Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions.
Brain. 2016-03-25; : aww061
DOI: 10.1093/brain/aww061
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1. 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.
Denora PS(1), Smets K(2), Zolfanelli F(3), Ceuterick-de Groote C(4), Casali C(5),
Deconinck T(6), Sieben A(7), Gonzales M(8), Zuchner S(8), Darios F(9), Peeters
D(10), Brice A(11), Malandrini A(12), De Jonghe P(2), Santorelli FM(13), Stevanin
G(14), Martin JJ(15), El Hachimi KH(16).
Author information:
(1)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.
(2)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.
(3)9 Pathology Department, San Giovanni di Dio Hospital, Florence, Italy.
(4)10 Institute Born-Bunge, University of Antwerp, Belgium.
(5)11 Department of Medico-Surgical Sciences and Biotechnologies, Sapienza
University, Polo Pontino Rome, Italy.
(6)6 Neurogenetics Group, VIB-Department of Molecular Genetics, University of
Antwerp, Belgium 7 Laboratories of Neurogenetics, Institute Born-Bunge,
University of Antwerp, Belgium.
(7)10 Institute Born-Bunge, University of Antwerp, Belgium 12 Department of
Neurology, University Hospital Gent, Belgium.
(8)13 Department of Human Genetics and Hussman Institute for Human Genomics,
Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
(9)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.
(10)14 Department of Neurology, AZ Groeninge, Kortrijk, Belgium.
(11)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.
(12)16 Department of Medicine, Surgery and Neuroscience, University of Siena,
Siena, Italy.
(13)17 Molecular Medicine Laboratory, IRCCS Stella Maris Foundation, Calambrone,
Pisa, Italy.
(14)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
.
(15)10 Institute Born-Bunge, University of Antwerp, Belgium
.
(16)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.
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.
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DOI: 10.1093/brain/aww061
PMCID: PMC5839621
PMID: 27016404 [Indexed for MEDLINE]