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 of4100 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1723-1734 |
| Number of pages | 12 |
| Journal | Brain |
| Volume | 139 |
| Issue number | 6 |
| DOIs | |
| State | Published - 2016 |
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Keywords
- Amyotrophic lateral sclerosis
- Lipofuscin
- Lysosome
- Spastic paraplegia 11
- Spatacsin
ASJC Scopus subject areas
- Clinical Neurology
Cite this
Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions. / Denora, Paola S.; Smets, Katrien; Zolfanelli, Federica; Groote, Chantal Ceuterick De; Casali, Carlo; Deconinck, Tine; Sieben, Anne; Gonzales, Michael; Zuchner, Stephan L; Darios, Frederic; Peeters, Dirk; Brice, Alexis; Malandrini, Alessandro; De Jonghe, Peter; Santorelli, Filippo M.; Stevanin, Giovanni; Martin, Jean Jacques; El Hachimi, Khalid H.
In: Brain, Vol. 139, No. 6, 2016, p. 1723-1734.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions
AU - Denora, Paola S.
AU - Smets, Katrien
AU - Zolfanelli, Federica
AU - Groote, Chantal Ceuterick De
AU - Casali, Carlo
AU - Deconinck, Tine
AU - Sieben, Anne
AU - Gonzales, Michael
AU - Zuchner, Stephan L
AU - Darios, Frederic
AU - Peeters, Dirk
AU - Brice, Alexis
AU - Malandrini, Alessandro
AU - De Jonghe, Peter
AU - Santorelli, Filippo M.
AU - Stevanin, Giovanni
AU - Martin, Jean Jacques
AU - El Hachimi, Khalid H.
PY - 2016
Y1 - 2016
N2 - 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 of4100 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.
AB - 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 of4100 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.
KW - Amyotrophic lateral sclerosis
KW - Lipofuscin
KW - Lysosome
KW - Spastic paraplegia 11
KW - Spatacsin
UR - http://www.scopus.com/inward/record.url?scp=84978852397&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84978852397&partnerID=8YFLogxK
U2 - 10.1093/brain/aww061
DO - 10.1093/brain/aww061
M3 - Article
VL - 139
SP - 1723
EP - 1734
JO - Brain
JF - Brain
SN - 0006-8950
IS - 6
ER -