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

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.