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The aim of this study was to investigate the clinical and genetic features of SPG6 in a Taiwanese HSP cohort.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We screened 242 unrelated Taiwanese patients with HSP for <jats:italic>NIPA1<\/jats:italic> mutations. The clinical features of patients with a <jats:italic>NIPA1<\/jats:italic> mutation were analyzed. Minigene\u2010based splicing assay, RT\u2010PCR analysis on the patients' RNA, and cell\u2010based protein expression study were utilized to assess the effects of the mutations on splicing and protein expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two patients were identified to carry a different heterozygous <jats:italic>NIPA1<\/jats:italic> mutation. The two mutations, c.316G&gt;A and c.316G&gt;C, are located in the 3\u2032 end of <jats:italic>NIPA1<\/jats:italic> exon 3 near the exon\u2013intron boundary and putatively lead to the same amino acid substitution, p.G106R. The patient harboring <jats:italic>NIPA1<\/jats:italic> c.316G&gt;A manifested spastic paraplegia, epilepsy and schizophrenia since age 17\u2009years, whereas the individual carrying <jats:italic>NIPA1<\/jats:italic> c.316G&gt;C had pure HSP since age 12\u2009years. We reviewed literature and found that epilepsy was present in multiple individuals with <jats:italic>NIPA1<\/jats:italic> c.316G&gt;A but none with <jats:italic>NIPA1<\/jats:italic> c.316G&gt;C. Functional studies demonstrated that both mutations did not affect splicing, but only the c.316G&gt;A mutation was associated with a significantly reduced NIPA1 protein expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>SPG6 accounted for 0.8% of HSP cases in the Taiwanese cohort. The <jats:italic>NIPA1<\/jats:italic> c.316G&gt;A and c.316G&gt;C mutations are associated with adolescent\u2010onset complex and pure form HSP, respectively. The different effects on protein expression of the two mutations may be associated with their phenotypic discrepancy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51724","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T14:09:20Z","timestamp":1673014160000},"page":"353-362","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Clinical and genetic characterization of <i>NIPA1<\/i> mutations in a Taiwanese cohort with hereditary spastic paraplegia"],"prefix":"10.1002","volume":"10","author":[{"given":"Shih\u2010Yu","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Neurology Taipei Veterans General Hospital  Taipei Taiwan"},{"name":"Department of Neurology National Yang Ming Chiao Tung University School of Medicine  Taipei 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