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Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

(2019) NEUROLOGY. 92(23). p.e2679-e2690
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Abstract
Objective : We took advantage of a large multinational recruitment to delineate genotype-phenotype correlations in a large, trans-European multicenter cohort of patients with spastic paraplegia gene 7 (SPG7). Methods : We analyzed clinical and genetic data from 241 patients with SPG7, integrating neurologic follow-up data. One case was examined neuropathologically. Results : Patients with SPG7 had a mean age of 35.5 +/- 14.3 years (n = 233) at onset and presented with spasticity (n = 89), ataxia (n = 74), or both (n = 45). At the first visit, patients with a longer disease duration (> 20 years, n = 62) showed more cerebellar dysarthria (p < 0.05), deep sensory loss (p < 0.01), muscle wasting (p < 0.01), ophthalmoplegia (p < 0.05), and sphincter dysfunction (p < 0.05) than those with a shorter duration (< 10 years, n = 93). Progression, measured by Scale for the Assessment and Rating of Ataxia evaluations, showed a mean annual increase of 1.0 +/- 1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n = 65) presented significantly more often with pyramidal signs (p < 0.05), diminished visual acuity due to optic atrophy (p < 0.0001), and deep sensory loss (p < 0.0001) than those with at least 1 missense variant (n = 176). Patients with at least 1 Ala510Val variant (58%) were older (age 37.6 +/- 13.7 vs 32.8 +/- 14.6 years, p < 0.05) and showed ataxia at onset (p < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons. Conclusions : This is the largest SPG7 cohort study to date and shows a spasticity-predominant phenotype of LOF variants and more frequent cerebellar ataxia and later onset in patients carrying at least 1 Ala510Val variant.
Keywords
M-AAA PROTEASE, MUTATIONS, GENE, DISEASE, SCALE

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MLA
Coarelli, G., et al. “Loss of Paraplegin Drives Spasticity Rather than Ataxia in a Cohort of 241 Patients with SPG7.” NEUROLOGY, vol. 92, no. 23, 2019, pp. e2679–90.
APA
Coarelli, G., Schule, R., van de Warrenburg, B., De Jonghe, P., Ewenczyk, C., Martinuzzi, A., … Durr, A. (2019). Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7. NEUROLOGY, 92(23), e2679–e2690.
Chicago author-date
Coarelli, G, R Schule, BPC van de Warrenburg, P De Jonghe, C Ewenczyk, A Martinuzzi, M Synofzik, et al. 2019. “Loss of Paraplegin Drives Spasticity Rather than Ataxia in a Cohort of 241 Patients with SPG7.” NEUROLOGY 92 (23): e2679–90.
Chicago author-date (all authors)
Coarelli, G, R Schule, BPC van de Warrenburg, P De Jonghe, C Ewenczyk, A Martinuzzi, M Synofzik, EG Hamer, J Baets, M Anheim, L Schöls, T Deconinck, P Masrori, B Fontaine, T Klockgether, MG D’Angelo, ML Monin, Jan De Bleecker, I Migeotte, P Charles, MT Bassi, T Klopstock, F Mochel, E Ollagnon-Roman, M D’Hooghe, C Kamm, D Kurzwelly, M Papin, CS Davoine, G Banneau, S Tezenas du Montcel, D Seilhean, A Brice, C Duyckaerts, G Stevanin, and A Durr. 2019. “Loss of Paraplegin Drives Spasticity Rather than Ataxia in a Cohort of 241 Patients with SPG7.” NEUROLOGY 92 (23): e2679–e2690.
Vancouver
1.
Coarelli G, Schule R, van de Warrenburg B, De Jonghe P, Ewenczyk C, Martinuzzi A, et al. Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7. NEUROLOGY. 2019;92(23):e2679–90.
IEEE
[1]
G. Coarelli et al., “Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7,” NEUROLOGY, vol. 92, no. 23, pp. e2679–e2690, 2019.
@article{8618345,
  abstract     = {{Objective : We took advantage of a large multinational recruitment to delineate genotype-phenotype correlations in a large, trans-European multicenter cohort of patients with spastic paraplegia gene 7 (SPG7). 
Methods : We analyzed clinical and genetic data from 241 patients with SPG7, integrating neurologic follow-up data. One case was examined neuropathologically. 
Results : Patients with SPG7 had a mean age of 35.5 +/- 14.3 years (n = 233) at onset and presented with spasticity (n = 89), ataxia (n = 74), or both (n = 45). At the first visit, patients with a longer disease duration (> 20 years, n = 62) showed more cerebellar dysarthria (p < 0.05), deep sensory loss (p < 0.01), muscle wasting (p < 0.01), ophthalmoplegia (p < 0.05), and sphincter dysfunction (p < 0.05) than those with a shorter duration (< 10 years, n = 93). Progression, measured by Scale for the Assessment and Rating of Ataxia evaluations, showed a mean annual increase of 1.0 +/- 1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n = 65) presented significantly more often with pyramidal signs (p < 0.05), diminished visual acuity due to optic atrophy (p < 0.0001), and deep sensory loss (p < 0.0001) than those with at least 1 missense variant (n = 176). Patients with at least 1 Ala510Val variant (58%) were older (age 37.6 +/- 13.7 vs 32.8 +/- 14.6 years, p < 0.05) and showed ataxia at onset (p < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons. 
Conclusions : This is the largest SPG7 cohort study to date and shows a spasticity-predominant phenotype of LOF variants and more frequent cerebellar ataxia and later onset in patients carrying at least 1 Ala510Val variant.}},
  author       = {{Coarelli, G and Schule, R and van de Warrenburg, BPC and De Jonghe, P and Ewenczyk, C and Martinuzzi, A and Synofzik, M and Hamer, EG and Baets, J and Anheim, M and Schöls, L and Deconinck, T and Masrori, P and Fontaine, B and Klockgether, T and D'Angelo, MG and Monin, ML and De Bleecker, Jan and Migeotte, I and Charles, P and Bassi, MT and Klopstock, T and Mochel, F and Ollagnon-Roman, E and D'Hooghe, M and Kamm, C and Kurzwelly, D and Papin, M and Davoine, CS and Banneau, G and Tezenas du Montcel, S and Seilhean, D and Brice, A and Duyckaerts, C and Stevanin, G and Durr, A}},
  issn         = {{0028-3878}},
  journal      = {{NEUROLOGY}},
  keywords     = {{M-AAA PROTEASE,MUTATIONS,GENE,DISEASE,SCALE}},
  language     = {{eng}},
  number       = {{23}},
  pages        = {{e2679--e2690}},
  title        = {{Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7}},
  url          = {{http://dx.doi.org/10.1212/wnl.0000000000007606}},
  volume       = {{92}},
  year         = {{2019}},
}

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