Hereditary Spastic Paraplegia

Causes/Genetics

Hereditary spastic paraplegia (HSP) may be transmitted as an autosomal dominant, autosomal recessive, or x-linked recessive trait and may result from changes or mutations of several different genes (genetic heterogeneity). Several of these genes have been mapped to certain locations (loci) on various chromosomes.

As mentioned earlier, uncomplicated HSP is considered the most common form of HSP. In this group of disorders, mutations of several different genes appear to cause similar symptoms and findings. According to some experts, up to 70 percent of cases of uncomplicated HSP may be transmitted as an autosomal dominant trait. Multiple genetic loci have been identified in different families with autosomal dominant HSP, such as on...

• Chromosome 2p (known as SPG4 [i.e., "spastic paraplegia gene 4"])
• Chromosome 8q (SPG8)
• Chromosome 12q (SPG10)
• Chromosome 14q (SPG3A)
• Chromosome 15q (SPG6)
• Chromosome 19q (SPG12)

In addition, a form of autosomal dominant complicated HSP has been mapped to chromosome 10q (SPG9).

Most kindreds in which linkage has been established are associated with the SPG4 gene locus, which is on the short arm (p) of chromosome 2 (2p22-p21). Evidence suggests that the SPG4 gene regulates production of a protein known as spastin. In members of certain families with this form of HSP, there may be reduced expression (reduced penetrance) of the disorder. As a result, some individuals who inherit a gene mutation for HSP may be without (asymptomatic) or unaware of associated symptoms.

Two x-linked recessive forms of HSP have also been identified. In one form, the disorder appears to result from mutations in a gene that regulates production of the L1 cell adhesion molecule (L1CAM). This gene has been mapped to chromosome Xq28 (SPG1). A second x-linked form of HSP is thought to be caused by mutations in a gene that regulates production of a myelin protein (proteolipid protein or PLP). The PLP gene is located on chromosome Xq22 (SPG2).

Genetic loci have also been identified in families with autosomal recessive HSP, such as on chromosome 8 (SPG5A), 15q (SPG11), and 16q (SPG7). The latter has been associated with mutations of a gene that regulates production of a protein known as paraplegin. Kindreds have also been described with autosomal recessive HSP (designated SPG5B) that may be the same as that known as SPG7.

It is important to note that, in many kindreds with HSP, linkage has not been established, suggesting that there are other, currently unknown genetic loci.