxia type 8","volume":"4","author":"Yoshinaga","year":"2017","journal-title":"Hum. Genome Var."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.nbd.2015.03.027","article-title":"A variant of Nesprin1 giant devoid of KASH domain underlies the molecular etiology of autosomal recessive cerebellar ataxia type I","volume":"78","author":"Razafsky","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.ajhg.2010.10.015","article-title":"Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia","volume":"87","author":"Vermeer","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1007\/s00415-014-7476-7","article-title":"ANO10 mutations cause ataxia and coenzyme Q(1)(0) deficiency","volume":"261","author":"Balreira","year":"2014","journal-title":"J. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/0006-291X(87)90767-4","article-title":"Evidence for a direct role of the DNA polymerase gamma in the replication of the human mitochondrial DNA in vitro","volume":"146","author":"Lestienne","year":"1987","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1093\/hmg\/ddi196","article-title":"Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome","volume":"14","author":"Luoma","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Schaller, A., Hahn, D., Jackson, C.B., Kern, I., Chardot, C., Belli, D.C., Gallati, S., and Nuoffer, J.M. (2011). Molecular and biochemical characterisation of a novel mutation in POLG associated with Alpers syndrome. BMC Neurol., 11.","DOI":"10.1186\/1471-2377-11-4"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1212\/01.WNL.0000140494.58732.83","article-title":"POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement","volume":"63","author":"Luoma","year":"2004","journal-title":"Neurology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/ng1303","article-title":"Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2","volume":"36","author":"Moreira","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s10048-009-0206-0","article-title":"Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin","volume":"11","author":"Airoldi","year":"2010","journal-title":"Neurogenetics"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Bernard, V., Minnerop, M., Burk, K., Kreuz, F., Gillessen-Kaesbach, G., and Zuhlke, C. (2009). Exon deletions and intragenic insertions are not rare in ataxia with oculomotor apraxia 2. BMC Med. Genet., 10.","DOI":"10.1186\/1471-2350-10-87"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1086\/421054","article-title":"DNA\/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)","volume":"74","author":"Chen","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.nbd.2006.02.007","article-title":"Senataxin, the yeast Sen1p orthologue: Characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease","volume":"23","author":"Chen","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1212\/01.wnl.0000247661.19601.28","article-title":"Novel mutations in the senataxin DNA\/RNA helicase domain in ataxia with oculomotor apraxia 2","volume":"67","author":"Fogel","year":"2006","journal-title":"Neurology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/j.jocn.2013.11.048","article-title":"Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage","volume":"21","author":"Roda","year":"2014","journal-title":"J. Clin. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/humu.22451","article-title":"Exome sequencing as a diagnostic tool for pediatric-onset ataxia","volume":"35","author":"Sawyer","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/ng.526","article-title":"Mutations in PNKP cause microcephaly, seizures and defects in DNA repair","volume":"42","author":"Shen","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6608","DOI":"10.1093\/nar\/gks318","article-title":"Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair","volume":"40","author":"Reynolds","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"6672","DOI":"10.1093\/nar\/gkaa489","article-title":"Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair","volume":"48","author":"Kalasova","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1002\/ajmg.a.61339","article-title":"From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations","volume":"179","author":"Gatti","year":"2019","journal-title":"Am J. Med. Genet. A"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/0925-4439(93)90134-M","article-title":"Molecular basis of an adult form of Sandhoff disease: Substitution of glutamine for arginine at position 505 of the beta-chain of beta-hexosaminidase results in a labile enzyme","volume":"1182","author":"Bolhuis","year":"1993","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/S0006-291X(05)81388-9","article-title":"Molecular basis of an adult form of beta-hexosaminidase B deficiency with motor neuron disease","volume":"181","author":"Banerjee","year":"1991","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0925-4439(96)00044-0","article-title":"Significance of two point mutations present in each HEXB allele of patients with adult GM2 gangliosidosis (Sandhoff disease) homozygosity for the Ile207-->Val substitution is not associated with a clinical or biochemical phenotype","volume":"1317","author":"Mahuran","year":"1996","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s10048-008-0145-1","article-title":"Molecular and functional analysis of the HEXB gene in Italian patients affected with Sandhoff disease: Identification of six novel alleles","volume":"10","author":"Zampieri","year":"2009","journal-title":"Neurogenetics"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.ymgme.2006.12.004","article-title":"Chronic GM2 gangliosidosis type Sandhoff associated with a novel missense HEXB gene mutation causing a double pathogenic effect","volume":"91","author":"Santoro","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Zampieri, S., Cattarossi, S., Oller Ramirez, A.M., Rosano, C., Lourenco, C.M., Passon, N., Moroni, I., Uziel, G., Pettinari, A., and Stanzial, F. (2012). Sequence and copy number analyses of HEXB gene in patients affected by Sandhoff disease: Functional characterization of 9 novel sequence variants. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041516"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/jhg.2013.68","article-title":"Molecular pathology of Sandhoff disease with p.Arg505Gln in HEXB: Application of simulation analysis","volume":"58","author":"Yasui","year":"2013","journal-title":"J. Hum. Genet."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.ajhg.2008.10.010","article-title":"Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia","volume":"83","author":"Edvardson","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"E1251","DOI":"10.1002\/humu.21205","article-title":"Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35)","volume":"31","author":"Dick","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1002\/ana.22122","article-title":"Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA)","volume":"68","author":"Kruer","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/72769","article-title":"ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF","volume":"24","author":"Engert","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ymgme.2017.04.002","article-title":"A multicenter clinical exome study in unselected cohorts from a consanguineous population of Saudi Arabia demonstrated a high diagnostic yield","volume":"121","author":"Alfares","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1093\/brain\/awm293","article-title":"Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration","volume":"131","author":"Stevanin","year":"2008","journal-title":"Brain"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1093\/brain\/awp325","article-title":"SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis","volume":"133","author":"Orlacchio","year":"2010","journal-title":"Brain"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1093\/brain\/awv320","article-title":"ALS5\/SPG11\/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease","volume":"139","author":"Montecchiani","year":"2016","journal-title":"Brain"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1093\/hmg\/ddm238","article-title":"Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity","volume":"16","author":"Zhang","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/90034","article-title":"Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions","volume":"28","author":"Dermaut","year":"2001","journal-title":"Nat. Genet"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1002\/ana.20079","article-title":"POLG mutations associated with Alpers\u2019 syndrome and mitochondrial DNA depletion","volume":"55","author":"Naviaux","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1212\/01.WNL.0000156516.77696.5A","article-title":"Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations","volume":"64","author":"Winterthun","year":"2005","journal-title":"Neurology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1212\/WNL.59.6.926","article-title":"Multiple mtDNA deletions with features of MNGIE","volume":"59","author":"Vissing","year":"2002","journal-title":"Neurology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"4758","DOI":"10.1093\/hmg\/ddu190","article-title":"Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2","volume":"23","author":"Fogel","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1212\/WNL.37.1.75","article-title":"Ganglioside storage, hexosaminidase lability, and urinary oligosaccharides in adult Sandhoff\u2019s disease","volume":"37","author":"Bolhuis","year":"1987","journal-title":"Neurology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Uhlen","year":"2015","journal-title":"Science"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/6\/981\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:35:39Z","timestamp":1760135739000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/6\/981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,12]]},"references-count":110,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["cells11060981"],"URL":"https:\/\/doi.org\/10.3390\/cells11060981","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,12]]}}}