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ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11\u201361 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and\/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific cortical and cerebellar atrophy. The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots. Spastic Paraplegia Rating Scale scores, SPATAX Disability Scores and the Four Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction. Plasma neurofilament light chain levels were significantly elevated in all patients (Mann\u2013Whitney U-test, P &amp;lt; 0.0001) and were correlated inversely with age (Spearman\u2019s rank correlation coefficient r = \u22120.65, P = 0.01). In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.<\/jats:p>","DOI":"10.1093\/brain\/awac391","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T18:28:50Z","timestamp":1667240930000},"page":"2003-2015","source":"Crossref","is-referenced-by-count":26,"title":["The clinical and molecular spectrum of <i>ZFYVE26<\/i>-associated hereditary spastic paraplegia: SPG15"],"prefix":"10.1093","volume":"146","author":[{"given":"Afshin","family":"Saffari","sequence":"first","affiliation":[{"name":"Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"},{"name":"Division of Child Neurology and Inherited Metabolic Diseases, Heidelberg University Hospital , Heidelberg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Kellner","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of T\u00fcbingen , T\u00fcbingen , Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE) , T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Jordan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Rosengarten","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"},{"name":"ICCTR Biostatistics and Research Design Center, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleksandr","family":"Strelko","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Neuser","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Leipzig Medical Center , Leipzig , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie Y","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Washington , Seattle, WA , USA"},{"name":"Department of Neurology, VA Puget Sound Healthcare System , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuaki","family":"Yoshikura","sequence":"additional","affiliation":[{"name":"Department of Neurology, Gifu University Graduate School of Medicine , Gifu , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naonobu","family":"Futamura","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Hospital Organization Hyogo-Chuo National Hospital , Ohara, Sanda , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital , Aichi , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8453-2028","authenticated-orcid":false,"given":"Shin","family":"Nabatame","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Osaka University Graduate School of Medicine , Suita, Osaka , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Ishiura","sequence":"additional","affiliation":[{"name":"Department of Neurology, Graduate School of Medicine, The University of Tokyo , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5602-5686","authenticated-orcid":false,"given":"Shoji","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo , Tokyo , Japan"},{"name":"Institute of Medical Genomics, International University of Health and Welfare , Chiba , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda Shujaa","family":"Aldeen","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Cali","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarissa","family":"Rocca","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2866-7777","authenticated-orcid":false,"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1838-6688","authenticated-orcid":false,"given":"Stephanie","family":"Efthymiou","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Assmann","sequence":"additional","affiliation":[{"name":"Division of Child Neurology and Inherited Metabolic Diseases, Heidelberg University Hospital , Heidelberg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Yoon","sequence":"additional","affiliation":[{"name":"Divisions of Clinical and Metabolic Genetics and Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto , Toronto , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca A","family":"Trombetta","sequence":"additional","affiliation":[{"name":"Alzheimer's Clinical and Translational Research Unit, Department of Neurology, Massachusetts General Hospital , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Kivis\u00e4kk","sequence":"additional","affiliation":[{"name":"Alzheimer's Clinical and Translational Research Unit, Department of Neurology, Massachusetts General Hospital , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6836-1089","authenticated-orcid":false,"given":"Florian","family":"Eichler","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitian","family":"Nan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi , Yamanashi , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5400-7107","authenticated-orcid":false,"given":"Yoshihisa","family":"Takiyama","sequence":"additional","affiliation":[{"name":"Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi , Yamanashi , Japan"},{"name":"Department of Neurology, Fuefuki Central Hospital , Yamanashi , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Tessa","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, IRCCS Fondazione Stella Maris , 56128 Pisa , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0475-2771","authenticated-orcid":false,"given":"Filippo M","family":"Santorelli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, IRCCS Fondazione Stella Maris , 56128 Pisa , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-2953","authenticated-orcid":false,"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8564-7836","authenticated-orcid":false,"given":"Craig","family":"Blackstone","sequence":"additional","affiliation":[{"name":"Movement Disorders Division, Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9912-4163","authenticated-orcid":false,"given":"Edward","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Neuroradiology, Department of Radiology, Boston Children's Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Sch\u00fcle","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of T\u00fcbingen , T\u00fcbingen , Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE) , T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0026-4714","authenticated-orcid":false,"given":"Darius","family":"Ebrahimi-Fakhari","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"},{"name":"Movement Disorders Program, Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children's Hospital , Boston, MA , USA"},{"name":"Intellectual and Developmental Disabilities Research Center, Boston Children\u2019s Hospital , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,10,31]]},"reference":[{"key":"2023080918525270100_awac391-B1","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/B978-0-444-64076-5.00041-7","article-title":"Hereditary spastic paraplegia","volume":"148","author":"Blackstone","year":"2018","journal-title":"Handb Clin Neurol"},{"key":"2023080918525270100_awac391-B2","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(4)","author":"Ebrahimi-Fakhari","year":"2022","journal-title":"Mol Genet Metab"},{"key":"2023080918525270100_awac391-B3","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1002\/mds.26527","article-title":"Nomenclature of genetic movement disorders: Recommendations of the international Parkinson and movement disorder society task force","volume":"31","author":"Marras","year":"2016","journal-title":"Mov Disord"},{"key":"2023080918525270100_awac391-B4","volume-title":"Genereviews\u00ae","author":"Ebrahimi-Fakhari","year":"2021"},{"key":"2023080918525270100_awac391-B5","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1001\/archneur.65.3.393","article-title":"Hereditary spastic paraplegia with mental impairment and thin corpus callosum in Tunisia: SPG11, SPG15, and further genetic heterogeneity","volume":"65","author":"Boukhris","year":"2008","journal-title":"Arch Neurol"},{"key":"2023080918525270100_awac391-B6","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.ajhg.2008.03.004","article-title":"Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome","volume":"82","author":"Hanein","year":"2008","journal-title":"Am J Hum Genet"},{"key":"2023080918525270100_awac391-B7","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jns.2008.09.039","article-title":"Spastic paraplegia with thinning of the corpus callosum and white matter abnormalities: Further mutations and relative frequency in ZFYVE26\/SPG15 in the Italian population","volume":"277","author":"Denora","year":"2009","journal-title":"J Neurol Sci"},{"key":"2023080918525270100_awac391-B8","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1212\/WNL.0b013e3181bacf59","article-title":"SPG15 Is the second most common cause of hereditary spastic paraplegia with thin corpus callosum","volume":"73","author":"Goizet","year":"2009","journal-title":"Neurology"},{"key":"2023080918525270100_awac391-B9","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1136\/jnnp.2008.167528","article-title":"Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia","volume":"80","author":"Schule","year":"2009","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2023080918525270100_awac391-B10","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1002\/mds.23472","article-title":"Atypical juvenile parkinsonism in a consanguineous SPG15 family","volume":"26","author":"Schicks","year":"2011","journal-title":"Mov Disord"},{"key":"2023080918525270100_awac391-B11","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s10048-013-0366-9","article-title":"Autosomal recessive hereditary spastic paraplegia-clinical and genetic characteristics of a well-defined cohort","volume":"14","author":"Yoon","year":"2013","journal-title":"Neurogenetics"},{"key":"2023080918525270100_awac391-B12","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s00415-013-7216-4","article-title":"SPG15: A cause of juvenile atypical levodopa responsive parkinsonism","volume":"261","author":"Mallaret","year":"2014","journal-title":"J Neurol"},{"key":"2023080918525270100_awac391-B13","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1093\/brain\/awu121","article-title":"Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48","volume":"137","author":"Pensato","year":"2014","journal-title":"Brain"},{"key":"2023080918525270100_awac391-B14","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1093\/brain\/aww111","article-title":"Genetic and phenotypic characterization of complex hereditary spastic paraplegia","volume":"139","author":"Kara","year":"2016","journal-title":"Brain"},{"key":"2023080918525270100_awac391-B15","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1007\/s12041-018-1038-1","article-title":"Novel c.C2254T (p.Q752*) mutation in ZFYVE26 (SPG15) gene in a patient with hereditary spastic paraparesis","volume":"97","author":"Vinci","year":"2018","journal-title":"J Genet"},{"key":"2023080918525270100_awac391-B16","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3174\/ajnr.A5935","article-title":"\u201cEars of the lynx\u201d MRI sign is associated with SPG11 and SPG15 hereditary spastic paraplegia","volume":"40","author":"Pascual","year":"2019","journal-title":"AJNR Am J Neuroradiol"},{"key":"2023080918525270100_awac391-B17","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1080\/00207454.2019.1653293","article-title":"A case of spastic paraplegia-15 with a novel pathogenic variant in ZFYVE26 gene","volume":"129","author":"\u00d6zdemir","year":"2019","journal-title":"Int J Neurosci"},{"key":"2023080918525270100_awac391-B18","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1002\/mdc3.13027","article-title":"SPG15: A rare correlation with atypical juvenile parkinsonism responsive to levodopa","volume":"7","author":"Araujo","year":"2020","journal-title":"Mov Disord Clin 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