title: Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions.
abstract: The most common form of autosomal recessive hereditary spastic paraplegia is caused by mutations in the SPG11/KIAA1840 gene on chromosome 15q. The nature of the vast majority of SPG11 mutations found to date suggests a loss-of-function mechanism of the encoded protein, spatacsin. The SPG11 phenotype is, in most cases, characterized by a progressive spasticity with neuropathy, cognitive impairment and a thin corpus callosum on brain MRI. Full neuropathological characterization has not been reported to date despite the description of >100 SPG11 mutations. We describe here the clinical and pathological features observed in two unrelated females, members of genetically ascertained SPG11 families originating from Belgium and Italy, respectively. We confirm the presence of lesions of motor tracts in medulla oblongata and spinal cord associated with other lesions of the central nervous system. Interestingly, we report for the first time pathological hallmarks of SPG11 in neurons that include intracytoplasmic granular lysosome-like structures mainly in supratentorial areas, and others in subtentorial areas that are partially reminiscent of those observed in amyotrophic lateral sclerosis, such as ubiquitin and p62 aggregates, except that they are never labelled with anti-TDP-43 or anti-cystatin C. The neuropathological overlap with amyotrophic lateral sclerosis, associated with some shared clinical manifestations, opens up new fields of investigation in the physiopathological continuum of motor neuron degeneration.
authors.affiliation: 1 Ecole Pratique des Hautes Etudes, EPHE, PSL université, laboratoire de neurogénétique, F-75013, Paris, France 2 Inserm, U1127, F-75013, Paris, France 3 CNRS, UMR7225, F-75013, Paris, France 4 Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière - ICM, Pitié-Salpêtrière Hospital, F-75013, Paris, France 5 Department of Genetics and Rare Diseases, IRCCS Bambino Gesu' Children Hospital, Rome, Italy.
authors.forename: Paola S
authors.initials: PS
authors.lastname: Denora
authors.affiliation: 6 Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Belgium 7 Laboratories of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium 8 Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Smets
authors.affiliation: 9 Pathology Department, San Giovanni di Dio Hospital, Florence, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Zolfanelli
authors.affiliation: 10 Institute Born-Bunge, University of Antwerp, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Ceuterick-de Groote
authors.affiliation: 11 Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University, Polo Pontino Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Casali
authors.affiliation: 6 Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Belgium 7 Laboratories of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.affiliation: 10 Institute Born-Bunge, University of Antwerp, Belgium 12 Department of Neurology, University Hospital Gent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Sieben
authors.affiliation: 13 Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzales
authors.affiliation: 13 Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: 2 Inserm, U1127, F-75013, Paris, France 3 CNRS, UMR7225, F-75013, Paris, France 4 Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière - ICM, Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Darios
authors.affiliation: 14 Department of Neurology, AZ Groeninge, Kortrijk, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Peeters
authors.affiliation: 2 Inserm, U1127, F-75013, Paris, France 3 CNRS, UMR7225, F-75013, Paris, France 4 Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière - ICM, Pitié-Salpêtrière Hospital, F-75013, Paris, France 15 APHP, Département de Génétique, Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: 16 Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Malandrini
authors.affiliation: 6 Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Belgium 7 Laboratories of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium 8 Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: 17 Molecular Medicine Laboratory, IRCCS Stella Maris Foundation, Calambrone, Pisa, Italy.
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.affiliation: 1 Ecole Pratique des Hautes Etudes, EPHE, PSL université, laboratoire de neurogénétique, F-75013, Paris, France 2 Inserm, U1127, F-75013, Paris, France 3 CNRS, UMR7225, F-75013, Paris, France 4 Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière - ICM, Pitié-Salpêtrière Hospital, F-75013, Paris, France 15 APHP, Département de Génétique, Pitié-Salpêtrière Hospital, F-75013, Paris, France giovanni.stevanin@upmc.fr jean-jacques.martin@uantwerpen.be.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.affiliation: 10 Institute Born-Bunge, University of Antwerp, Belgium giovanni.stevanin@upmc.fr jean-jacques.martin@uantwerpen.be.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.affiliation: 1 Ecole Pratique des Hautes Etudes, EPHE, PSL université, laboratoire de neurogénétique, F-75013, Paris, France 2 Inserm, U1127, F-75013, Paris, France 3 CNRS, UMR7225, F-75013, Paris, France 4 Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière - ICM, Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Khalid H
authors.initials: KH
authors.lastname: El Hachimi
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D001921:Brain / Q000473:pathology; D005260:Female; D005727:Ganglia, Spinal / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000648:ultrastructure; D008297:Male; D008526:Medulla Oblongata / Q000473:pathology; D008875:Middle Aged; D009046:Motor Neurons / Q000473:pathology*; D009154:Mutation; D009410:Nerve Degeneration / Q000473:pathology*; D011506:Proteins / Q000235:genetics; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000473:pathology*; D013116:Spinal Cord / Q000473:pathology
chemical_list: D011506:Proteins; C520412:SPG11 protein, human
keywords: amyotrophic lateral sclerosis; lipofuscin; lysosome; spastic paraplegia 11; spatacsin