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 - 2008/3
Y1 - 2008/3
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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UR - http://www.scopus.com/inward/citedby.url?scp=39749114979&partnerID=8YFLogxK
U2 - 10.1093/brain/awm293
DO - 10.1093/brain/awm293
M3 - Article
C2 - 18079167
AN - SCOPUS:39749114979
VL - 131
SP - 772
EP - 784
JO - Brain
JF - Brain
SN - 0006-8950
IS - 3
ER -