Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration

Giovanni Stevanin, Hamid Azzedine, Paola Denora, Amir Boukhris, Meriem Tazir, Alexander Lossos, Alberto Luis Rosa, Israela Lerer, Abdelmadjid Hamri, Paulo Alegria, José Loureiro, Masayoshi Tada, Didier Hannequin, Mathieu Anheim, Cyril Goizet, Victoria Gonzalez-Martinez, Isabelle Le Ber, Sylvie Forlani, Kiyoshi Iwabuchi, Vardiela Meiner & 18 others Goekhan Uyanik, Anne Kjersti Erichsen, Imed Feki, Florence Pasquier, Soreya Belarbi, Vitor T. Cruz, Christel Depienne, Jeremy Truchetto, Guillaume Garrigues, Chantal Tallaksen, Christine Tranchant, Masatoyo Nishizawa, José Vale, Paula Coutinho, Filippo M. Santorelli, Chokri Mhiri, Alexis Brice, Alexandra Durr

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity associated, in complicated forms, with additional neurological signs. We have analysed a large series of index patients (n = 76) with this condition, either from families with an autosomal recessive inheritance (n = 43) or isolated patients (n = 33), for mutations in the recently identified SPG11 gene. We found 22 truncating mutations, including the first four splice-site mutations, segregating in seven isolated cases and 13 families. Nineteen mutations were novel. Two recurrent mutations were found in Portuguese and North-African patients indicating founder effects in these populations. The mutation frequency varied according to the phenotype, from 41%, in HSP patients presenting with a thin corpus callosum (TCC) visualized by MRI, to 4.5%, in patients with mental impairment without a TCC. Disease onset occurred during the first to the third decade mainly by problems with gait and/or mental retardation. After a mean disease duration of 14.9 ± 6.6 years, the phenotype of 38 SPG11 patients was severe with 53% of patients wheelchair bound or bedridden. In addition to mental retardation, 80% of the patients showed cognitive decline with executive dysfunction. Interestingly, the phenotype also frequently included lower motor neuron degeneration (81%) with wasting (53%). Slight ocular cerebellar signs were also noted in patients with long disease durations. In addition to a TCC (95%), brain MRI revealed white matter alterations (69%) and cortical atrophy (81%), which worsened with disease duration. In conclusion, our study reveals the high frequency of SPG11 mutations in patients with HSP, a TCC and cognitive impairment, including in isolated patients, and extends the associated phenotype.

Original languageEnglish
Pages (from-to)772-784
Number of pages13
JournalBrain
Volume131
Issue number3
DOIs
Publication statusPublished - 1 Jan 2008

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Nerve Degeneration
Corpus Callosum
Motor Neurons
Mutation
Hereditary Spastic Paraplegia
Phenotype
Mutation Rate
Intellectual Disability
Cognitive Dysfunction
Recessive Spastic paraplegia type 5A
Founder Effect
Wheelchairs
Mentally Ill Persons
Gait
Neurodegenerative Diseases
Atrophy
Lower Extremity

Keywords

  • Lower motor neuron degeneration
  • Mental retardation
  • Spastic paraplegias
  • SPG11
  • Thin corpus callosum

Cite this

Stevanin, Giovanni ; Azzedine, Hamid ; Denora, Paola ; Boukhris, Amir ; Tazir, Meriem ; Lossos, Alexander ; Rosa, Alberto Luis ; Lerer, Israela ; Hamri, Abdelmadjid ; Alegria, Paulo ; Loureiro, José ; Tada, Masayoshi ; Hannequin, Didier ; Anheim, Mathieu ; Goizet, Cyril ; Gonzalez-Martinez, Victoria ; Le Ber, Isabelle ; Forlani, Sylvie ; Iwabuchi, Kiyoshi ; Meiner, Vardiela ; Uyanik, Goekhan ; Erichsen, Anne Kjersti ; Feki, Imed ; Pasquier, Florence ; Belarbi, Soreya ; Cruz, Vitor T. ; Depienne, Christel ; Truchetto, Jeremy ; Garrigues, Guillaume ; Tallaksen, Chantal ; Tranchant, Christine ; Nishizawa, Masatoyo ; Vale, José ; Coutinho, Paula ; Santorelli, Filippo M. ; Mhiri, Chokri ; Brice, Alexis ; Durr, Alexandra. / Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. In: Brain. 2008 ; Vol. 131, No. 3. pp. 772-784.
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abstract = "Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity associated, in complicated forms, with additional neurological signs. We have analysed a large series of index patients (n = 76) with this condition, either from families with an autosomal recessive inheritance (n = 43) or isolated patients (n = 33), for mutations in the recently identified SPG11 gene. We found 22 truncating mutations, including the first four splice-site mutations, segregating in seven isolated cases and 13 families. Nineteen mutations were novel. Two recurrent mutations were found in Portuguese and North-African patients indicating founder effects in these populations. The mutation frequency varied according to the phenotype, from 41{\%}, in HSP patients presenting with a thin corpus callosum (TCC) visualized by MRI, to 4.5{\%}, in patients with mental impairment without a TCC. Disease onset occurred during the first to the third decade mainly by problems with gait and/or mental retardation. After a mean disease duration of 14.9 ± 6.6 years, the phenotype of 38 SPG11 patients was severe with 53{\%} of patients wheelchair bound or bedridden. In addition to mental retardation, 80{\%} of the patients showed cognitive decline with executive dysfunction. Interestingly, the phenotype also frequently included lower motor neuron degeneration (81{\%}) with wasting (53{\%}). Slight ocular cerebellar signs were also noted in patients with long disease durations. In addition to a TCC (95{\%}), brain MRI revealed white matter alterations (69{\%}) and cortical atrophy (81{\%}), which worsened with disease duration. In conclusion, our study reveals the high frequency of SPG11 mutations in patients with HSP, a TCC and cognitive impairment, including in isolated patients, and extends the associated phenotype.",
keywords = "Lower motor neuron degeneration, Mental retardation, Spastic paraplegias, SPG11, Thin corpus callosum",
author = "Giovanni Stevanin and Hamid Azzedine and Paola Denora and Amir Boukhris and Meriem Tazir and Alexander Lossos and Rosa, {Alberto Luis} and Israela Lerer and Abdelmadjid Hamri and Paulo Alegria and Jos{\'e} Loureiro and Masayoshi Tada and Didier Hannequin and Mathieu Anheim and Cyril Goizet and Victoria Gonzalez-Martinez and {Le Ber}, Isabelle and Sylvie Forlani and Kiyoshi Iwabuchi and Vardiela Meiner and Goekhan Uyanik and Erichsen, {Anne Kjersti} and Imed Feki and Florence Pasquier and Soreya Belarbi and Cruz, {Vitor T.} and Christel Depienne and Jeremy Truchetto and Guillaume Garrigues and Chantal Tallaksen and Christine Tranchant and Masatoyo Nishizawa and Jos{\'e} Vale and Paula Coutinho and Santorelli, {Filippo M.} and Chokri Mhiri and Alexis Brice and Alexandra Durr",
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Stevanin, G, Azzedine, H, Denora, P, Boukhris, A, Tazir, M, Lossos, A, Rosa, AL, Lerer, I, Hamri, A, Alegria, P, Loureiro, J, Tada, M, Hannequin, D, Anheim, M, Goizet, C, Gonzalez-Martinez, V, Le Ber, I, Forlani, S, Iwabuchi, K, Meiner, V, Uyanik, G, Erichsen, AK, Feki, I, Pasquier, F, Belarbi, S, Cruz, VT, Depienne, C, Truchetto, J, Garrigues, G, Tallaksen, C, Tranchant, C, Nishizawa, M, Vale, J, Coutinho, P, Santorelli, FM, Mhiri, C, Brice, A & Durr, A 2008, 'Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration', Brain, vol. 131, no. 3, pp. 772-784. https://doi.org/10.1093/brain/awm293

Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. / Stevanin, Giovanni; Azzedine, Hamid; Denora, Paola; Boukhris, Amir; Tazir, Meriem; Lossos, Alexander; Rosa, Alberto Luis; Lerer, Israela; Hamri, Abdelmadjid; Alegria, Paulo; Loureiro, José; Tada, Masayoshi; Hannequin, Didier; Anheim, Mathieu; Goizet, Cyril; Gonzalez-Martinez, Victoria; Le Ber, Isabelle; Forlani, Sylvie; Iwabuchi, Kiyoshi; Meiner, Vardiela; Uyanik, Goekhan; Erichsen, Anne Kjersti; Feki, Imed; Pasquier, Florence; Belarbi, Soreya; Cruz, Vitor T.; Depienne, Christel; Truchetto, Jeremy; Garrigues, Guillaume; Tallaksen, Chantal; Tranchant, Christine; Nishizawa, Masatoyo; Vale, José; Coutinho, Paula; Santorelli, Filippo M.; Mhiri, Chokri; Brice, Alexis; Durr, Alexandra.

In: Brain, Vol. 131, No. 3, 01.01.2008, p. 772-784.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration

AU - Stevanin, Giovanni

AU - Azzedine, Hamid

AU - Denora, Paola

AU - Boukhris, Amir

AU - Tazir, Meriem

AU - Lossos, Alexander

AU - Rosa, Alberto Luis

AU - Lerer, Israela

AU - Hamri, Abdelmadjid

AU - Alegria, Paulo

AU - Loureiro, José

AU - Tada, Masayoshi

AU - Hannequin, Didier

AU - Anheim, Mathieu

AU - Goizet, Cyril

AU - Gonzalez-Martinez, Victoria

AU - Le Ber, Isabelle

AU - Forlani, Sylvie

AU - Iwabuchi, Kiyoshi

AU - Meiner, Vardiela

AU - Uyanik, Goekhan

AU - Erichsen, Anne Kjersti

AU - Feki, Imed

AU - Pasquier, Florence

AU - Belarbi, Soreya

AU - Cruz, Vitor T.

AU - Depienne, Christel

AU - Truchetto, Jeremy

AU - Garrigues, Guillaume

AU - Tallaksen, Chantal

AU - Tranchant, Christine

AU - Nishizawa, Masatoyo

AU - Vale, José

AU - Coutinho, Paula

AU - Santorelli, Filippo M.

AU - Mhiri, Chokri

AU - Brice, Alexis

AU - Durr, Alexandra

PY - 2008/1/1

Y1 - 2008/1/1

N2 - Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity associated, in complicated forms, with additional neurological signs. We have analysed a large series of index patients (n = 76) with this condition, either from families with an autosomal recessive inheritance (n = 43) or isolated patients (n = 33), for mutations in the recently identified SPG11 gene. We found 22 truncating mutations, including the first four splice-site mutations, segregating in seven isolated cases and 13 families. Nineteen mutations were novel. Two recurrent mutations were found in Portuguese and North-African patients indicating founder effects in these populations. The mutation frequency varied according to the phenotype, from 41%, in HSP patients presenting with a thin corpus callosum (TCC) visualized by MRI, to 4.5%, in patients with mental impairment without a TCC. Disease onset occurred during the first to the third decade mainly by problems with gait and/or mental retardation. After a mean disease duration of 14.9 ± 6.6 years, the phenotype of 38 SPG11 patients was severe with 53% of patients wheelchair bound or bedridden. In addition to mental retardation, 80% of the patients showed cognitive decline with executive dysfunction. Interestingly, the phenotype also frequently included lower motor neuron degeneration (81%) with wasting (53%). Slight ocular cerebellar signs were also noted in patients with long disease durations. In addition to a TCC (95%), brain MRI revealed white matter alterations (69%) and cortical atrophy (81%), which worsened with disease duration. In conclusion, our study reveals the high frequency of SPG11 mutations in patients with HSP, a TCC and cognitive impairment, including in isolated patients, and extends the associated phenotype.

AB - Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity associated, in complicated forms, with additional neurological signs. We have analysed a large series of index patients (n = 76) with this condition, either from families with an autosomal recessive inheritance (n = 43) or isolated patients (n = 33), for mutations in the recently identified SPG11 gene. We found 22 truncating mutations, including the first four splice-site mutations, segregating in seven isolated cases and 13 families. Nineteen mutations were novel. Two recurrent mutations were found in Portuguese and North-African patients indicating founder effects in these populations. The mutation frequency varied according to the phenotype, from 41%, in HSP patients presenting with a thin corpus callosum (TCC) visualized by MRI, to 4.5%, in patients with mental impairment without a TCC. Disease onset occurred during the first to the third decade mainly by problems with gait and/or mental retardation. After a mean disease duration of 14.9 ± 6.6 years, the phenotype of 38 SPG11 patients was severe with 53% of patients wheelchair bound or bedridden. In addition to mental retardation, 80% of the patients showed cognitive decline with executive dysfunction. Interestingly, the phenotype also frequently included lower motor neuron degeneration (81%) with wasting (53%). Slight ocular cerebellar signs were also noted in patients with long disease durations. In addition to a TCC (95%), brain MRI revealed white matter alterations (69%) and cortical atrophy (81%), which worsened with disease duration. In conclusion, our study reveals the high frequency of SPG11 mutations in patients with HSP, a TCC and cognitive impairment, including in isolated patients, and extends the associated phenotype.

KW - Lower motor neuron degeneration

KW - Mental retardation

KW - Spastic paraplegias

KW - SPG11

KW - Thin corpus callosum

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U2 - 10.1093/brain/awm293

DO - 10.1093/brain/awm293

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