Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy

C Mancini, E Giorgio, A Rubegni, L Pradotto, S Bagnoli, E Rubino, P Prontera, S Cavalieri, E Di Gregorio, M Ferrero, E Pozzi, E Riberi, P Ferrero, P Nigro, A Mauro, M Zibetti, A Tessa, M Barghigiani, A Antenora, F SirchiaS Piacentini, G Silvestri, G De Michele, A Filla, L Orsi, F M Santorelli, A Brusco

Research output: Contribution to journalArticle

Abstract

BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant.

METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing.

RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80% of patients), urinary urgency (~30%) and pyramidal signs (~70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes.

CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.

Original languageEnglish
Pages (from-to)80-86
Number of pages7
JournalEuropean Journal of Neurology
Volume26
Issue number1
DOIs
Publication statusPublished - Jan 2019

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Cerebellar Ataxia
Homozygote
Ataxia
Heterozygote
Italy
Phenotype
Dysarthria
Spinocerebellar Degenerations
Cerebellar Diseases
Restriction Mapping
Genetic Association Studies
Age of Onset
Neurodegenerative Diseases
Disease Progression
Genotype
Polymerase Chain Reaction
Mutation
Genes

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Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy. / Mancini, C; Giorgio, E; Rubegni, A; Pradotto, L; Bagnoli, S; Rubino, E; Prontera, P; Cavalieri, S; Di Gregorio, E; Ferrero, M; Pozzi, E; Riberi, E; Ferrero, P; Nigro, P; Mauro, A; Zibetti, M; Tessa, A; Barghigiani, M; Antenora, A; Sirchia, F; Piacentini, S; Silvestri, G; De Michele, G; Filla, A; Orsi, L; Santorelli, F M; Brusco, A.

In: European Journal of Neurology, Vol. 26, No. 1, 01.2019, p. 80-86.

Research output: Contribution to journalArticle

Mancini, C, Giorgio, E, Rubegni, A, Pradotto, L, Bagnoli, S, Rubino, E, Prontera, P, Cavalieri, S, Di Gregorio, E, Ferrero, M, Pozzi, E, Riberi, E, Ferrero, P, Nigro, P, Mauro, A, Zibetti, M, Tessa, A, Barghigiani, M, Antenora, A, Sirchia, F, Piacentini, S, Silvestri, G, De Michele, G, Filla, A, Orsi, L, Santorelli, FM & Brusco, A 2019, 'Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy', European Journal of Neurology, vol. 26, no. 1, pp. 80-86. https://doi.org/10.1111/ene.13768
Mancini, C ; Giorgio, E ; Rubegni, A ; Pradotto, L ; Bagnoli, S ; Rubino, E ; Prontera, P ; Cavalieri, S ; Di Gregorio, E ; Ferrero, M ; Pozzi, E ; Riberi, E ; Ferrero, P ; Nigro, P ; Mauro, A ; Zibetti, M ; Tessa, A ; Barghigiani, M ; Antenora, A ; Sirchia, F ; Piacentini, S ; Silvestri, G ; De Michele, G ; Filla, A ; Orsi, L ; Santorelli, F M ; Brusco, A. / Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy. In: European Journal of Neurology. 2019 ; Vol. 26, No. 1. pp. 80-86.
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T1 - Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy

AU - Mancini, C

AU - Giorgio, E

AU - Rubegni, A

AU - Pradotto, L

AU - Bagnoli, S

AU - Rubino, E

AU - Prontera, P

AU - Cavalieri, S

AU - Di Gregorio, E

AU - Ferrero, M

AU - Pozzi, E

AU - Riberi, E

AU - Ferrero, P

AU - Nigro, P

AU - Mauro, A

AU - Zibetti, M

AU - Tessa, A

AU - Barghigiani, M

AU - Antenora, A

AU - Sirchia, F

AU - Piacentini, S

AU - Silvestri, G

AU - De Michele, G

AU - Filla, A

AU - Orsi, L

AU - Santorelli, F M

AU - Brusco, A

N1 - © 2018 EAN.

PY - 2019/1

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N2 - BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant.METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing.RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80% of patients), urinary urgency (~30%) and pyramidal signs (~70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes.CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.

AB - BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant.METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing.RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80% of patients), urinary urgency (~30%) and pyramidal signs (~70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes.CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.

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DO - 10.1111/ene.13768

M3 - Article

C2 - 30098094

VL - 26

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JO - European Journal of Neurology

JF - European Journal of Neurology

SN - 1351-5101

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