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Brain. 2016 Jun;139(Pt 6):1723-34. doi: 10.1093/brain/aww061. Epub 2016 Mar 25.

Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions.

Author information

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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.
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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.
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9 Pathology Department, San Giovanni di Dio Hospital, Florence, Italy.
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10 Institute Born-Bunge, University of Antwerp, Belgium.
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11 Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University, Polo Pontino Rome, Italy.
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6 Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Belgium 7 Laboratories of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
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10 Institute Born-Bunge, University of Antwerp, Belgium 12 Department of Neurology, University Hospital Gent, Belgium.
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13 Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
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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.
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14 Department of Neurology, AZ Groeninge, Kortrijk, Belgium.
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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.
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16 Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
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17 Molecular Medicine Laboratory, IRCCS Stella Maris Foundation, Calambrone, Pisa, Italy.
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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.
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10 Institute Born-Bunge, University of Antwerp, Belgium giovanni.stevanin@upmc.fr jean-jacques.martin@uantwerpen.be.
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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.

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.

KEYWORDS:

amyotrophic lateral sclerosis; lipofuscin; lysosome; spastic paraplegia 11; spatacsin

PMID:
27016404
PMCID:
PMC5839621
DOI:
10.1093/brain/aww061
[Indexed for MEDLINE]
Free PMC Article

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