{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:01:45Z","timestamp":1760241705758,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2018,7,19]],"date-time":"2018-07-19T00:00:00Z","timestamp":1531958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurological disorders. HSP is classified as pure when only a spastic weakness of the lower extremities is present. Complex HSP comes with additional neurological or systemic abnormalities. Complex HSP with skeletal abnormalities is rare and mostly seen in autosomal recessive HSP. Autosomal dominant (AD) complex HSP with skeletal abnormalities are consistently seen only in SPG9 (spastic gait type 9). In this paper, we report a kindred condition with AD HSP among four living affected individuals who had progressive, adult onset spastic paraparesis that was associated with a distal arthrogryposis (DA) in every affected individual. They also had episodes of rhabdomyolysis without any clinical signs of myopathy. Exhaustive genetic analysis including targeted sequencing of known HSP and DA genes and whole exome sequencing did not identify the disease-causing gene. It excluded all known HSP and DA genes. We propose that this is a novel genetic type of complex AD HSP. Elucidation of a genetic cause of this type of HSP will further contribute to our understanding of axonal degeneration and skeletal abnormalities.<\/jats:p>","DOI":"10.3390\/brainsci8070136","type":"journal-article","created":{"date-parts":[[2018,7,20]],"date-time":"2018-07-20T02:10:11Z","timestamp":1532052611000},"page":"136","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel Type of Complicated Autosomal Dominant Hereditary Spastic Paraplegia Associated with Congenital Distal Arthrogryposis Type I"],"prefix":"10.3390","volume":"8","author":[{"given":"Peter","family":"Hedera","sequence":"first","affiliation":[{"name":"Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7462-4436","authenticated-orcid":false,"given":"Paolo","family":"Moretti","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA"},{"name":"George E. Wahlen Department of Veterans Administration Medical Center, Salt Lake City, UT 84148, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Howard","sequence":"additional","affiliation":[{"name":"Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"},{"name":"Tennessee Valley Health Care System, Veterans Administration Medical Center, Nashville, TN 37212-2637, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiali","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s12311-016-0803-z","article-title":"Hereditary spastic paraplegia: Clinical and genetic hallmarks","volume":"16","author":"Bortholin","year":"2017","journal-title":"Cerebellum"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jns.2012.03.025","article-title":"Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance","volume":"318","author":"Finsterer","year":"2012","journal-title":"J. Neurol. Sci."},{"key":"ref_3","first-page":"523","article-title":"Hereditary myelopathies","volume":"24","author":"Hedera","year":"2018","journal-title":"Continuum (Minneap Minn)."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1055\/s-2008-1040846","article-title":"Hereditary spastic paraplegia: Genetic heterogeneity and genotype-phenotype correlation","volume":"19","author":"Fink","year":"1999","journal-title":"Semin. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1212\/WNL.0b013e3181b04c6c","article-title":"Dementia in SPG4 hereditary spastic paraplegia: Clinical, genetic, and neuropathologic evidence","volume":"73","author":"Murphy","year":"2009","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1212\/WNL.0000000000000691","article-title":"Extended phenotypic spectrum of KIF5A mutations: From spastic paraplegia to axonal neuropathy","volume":"83","author":"Liu","year":"2014","journal-title":"Neurology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/ng937","article-title":"SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia","volume":"31","author":"Patel","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_8","first-page":"1105","article-title":"Troyer syndrome revisited. A clinical and radiological study of a complicated hereditary spastic paraplegia","volume":"251","author":"Proukakis","year":"2004","journal-title":"J. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.ajhg.2007.12.018","article-title":"Neuropathy target esterase gene mutations cause motor neuron disease","volume":"82","author":"Rainier","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1136\/jmedgenet-2014-102856","article-title":"Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes","volume":"52","author":"Hufnagel","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1097\/OGX.0b013e31822bf5bb","article-title":"Arthrogryposis: A review and approach to prenatal diagnosis","volume":"66","author":"Rink","year":"2011","journal-title":"Obstet. Gynecol. Surv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/B978-0-444-59565-2.00003-4","article-title":"Arthrogryposis and fetal hypomobility syndrome","volume":"113","author":"Haliloglu","year":"2013","journal-title":"Handb. Clin. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00401-012-1024-2","article-title":"Myosinopathies: Pathology and mechanisms","volume":"125","author":"Tajsharghi","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/978-0-387-85766-4_12","article-title":"Tropomyosins in skeletal muscle diseases","volume":"644","author":"Kee","year":"2008","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1001\/archneur.61.10.1600","article-title":"Novel mutation in the SPG3A gene in an African American family with an early onset of hereditary spastic paraplegia","volume":"61","author":"Hedera","year":"2004","journal-title":"Arch. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tian, J., Vemula, S.R., Xiao, J., Valente, E.M., Defazio, G., Petrucci, S., Gigante, A.F., Rudzi\u0144ska-Bar, M., Wszolek, Z.K., and Kennelly, K.D. (2018). Whole-exome sequencing for variant discovery in blepharospasm. Mol. Genet. Genom. Med.","DOI":"10.1002\/mgg3.411"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from next-generation sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1002\/humu.21517","article-title":"dbNSFP: Lightweight database of human nonsynonymous SNPs and their functional predictions","volume":"32","author":"Liu","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: Predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e118","DOI":"10.1093\/nar\/gkr407","article-title":"Predicting the functional impact of protein mutations: Application to cancer genomics","volume":"39","author":"Reva","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1126\/science.1247363","article-title":"Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders","volume":"343","author":"Novarino","year":"2014","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s00439-015-1536-7","article-title":"Delving into the complexity of hereditary spastic paraplegias: How unexpected phenotypes and inheritance modes are revolutionizing their nosology","volume":"134","author":"Tesson","year":"2015","journal-title":"Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1111\/j.1468-1331.2008.02117.x","article-title":"Refinement of the SPG9 locus on chromosome 10q23.3-24.2 and exclusion of candidate genes","volume":"5","author":"Panza","year":"2008","journal-title":"Eur. J. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1093\/brain\/awv143","article-title":"Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia","volume":"138","author":"Coutelier","year":"2015","journal-title":"Brain"},{"key":"ref_27","first-page":"494","article-title":"Spastic disorder in patients with hereditary multiple exostoses, but without spinal cord compression: A new syndrome?","volume":"29","author":"Hamann","year":"1992","journal-title":"J. Med. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1086\/504927","article-title":"ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia","volume":"79","author":"Mannan","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ajhg.2008.05.014","article-title":"The role of ZFYVE27\/protrudin in hereditary spastic paraplegia","volume":"83","author":"Martignoni","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nrn2946","article-title":"Hereditary spastic paraplegias: Membrane traffic and the motor pathway","volume":"12","author":"Blackstone","year":"2011","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/S1474-4422(08)70258-8","article-title":"Hereditary spastic paraplegia: Clinical features and pathogenetic mechanisms","volume":"7","author":"Salinas","year":"2008","journal-title":"Lancet. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1146\/annurev-neuro-062111-150400","article-title":"Cellular pathways of hereditary spastic paraplegia","volume":"35","author":"Blackstone","year":"2012","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.neuron.2010.09.039","article-title":"Molecular motors in neurons: Transport mechanisms and roles in brain function and disease","volume":"68","author":"Horokawa","year":"2010","journal-title":"Neuron"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/8\/7\/136\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:13:06Z","timestamp":1760195586000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/8\/7\/136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,19]]},"references-count":33,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2018,7]]}},"alternative-id":["brainsci8070136"],"URL":"https:\/\/doi.org\/10.3390\/brainsci8070136","relation":{},"ISSN":["2076-3425"],"issn-type":[{"type":"electronic","value":"2076-3425"}],"subject":[],"published":{"date-parts":[[2018,7,19]]}}}