New hypothesis for the etiology of SPAST-based hereditary spastic paraplegia

Mutations of the SPAST gene are the chief cause of hereditary spastic paraplegia. Controversy exists in the medical community as to whether the etiology of the disease is haploinsufficiency or toxic gain-of-function properties of the mutant spastin proteins. In recognition of strong reasons that support each possible mechanism, here we present a novel perspective, based in part on new studies with mouse models and in part on the largest study to date on patients with the disease. We posit that haploinsufficiency does not cause the disease but makes the corticospinal tracts vulnerable to a second hit, which is usually the mutant spastin proteins but could also be proteins generated by mutations of other genes that may or may not cause the disease on their own.