Atypical late-onset hereditary spastic paraplegia with thin corpus callosum due to novel compound heterozygous mutations in the SPG11 gene.

Abstract

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is a heterogeneous group of complicated HSP with intellectual disability, among which SPG11 represents the most frequent subtype [1]. Disease onset occurs mainly during infancy/adolescence and is usually characterized by progressive spasticity and mental retardation and/or progressive cognitive decline [1]. Here, we describe an atypical phenotype of HSP-TCC related to new compound heterozygous mutations in the Spatacsin (SPG11) gene. The non-consanguineous family under examination has two affected brothers (Fig. 1). Patient II-3 is a 47-year-old male who developed walking difficulties and urinary disturbances at age 42 years. A brain MRI was considered as normal. His affected 53-years-old brother (II-1) developed spastic paraplegia at age 49 associated with urinary urgency and modifications in mood and character. His detailed evaluation was not performed as he refused to undergo to further investigations. Neurologic examination of patient II-3 showed nystagmus, lower limbs spasticity with brisk tendon reflexes and Babinski sign. Mini-mental state examination score was 26/30. The evaluation of the previous brain MRI revealed TCC and periventricular frontal hyperintensity on axial FLAIR images, termed ‘‘ears of the lynx sign’’ [2] (Fig. 1). Based on family history and MRI findings, we searched for mutations in SPG11 (by direct sequencing of all coding exons) after obtaining informed consent from the patient and his family (Ethics Committees of the two Institutions approved the study). Genetic analysis showed compound heterozygosity for a splice site mutation c.1891?1 G[T in intron 9 and a missense mutation c.7000G[C/p.A2334P in exon 39 of the SPG11 gene. The splice mutation is of paternal origin, while the missense change was transmitted by the mother. The analysis by RT-PCR and sequencing of the full-length SPG11 transcript from patient’s cells demonstrated that the splice site mutation leads to skipping of exon 9. The resulting in-frame deletion of 156 bp (c.1736_1891del156) leads to a putative protein-lacking 52 residues and carrying an amino acid change at the deletion junction (p.N579_E631[K). No other splicing alteration was observed, not even in the region encompassing the missense mutation, thereby excluding any possible effect of the missense mutation c.7000G[C on splicing. A deleterious effect on the processing of the SPG11 transcript was instead demonstrated for another missense change c.2608A[G/p.Ile870ValfsX20, which leads to early protein truncation [3]. In summary, the compound heterozygous mutations in this patient lead to the expression of a putative protein lacking only 52 residues from one allele and to a protein carrying a missense change from the other. The Ala2334 residue is quite conserved through evolution, and different softwares (see Fig. 1 legend) predict damaging/deleterious effects deriving from the missense change. The absence of any recognizable domain in the deleted portion of the protein along with the lack of definite functional data on M. P. Giannoccaro R. Liguori P. Avoni Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy