title: Genetic and phenotypic characterization of complex hereditary spastic paraplegia.
abstract: The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns. Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15, SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined. The overlap with other neurodegenerative disorders has been implied in a small number of reports, but not in larger disease series. This deficiency has been largely due to the lack of suitable high throughput techniques to investigate the genetic basis of disease, but the recent availability of next generation sequencing can facilitate the identification of disease-causing mutations even in extremely heterogeneous disorders. We investigated a series of 97 index cases with complex spastic paraplegia referred to a tertiary referral neurology centre in London for diagnosis or management. The mean age of onset was 16 years (range 3 to 39). The SPG11 gene was first analysed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of probands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia in the UK, with severe and progressive clinical features and other neurological manifestations, linked with magnetic resonance imaging defects. Given the high frequency of SPG11 mutations, we studied the autophagic response to starvation in eight affected SPG11 cases and control fibroblast cell lines, but in our restricted study we did not observe correlations between disease status and autophagic or lysosomal markers. In the remaining cases, next generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15 Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson's disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes.
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 2 Alzheimer's Disease Research Centre, Department of Neurology, Harvard Medical School and Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA.
authors.forename: Eleanna
authors.initials: E
authors.lastname: Kara
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 3 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Tucci
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 4 School of Pharmacy, University of Reading, Reading RG6 6AP, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzoni
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: David S
authors.initials: DS
authors.lastname: Lynch
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Marilena
authors.initials: M
authors.lastname: Elpidorou
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Conceicao
authors.initials: C
authors.lastname: Bettencourt
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Viorica
authors.initials: V
authors.lastname: Chelban
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Andreea
authors.initials: A
authors.lastname: Manole
authors.affiliation: 5 Department of Neurology and Psychiatry, Assiut University Hospital, Faculty of Medicine, Assiut, Egypt.
authors.forename: Sherifa A
authors.initials: SA
authors.lastname: Hamed
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 5 Department of Neurology and Psychiatry, Assiut University Hospital, Faculty of Medicine, Assiut, Egypt.
authors.forename: Nourelhoda A
authors.initials: NA
authors.lastname: Haridy
authors.affiliation: 6 Laboratory of Neurogenetics, NIH/NIA, Bethesda, MD 20892, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Federoff
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Preza
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hughes
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Pittman
authors.affiliation: 7 Division of Neuropathology and Department of Neurodegenerative Disease, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Zane
authors.initials: Z
authors.lastname: Jaunmuktane
authors.affiliation: 7 Division of Neuropathology and Department of Neurodegenerative Disease, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 8 Department of Neurology, Papageorgiou Hospital, Thessaloniki, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Xiromerisiou
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wiethoff
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Schottlaender
authors.affiliation: 9 Department of Clinical Neuroscience, Royal Free Campus, UCL Institute of Neurology, London, UK.
authors.forename: Christos
authors.initials: C
authors.lastname: Proukakis
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 9 Department of Clinical Neuroscience, Royal Free Campus, UCL Institute of Neurology, London, UK.
authors.forename: Huw
authors.initials: H
authors.lastname: Morris
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 10 Reta Lila Weston Institute of Neurological Studies and Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Warner
authors.affiliation: 11 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.affiliation: 11 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: L V Prasad
authors.initials: LV
authors.lastname: Korlipara
authors.affiliation: 6 Laboratory of Neurogenetics, NIH/NIA, Bethesda, MD 20892, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 12 Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 4 School of Pharmacy, University of Reading, Reading RG6 6AP, UK.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lewis
authors.affiliation: 1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 2 Alzheimer's Disease Research Centre, Department of Neurology, Harvard Medical School and Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA h.houlden@ucl.ac.uk.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000293:Adolescent; D000328:Adult; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D000091346:Tripeptidyl-Peptidase 1; D006113:United Kingdom; D055815:Young Adult
chemical_list: D011506:Proteins; C520412:SPG11 protein, human; D000091346:Tripeptidyl-Peptidase 1; C000717267:TPP1 protein, human
keywords: Parkinson’s disease; SPG11; gene; hereditary spastic paraplegia; mutation