{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T20:42:56Z","timestamp":1785357776467,"version":"3.55.0"},"reference-count":105,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T00:00:00Z","timestamp":1729468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Italian Health Ministry\u2014Ricerca Corrente","award":["RRC-2024-23684513"],"award-info":[{"award-number":["RRC-2024-23684513"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Inherited pediatric motor neuron diseases (MNDs) are a group of neurodegenerative disorders characterized by the degeneration of motor neurons in the brain and the spinal cord. These diseases can manifest as early as infancy and originate from inherited pathogenic mutations in known genes. Key clinical features of MNDs include muscle weakness, hypotonia, and atrophy due to the degeneration of lower motor neurons or spasticity, hypertonia, and hyperreflexia caused by upper motor neuron dysfunction. The course of the disease varies among individuals and is influenced by the specific subtype. Methods: We performed a non-systematic, narrative clinical review, employing a systematic methodology for the literature search and article selection to delineate the features of hereditary pediatric motor neuron diseases. Results: The growing availability of advanced molecular testing, such as whole-exome sequencing (WES) and whole-genome sequencing (WGS), has expanded the range of identified genetic factors. These advancements provide insights into the genetic complexity and underlying mechanisms of these disorders. As more MND-related genes are discovered, the accumulating genetic data will help prioritize promising candidate genes for future research. In some cases, targeted treatments based on specific genetic mechanisms have already emerged, underscoring the critical role of early and timely diagnosis in improving patient outcomes. Common MNDs include amyotrophic lateral sclerosis, spinal muscular atrophy, and bulbar spinal muscular atrophy. Conclusion: This narrative clinical review covers the clinical presentation, genetics, molecular features, and pathophysiology of inherited pediatric MNDs.<\/jats:p>","DOI":"10.3390\/genes15101346","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T08:53:11Z","timestamp":1729500791000},"page":"1346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Update on Inherited Pediatric Motor Neuron Diseases: Clinical Features and Outcome"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3165-0105","authenticated-orcid":false,"given":"Antonio","family":"Trabacca","sequence":"first","affiliation":[{"name":"Scientific Institute IRCCS. \u201cE. Medea\u201d, Scientific Direction, 23842 Bosisio Parini, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Ferrante","sequence":"additional","affiliation":[{"name":"Associazione \u201cLa Nostra Famiglia\u201d, IRCCS \u201cE. Medea\u201d, Scientific Hospital for Neurorehabilitation, Unit for Severe Disabilities in Developmental Age and Young Adults, Developmental Neurology and Neurorehabilitation, 72100 Brindisi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carmela","family":"Oliva","sequence":"additional","affiliation":[{"name":"Associazione \u201cLa Nostra Famiglia\u201d, IRCCS \u201cE. Medea\u201d, Scientific Hospital for Neurorehabilitation, Unit for Severe Disabilities in Developmental Age and Young Adults, Developmental Neurology and Neurorehabilitation, 72100 Brindisi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Fanizza","sequence":"additional","affiliation":[{"name":"Associazione \u201cLa Nostra Famiglia\u201d, IRCCS \u201cE. Medea\u201d, Scientific Hospital for Neurorehabilitation, Unit for Severe Disabilities in Developmental Age and Young Adults, Developmental Neurology and Neurorehabilitation, 72100 Brindisi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Gallo","sequence":"additional","affiliation":[{"name":"Associazione \u201cLa Nostra Famiglia\u201d, IRCCS \u201cE. 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Med."},{"key":"ref_2","unstructured":"Zayia, L.C., and Tadi, P. (2020). Neuroanatomy, motor neuron. StatPearls [Internet], StatPearls Publishing."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Verber, N.S., Shepheard, S.R., Sassani, M., McDonough, H.E., Moore, S.A., Alix, J.J.P., Wilkinson, I.D., Jenkins, T.M., and Shaw, P.J. (2019). Biomarkers in Motor Neuron Disease: A State of the Art Review. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00291"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.bbadis.2006.04.003","article-title":"The molecular genetics of non-ALS motor neuron diseases","volume":"1762","author":"James","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/bs.pmbts.2020.03.009","article-title":"Autophagy in motor neuron diseases","volume":"172","year":"2020","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1136\/bmj.39493.511759.BE","article-title":"Diagnosis and management of motor neurone disease","volume":"336","author":"McDermott","year":"2008","journal-title":"BMJ (Clin. Res. Ed.)"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"120099","DOI":"10.1016\/j.jns.2021.120099","article-title":"Genetic architecture of motor neuron diseases","volume":"434","author":"Chaudhary","year":"2022","journal-title":"J. Neurol. Sci."},{"key":"ref_8","first-page":"2413","article-title":"Meta-analysis and multidisciplinary consensus statement: Exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders","volume":"21","author":"Srivastava","year":"2019","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/nrg2680","article-title":"Genetics of motor neuron disorders: New insights into pathogenic mechanisms","volume":"10","author":"Dion","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ruffo, P., Cavallaro, S., and Conforti, F.L. (2022). The advent of omics sciences in clinical trials of motor neuron diseases. J. Pers. Med., 12.","DOI":"10.3390\/jpm12050758"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Waung, M.W., Ma, F., Wheeler, A.G., Zai, C.C., and So, J. (2023). The Diagnostic Landscape of Adult Neurogenetic Disorders. Biology, 12.","DOI":"10.3390\/biology12121459"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chamakioti, M., Karantzelis, N., and Taraviras, S. (2022). Advanced Gene-Targeting Therapies for Motor Neuron Diseases and Muscular Dystrophies. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094824"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s13311-014-0332-8","article-title":"Challenges in the Understanding and Treatment of Amyotrophic Lateral Sclerosis\/Motor Neuron Disease","volume":"12","author":"Rosenfeld","year":"2015","journal-title":"Neurother. J. Am. Soc. Exp. NeuroTherapeutics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s41073-019-0064-8","article-title":"SANRA\u2014A scale for the quality assessment of narrative review articles","volume":"4","author":"Baethge","year":"2019","journal-title":"Res. Integr. Peer Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan-a web and mobile app for systematic reviews","volume":"5","author":"Ouzzani","year":"2016","journal-title":"Syst. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1007\/s13760-022-02028-6","article-title":"Biomarkers of therapeutic efficacy in adolescents and adults with 5q spinal muscular atrophy: A systematic review","volume":"123","author":"Gavriilaki","year":"2023","journal-title":"Acta Neurol. Belg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/mus.28091","article-title":"Motor unit number estimation via MScanFit MUNE in spinal muscular atrophy","volume":"70","author":"Vacchiano","year":"2024","journal-title":"Muscle Nerve"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1002\/mus.26304","article-title":"Following disease progression in motor neuron disorders with 3 motor unit number estimation methods","volume":"59","author":"Jacobsen","year":"2019","journal-title":"Muscle Nerve"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6509493","DOI":"10.1155\/2017\/6509493","article-title":"Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy","volume":"2017","author":"Teoh","year":"2017","journal-title":"Neural Plast."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Satam, H., Joshi, K., Mangrolia, U., Waghoo, S., Zaidi, G., Rawool, S., Thakare, R.P., Banday, S., Mishra, A.K., and Das, G. (2023). Next-Generation Sequencing Technology: Current Trends and Advancements. Biology, 12.","DOI":"10.3390\/biology12070997"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1080\/21678421.2021.1936062","article-title":"Muscle MRI in motor neuron diseases: A systematic review","volume":"23","author":"Kriss","year":"2022","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"87","DOI":"10.31083\/j.jin2103087","article-title":"Neurometabolic Alterations in Motor Neuron Disease: Insights from Magnetic Resonance Spectroscopy","volume":"21","author":"Christidi","year":"2022","journal-title":"J. Integr. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3676","DOI":"10.1007\/s12035-018-1334-z","article-title":"Cellular Proteostasis in Neurodegeneration","volume":"56","author":"Kurtishi","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1146\/annurev-cellbio-120219-035530","article-title":"Mechanisms of Selective Autophagy","volume":"37","author":"Lamark","year":"2021","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ceb.2019.12.001","article-title":"The ATG conjugation systems in autophagy","volume":"63","author":"Mizushima","year":"2020","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1126\/science.1165942","article-title":"Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6","volume":"323","author":"Vance","year":"2009","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eaad9157","DOI":"10.1126\/scitranslmed.aad9157","article-title":"Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis","volume":"9","author":"Smith","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1042\/BST20220778","article-title":"The role of autophagy-lysosomal pathway in motor neuron diseases","volume":"50","author":"Tedesco","year":"2022","journal-title":"Biochem. Soc. Trans."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1001\/archneurol.2011.74","article-title":"Spinal muscular atrophy: A timely review","volume":"68","author":"Kolb","year":"2011","journal-title":"Arch. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1212\/WNL.0000000000201654","article-title":"Prevalence of Spinal Muscular Atrophy in the Era of Disease-Modifying Therapies: An Italian Nationwide Survey","volume":"100","author":"Coratti","year":"2023","journal-title":"Neurology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"243","DOI":"10.23736\/S1973-9087.20.05968-7","article-title":"The International Classification of Functioning, Disability and Health-Children and Youth as a framework for the management of spinal muscular atrophy in the era of gene therapy: A proof-of-concept study","volume":"56","author":"Trabacca","year":"2020","journal-title":"Eur. J. Phys. Rehabil. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Aslesh, T., and Yokota, T. (2022). Restoring SMN expression: An overview of the therapeutic developments for the treatment of spinal muscular atrophy. Cells, 11.","DOI":"10.3390\/cells11030417"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S1090-3798(99)80012-9","article-title":"Very severe spinal muscular atrophy (SMA type 0): An expanding clinical phenotype","volume":"3","author":"Dubowitz","year":"1999","journal-title":"Eur. J. Paediatr. Neurol. EJPN Off. J. Eur. Paediatr. Neurol. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/0960-8966(94)90090-6","article-title":"The natural history of type I (severe) spinal muscular atrophy","volume":"4","author":"Thomas","year":"1994","journal-title":"Neuromuscul. Disord. NMD"},{"key":"ref_35","first-page":"20","article-title":"Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2","volume":"4","author":"Mailman","year":"2002","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"ref_36","first-page":"3699","article-title":"Exploring variability in cognitive functioning in patients with spinal muscular atrophy: A scoping review","volume":"45","author":"Giannotta","year":"2024","journal-title":"Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0022-510X(96)00284-5","article-title":"A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients","volume":"146","author":"Zerres","year":"1997","journal-title":"J. Neurol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.ncl.2015.07.004","article-title":"Spinal Muscular Atrophy","volume":"33","author":"Kolb","year":"2015","journal-title":"Neurol. Clin."},{"key":"ref_39","first-page":"1971","article-title":"Neuromuscular diseases rehabilitation in the era of gene therapy","volume":"41","author":"Trabacca","year":"2020","journal-title":"Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1136\/archdischild-2021-323605","article-title":"New treatments in spinal muscular atrophy","volume":"108","author":"Gowda","year":"2023","journal-title":"Arch. Dis. Child."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1007\/s40263-021-00878-x","article-title":"Nusinersen: A Review in 5q Spinal Muscular Atrophy","volume":"35","author":"Hoy","year":"2021","journal-title":"CNS Drugs"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1007\/s40265-019-01162-5","article-title":"Onasemnogene Abeparvovec: First Global Approval","volume":"79","author":"Hoy","year":"2019","journal-title":"Drugs"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1007\/s40265-020-01410-z","article-title":"Risdiplam: First Approval","volume":"80","author":"Dhillon","year":"2020","journal-title":"Drugs"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.nmd.2017.05.011","article-title":"Spinal muscular atrophy: A changing phenotype beyond the clinical trials","volume":"27","author":"Tizzano","year":"2017","journal-title":"Neuromuscul. Disord."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0960-8966(02)00211-0","article-title":"93rd ENMC international workshop: Non-5q-spinal muscular atrophies (SMA)\u2013clinical picture (6\u20138 April 2001, Naarden, The Netherlands)","volume":"13","author":"Zerres","year":"2003","journal-title":"Neuromuscul. Disord."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Le\u015bniak, A., Gli\u0144ska, M., Patalan, M., Ostrowska, I., \u015awirska-Sobolewska, M., Gi\u017cewska-Kacprzak, K., Kotkowiak, A., Le\u015bniak, A., Walczak, M., and \u015amigiel, R. (2024). The Clinical Heterogeneity of Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1)-A Report of Three Cases, Including Twins. Genes, 15.","DOI":"10.3390\/genes15080997"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/ng703","article-title":"Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1","volume":"29","author":"Grohmann","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1055\/s-2004-820994","article-title":"Long-term observations of patients with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1)","volume":"35","author":"Stolz","year":"2004","journal-title":"Neuropediatrics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1212\/WNL.0000000000000305","article-title":"Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis","volume":"82","author":"Butterfield","year":"2014","journal-title":"Neurology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1136\/jmg.39.1.74","article-title":"Infantile spinal muscular atrophy variant with congenital fractures in a female neonate: Evidence for autosomal recessive inheritance","volume":"39","author":"Courtens","year":"2002","journal-title":"J. Med. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.ajhg.2007.09.009","article-title":"Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy","volume":"82","author":"Ramser","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1093\/hmg\/4.7.1213","article-title":"A gene for a severe lethal form of X-linked arthrogryposis (X-linked infantile spinal muscular atrophy) maps to human chromosome Xp11. 3\u2013q11. 2","volume":"4","author":"Kobayashi","year":"1995","journal-title":"Hum. Mol. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1002\/ajmg.a.31381","article-title":"Lethal congenital contracture syndrome (LCCS) and other lethal arthrogryposes in Finland\u2014An epidemiological study","volume":"140a","author":"Ritvanen","year":"2006","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/ng.2007.65","article-title":"Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease","volume":"40","author":"Nousiainen","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1086\/520770","article-title":"Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase\/Akt pathway","volume":"81","author":"Narkis","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1086\/520771","article-title":"Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI\u03b3 of the phophatidylinsitol pathway","volume":"81","author":"Narkis","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1002\/humu.22122","article-title":"Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a mutation in MYBPC1","volume":"33","author":"Markus","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1023\/B:BOLI.0000016614.47380.2f","article-title":"Reversion of hypertrophic cardiomyopathy in a patient with deficiency of the mitochondrial copper binding protein Sco2: Is there a potential effect of copper?","volume":"27","author":"Freisinger","year":"2004","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.pediatrneurol.2009.10.004","article-title":"A novel mutation in the SCO2 gene in a neonate with early-onset cardioencephalomyopathy","volume":"42","author":"Joost","year":"2010","journal-title":"Pediatr. Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1001\/archneur.62.5.745","article-title":"New DGK gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome","volume":"62","author":"Mancuso","year":"2005","journal-title":"Arch. Neurol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1212\/01.WNL.0000028689.93049.9A","article-title":"Mitochondrial DNA depletion: Mutations in thymidine kinase gene with myopathy and SMA","volume":"59","author":"Mancuso","year":"2002","journal-title":"Neurology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1750-1172-3-9","article-title":"Brown-Vialetto-Van Laere syndrome","volume":"3","author":"Sathasivam","year":"2008","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/(SICI)1096-8628(20000515)92:2<117::AID-AJMG7>3.0.CO;2-C","article-title":"Brown-Vialetto-Van Laere syndrome in a large inbred Lebanese family: Confirmation of autosomal recessive inheritance?","volume":"92","author":"Desguerres","year":"2000","journal-title":"Am. J. Med. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1093\/brain\/awt315","article-title":"Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2","volume":"137","author":"Foley","year":"2014","journal-title":"Brain"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.nbd.2012.06.018","article-title":"Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS","volume":"48","author":"Lu","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s10545-010-9242-z","article-title":"Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: A new inborn error of metabolism with potential treatment","volume":"34","author":"Bosch","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"87","DOI":"10.4103\/0972-2327.144283","article-title":"Fazio Londe syndrome: A treatable disorder","volume":"18","author":"Varadarajan","year":"2015","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_68","first-page":"173","article-title":"Pontocerebellar hypoplasia","volume":"166c","author":"Barth","year":"2014","journal-title":"Am. J. Med. Genet. Part C Semin. Med. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.ajhg.2009.07.006","article-title":"Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene","volume":"85","author":"Renbaum","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/ng.2254","article-title":"Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration","volume":"44","author":"Wan","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4287","DOI":"10.1038\/ncomms5287","article-title":"EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia","volume":"5","author":"Boczonadi","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.1093\/brain\/aww212","article-title":"Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia","volume":"139","author":"Wan","year":"2016","journal-title":"Brain"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e70","DOI":"10.1093\/brain\/aww252","article-title":"MORC2 mutation causes severe spinal muscular atrophy-phenotype, cerebellar atrophy, and diaphragmatic paralysis","volume":"139","author":"Schottmann","year":"2016","journal-title":"Brain"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ajhg.2012.05.001","article-title":"Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1","volume":"91","author":"Zhou","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1212\/WNL.0000000000001269","article-title":"Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy","volume":"84","author":"Scoto","year":"2015","journal-title":"Neurology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1093\/brain\/awu356","article-title":"Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2","volume":"138","author":"Rossor","year":"2015","journal-title":"Brain"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.nmd.2016.02.010","article-title":"TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature","volume":"26","author":"Biasini","year":"2016","journal-title":"Neuromuscul. Disord. NMD"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3978","DOI":"10.1007\/s00415-024-12462-6","article-title":"The various forms of hereditary motor neuron disorders and their historical descriptions","volume":"271","author":"Mathis","year":"2024","journal-title":"J. Neurol."},{"key":"ref_79","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (1993). Hereditary Spastic Paraplegia Overview. GeneReviews(\u00ae), University of Washington."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.ymgme.2021.06.006","article-title":"Childhood-onset hereditary spastic paraplegia and its treatable mimics","volume":"137","author":"Saffari","year":"2022","journal-title":"Mol. Genet. Metab."},{"key":"ref_81","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (1993). Spastic Paraplegia 4. GeneReviews(\u00ae), University of Washington."},{"key":"ref_82","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (1993). Spastic Paraplegia 3A. GeneReviews(\u00ae), University of Washington."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s40035-022-00320-2","article-title":"Association of variants in the KIF1A gene with amyotrophic lateral sclerosis","volume":"11","author":"Liao","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Simone, M., Trabacca, A., Panzeri, E., Losito, L., Citterio, A., and Bassi, M.T. (2018). KIF5A and ALS2 Variants in a Family With Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis. Front. Neurol., 9.","DOI":"10.3389\/fneur.2018.01078"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.pediatrneurol.2022.02.007","article-title":"Childhood-Onset Hereditary Spastic Paraplegia (HSP): A Case Series and Review of Literature","volume":"130","author":"Panwala","year":"2022","journal-title":"Pediatr. Neurol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1080\/01677063.2021.1895146","article-title":"Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families","volume":"35","author":"Pashaei","year":"2021","journal-title":"J. Neurogenet."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/s41573-022-00612-2","article-title":"Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation","volume":"22","author":"Mead","year":"2023","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1212\/WNL.0000000000000254","article-title":"ALS2 mutations: Juvenile amyotrophic lateral sclerosis and generalized dystonia","volume":"82","author":"Sheerin","year":"2014","journal-title":"Neurology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1002\/ajmg.a.61951","article-title":"Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations","volume":"185","author":"Sprute","year":"2021","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1007\/s12031-023-02169-0","article-title":"Role of Senataxin in Amyotrophic Lateral Sclerosis","volume":"73","author":"Tsui","year":"2023","journal-title":"J. Mol. Neurosci. MN"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1002\/ana.25681","article-title":"Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4","volume":"87","author":"Grunseich","year":"2020","journal-title":"Ann. Neurol."},{"key":"ref_92","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_93","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1002\/ana.24633","article-title":"GSK3\u00df-dependent dysregulation of neurodevelopment in SPG11-patient induced pluripotent stem cell model","volume":"79","author":"Mishra","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s12015-022-10489-8","article-title":"Amyotrophic Lateral Sclerosis, FUS and Protein Synthesis Defects","volume":"19","author":"Assoni","year":"2023","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1124\/mol.116.104018","article-title":"Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases","volume":"90","author":"Wong","year":"2016","journal-title":"Mol. Pharmacol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.nmd.2009.02.006","article-title":"A novel form of juvenile recessive ALS maps to loci on 6p25 and 21q22","volume":"19","author":"Butterfield","year":"2009","journal-title":"Neuromuscul. Disord. NMD"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1002\/ana.22534","article-title":"A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis","volume":"70","author":"Bohlega","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1111\/ene.12941","article-title":"Evaluation of the application of the European guidelines for the diagnosis and clinical care of amyotrophic lateral sclerosis (ALS) patients in six French ALS centres","volume":"23","author":"Marin","year":"2016","journal-title":"Eur. J. Neurol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1212\/WNL.0b013e3181bc0141","article-title":"Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional, and respiratory therapies (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology","volume":"73","author":"Miller","year":"2009","journal-title":"Neurology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1056\/NEJM199403033300901","article-title":"A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS\/Riluzole Study Group","volume":"330","author":"Bensimon","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/S0140-6736(96)91680-3","article-title":"Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis\/Riluzole Study Group II","volume":"347","author":"Lacomblez","year":"1996","journal-title":"Lancet"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40035-016-0050-8","article-title":"Genotype-phenotype correlations of amyotrophic lateral sclerosis","volume":"5","author":"Li","year":"2016","journal-title":"Transl. Neurodegener."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1007\/s40265-023-01904-6","article-title":"Tofersen: First Approval","volume":"83","author":"Blair","year":"2023","journal-title":"Drugs"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e16140","DOI":"10.1111\/ene.16140","article-title":"Breaking barriers with tofersen: Enhancing therapeutic opportunities in amyotrophic lateral sclerosis","volume":"31","author":"Saini","year":"2024","journal-title":"Eur. J. Neurol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Cantara, S., Simoncelli, G., and Ricci, C. (2024). Antisense oligonucleotides (ASOs) in motor neuron diseases: A road to cure in light and shade. Int. J. Mol. 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