Dementia in some SPG4 HSPers

Linked with Alzheimer’s gene


Deletion of exon 17 can cause SPG4 HSP. This mutation type may affect a neighboring gene that causes Alzheimer’s disease, the most common form of dementia among older people.



Autosomal dominant spastic paraplegia, type 4 (SPG4), a debilitating disorder of progressive spasticity and weakness of the lower limbs, results from heterozygous mutations in the SPAST gene. The full spectrum of SPAST mutations causing SPG4 and their mechanisms of formation remain to be determined.


We used multiplex ligation-dependent probe amplification, locus-specific array comparative genomic hybridization, and breakpoint DNA sequencing to identify and describe genomic rearrangements in three patients with a clinical presentation of hereditary spastic paraplegia.


We describe three SPG4 patients with intragenic rearrangements in SPAST; all specifically delete the final exon, exon 17. Breakpoint sequence analyses provide evidence for Alu-specific microhomology-mediated deletion as the mechanism of exon loss; one complex rearrangement apparently occurred by multiple Alu-facilitated template switches.


We hypothesize that the high concentration of Alu family members in the introns and flanking sequence of SPAST may predispose to intragenic rearrangements. Thus, Alu-specific microhomology-mediated intragenic rearrangements in SPAST may be a common cause of SPG4. Furthermore, we propose that genomic deletions encompassing the final exon of SPAST may affect expression of SLC30A6, the most proximal downstream locus and a gene that has been implicated in the pathogenesis of Alzheimer’s disease, potentially explaining recent reports of dementia in selected SPG4 patients.


SOURCE:  Genet Med. 2011 Jun;13(6):582-92.

Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia.

Boone PM, Liu P, Zhang F, Carvalho CM, Towne CF, Batish SD, Lupski JR.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.


Your email address will not be published. Required fields are marked *