Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration.
2 CHU Pitié-Salpêtrière [AP-HP]
3 Department of neurology
4 Service de Neurologie
5 Department of Neurology
6 Laboratorio de Biologia Cellular y Molecular
7 Department of Human Genetics
8 Service de Neurologie
9 Serviçio Neurologia
10 Departamento de Neurologia
11 Department of Neurology
12 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
13 Service de neurologie [Rouen]
14 Department of Genetics
15 Neurology Department
16 Service de génétique médicale
17 Département de neurologie [Montpellier]
18 Neurological Clinic of Yokohama
19 Department of Histopathology
20 Département de neurologie [Lille]
21 Department of Neurology
22 Département de Neurologie
23 Service de Neurologie [Strasbourg]
24 Unit of Molecular Medicine
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Résumé
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.