Alu elements mediate large SPG11 gene rearrangements: further spatacsin mutations.

PURPOSE: Hereditary spastic paraplegias compose a group of neurodegenerative disorders with a large clinical and genetic heterogeneity. Among the autosomal recessive forms, spastic paraplegia type 11 is the most common. METHODS: To better understand the spastic paraplegia type 11 mutation spectrum, we studied a group of 54 patients with hereditary spastic paraplegia. Mutation screening was performed by PCR amplification of SPG11 coding regions and intron boundaries, followed by sequencing. For the detection of large gene rearrangements, we performed multiplex ligation-dependent probe amplification. RESULTS: We report 13 families with spastic paraplegia type 11 carrying either novel or previously identified mutations. We describe a complex entire SPG11 rearrangement and show that large gene rearrangements are frequent among patients with spastic paraplegia type 11. Moreover, we mapped the deletion breakpoints of three different large SPG11 deletions and provide evidence for Alu microhomology-mediated exon deletion. CONCLUSION: Our analysis shows that the high number of repeated elements in SPG11 together with the presence of recombination hotspots and the high intrinsic instability of the 15q locus all contribute toward making this genomic region more prone to large gene rearrangements. These findings enlarge the amount of data relating repeated elements with neurodegenerative disorders and highlight their importance in human disease and genome evolution.

A novel hereditary small vessel disease of the brain.

OBJECTIVE: Only few hereditary ischemic small vessel diseases of the brain (SVDB) have been reported so far. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent of them. Herein, we report a family affected by a SVDB distinct from CADASIL. METHODS: After the occurrence of a small deep infarct associated with white matter lesions both in a 46-year-old man and in his 52-year-old sister, clinical and neuroimaging investigations were conducted in 13 of their relatives originating from Portugal. Other investigations included (1) skin biopsy immunostaining with a Notch3 monoclonal antibody, (2) sequencing of the 23 exons encoding the epidermal growth factor-like domains of the NOTCH3 gene, and (3) a NOTCH3 locus haplotype analysis. RESULTS: Diffuse white matter hyperintensities were observed on T2-weighted magnetic resonance imaging (MRI) in six individuals. In contrast with MRI results in the father and paternal uncle of the proband who were hypertensive, white matter lesions were extensive in the mother who had no vascular risk factor. MRI data in four asymptomatic family members together with the results in the two initial cases were suggestive of an underlying hereditary small vessel disease of the brain. Skin biopsy and NOTCH3 gene mutation screening were negative. Haplotype analysis excluded the NOTCH3 locus. INTERPRETATION: These data strongly suggest that this family is affected by a novel hereditary small vessel disease of the brain and that the mutated gene is distinct from NOTCH3.