Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration.
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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; Isabelle, Le Ber; Forlani, Sylvie; Iwabuchi, Kiyoshi; Meiner, Vardiela; Uyanik, Gökhan; 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, Jahrgang 131, Nr. 3, 3, 2008, S. 772-784.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 - Isabelle, Le Ber
AU - Forlani, Sylvie
AU - Iwabuchi, Kiyoshi
AU - Meiner, Vardiela
AU - Uyanik, Gökhan
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
Y1 - 2008
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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 131
SP - 772
EP - 784
JO - BRAIN
JF - BRAIN
SN - 0006-8950
IS - 3
M1 - 3
ER -
