SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

Abstract

Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In Quebec, a significant number of patients affected with cerebellar ataxia and spasticity remain without a molecular diagnosis. We performed whole-exome sequencing in three French Canadian (FC) patients affected with spastic ataxia and uncovered compound heterozygous variants in SPG7 in all three. Sanger sequencing of SPG7 exons and exon/intron boundaries was used to screen additional patients. In total, we identified recessive variants in SPG7 in 22 FC patients belonging to 12 families (38.7% of the families screened), including two novel variants. The p.(Ala510Val) variant was the most common in our cohort. Cerebellar features, including ataxia, were more pronounced than spasticity in this cohort. These results strongly suggest that variants affecting the function of SPG7 are the fourth most common form of recessive ataxia in FC patients. Thus, we propose that SPG7 mutations explain a significant proportion of FC spastic ataxia cases and that this gene should be considered in unresolved patients.

Figure 1

cDNA analysis of the splice site variant c.988-1G>A. (a) Complementary DNA sequence chromatograms are shown for a non-affected control and patient 19 who is homozygous for the c.988-1G>A variant. The G to A substitution leads to the loss of the acceptor splice site and the use of two alternate cryptic acceptor sites located within exon 8, causing the deletion of 2 and 21 nucleotides from the beginning of exon 8, respectively, as well as a frameshift and premature stop codon. (b) Schematic representation of normal splicing of SPG7 (upper panel) and aberrant splicing as seen in case 19 (middle and lower panel).

Figure 2

Brain MRI of FC cases with SPG7 variants. (a–f) Sagittal T1-weighted (a, b, d, e) and coronal T2-weighted (c, f) images show moderate atrophy of the cerebellar vermis and hemispheres in subject 2 at age 57 (a–c), whereas cerebellar atrophy is milder in subject 3 at age 51 (d–f). Sagittal T1- (g) and T2- (h) weighted images show mild cerebellar atrophy on the initial MRI of subject 13 at age 51 (g) without significant progression at the follow-up MRI at age 58.