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These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile\u2010onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next\u2010generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with <jats:italic>ALS2<\/jats:italic>\u2010related MND. We identified five novel homozygous pathogenic variants in <jats:italic>ALS2<\/jats:italic> at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C&gt;G (p.Tyr348Ter), c.1718C&gt;A (p.Ala573Glu), c.3161T&gt;C (p.Leu1054Pro), and c.1471+1G&gt;A (NM_020919.3, NP_065970.2). In our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N\u2010terminal Alsin domains are most prevalent. We enriched the mutational spectrum of <jats:italic>ALS2<\/jats:italic>\u2010related disorders with five novel pathogenic variants. Our study indicates a high detection rate of <jats:italic>ALS2<\/jats:italic> mutations in patients with a clinically well\u2010characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression.<\/jats:p>","DOI":"10.1002\/ajmg.a.61951","type":"journal-article","created":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T04:03:33Z","timestamp":1604635413000},"page":"344-354","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Genotype\u2013phenotype correlation in seven motor neuron disease families with novel <scp><i>ALS2<\/i><\/scp> mutations"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2457-6437","authenticated-orcid":false,"given":"Rosanne","family":"Sprute","sequence":"first","affiliation":[{"name":"Faculty of Medicine and the Faculty of Mathematics and Natural Sciences Center for Molecular Medicine Cologne (CMMC), University of Cologne  Cologne Germany"},{"name":"Faculty of Medicine and University Hospital 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for Genomics, University of Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatice","family":"Karasoy","sequence":"additional","affiliation":[{"name":"Department of Neurology Ege University School of Medicine  Izmir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hormos Salimi","family":"Dafsari","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and the Faculty of Mathematics and Natural Sciences Center for Molecular Medicine Cologne (CMMC), University of Cologne  Cologne Germany"},{"name":"Faculty of Medicine and University Hospital Cologne, Department of Pediatrics University of Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Becker","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and the Faculty of Mathematics and Natural Sciences Center for Molecular Medicine Cologne (CMMC), University of Cologne  Cologne Germany"},{"name":"Faculty of Medicine and University Hospital Cologne, Department of Pediatrics University of Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00fclya\u2010Sevcan","family":"Daimag\u00fcler","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and the Faculty of Mathematics and Natural Sciences Center for Molecular Medicine Cologne (CMMC), University of Cologne  Cologne Germany"},{"name":"Faculty of Medicine and University Hospital Cologne, Department of Pediatrics University of Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"N\u00fcrnberg","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and the Faculty of Mathematics and Natural Sciences Center for Molecular Medicine Cologne (CMMC), University of Cologne  Cologne Germany"},{"name":"Cologne Center for Genomics, University of Cologne  Cologne 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