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We identified 19 unique variants (16\/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0\u2009months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8\u2009\u00b1\u20099.7 (standard deviation).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results confirm that de novo variants in <jats:italic>SPAST<\/jats:italic> lead to a severe and complex form of HSP that differs from classic familial pure HSP\u2010<jats:italic>SPAST<\/jats:italic>. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. \u00a9 2022 International Parkinson and Movement Disorder Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.29225","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T13:35:09Z","timestamp":1663162509000},"page":"2440-2446","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["<scp>Early\u2010Onset<\/scp> and Severe Complex Hereditary Spastic Paraplegia Caused by <i>De Novo<\/i> Variants in <scp><i>SPAST<\/i><\/scp>"],"prefix":"10.1002","volume":"37","author":[{"given":"Alisa","family":"Mo","sequence":"first","affiliation":[{"name":"Department of Neurology Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afshin","family":"Saffari","sequence":"additional","affiliation":[{"name":"Department of 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K.","family":"Fink","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linsley","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Neurology and Rehabilitation Medicine Texas Scottish Rite Hospital, University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Posey","sequence":"additional","affiliation":[{"name":"Department of Molecular &amp; Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine E.","family":"Alter","sequence":"additional","affiliation":[{"name":"Functional and Applied Biomechanics Section, Department of Rehabilitation Medicine Clinical Center, National Institutes of Health  Bethesda Maryland 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