Spastic Paraplegia 4 via the SPAST Gene

Spastic paraplegia 4 (SPG4) is a type of hereditary spastic paraplegia (HSP) characterized by progressive bilateral lower-limb gait spasticity. Over 50% of SPG4 patients have weakness in the legs and abnormal vibration sensation at the ankles. About 30% have sphincter disturbances (Dürr et al. 2003). Onset in young adulthood is common, although in some rare cases symptoms may start as late as in the 70s (Depienne et al. 2007). The average age of onset is 34 (McDermott et al. 2006). SPG4 is the most prevalent type of HSP and accounts for almost 40% of familial HSP and about 18% of sporadic or apparent sporadic HSP (Lo Giudice et al. 2014). Typically, SPG4 is characterized by a pure HSP phenotype, i.e., the symptoms are limited to the lower limbs. A minority of SPG4 cases are complicated by some additional features such as seizures, cerebellar ataxia, and intellectual disability (Nielsen et al. 2004; Ribaï et al. 2008).

SPG4 is caused by pathogenic variants in the SPAST gene and hence is also known as SPAST-associated HSP (Hazan et al. 1999). It is inherited in an autosomal dominant manner, though one unusual recessive pathogenic variant has been reported (Lindsey et al. 2000). The penetrance is age dependent, and is estimated to be about 85% by the age of 45 (Fonknechten et al. 2000). A few individuals with a pathogenic variant may remain lifelong asymptomatic (Dürr et al. 1996). In addition, intrafamilial symptomatic variability is considerable, suggesting the involvement of environmental factors and genetic modifiers (Tesson et al. 2015).

SPAST encodes the protein spastin, which is ubiquitously expressed and has a higher expression level in the fetal brain, playing roles in membrane trafficking and microtubule dynamics (Salinas et al. 2007). Spastin has two main domains, the MIT (microtubule interacting and transport) domain, and the AAA (ATPases associated with diverse cellular activities) domain. Over 300 different pathogenic variants have been identified in SPAST gene: nonsense, missense, splice site variants, small indels, and rare large deletions. With rare exceptions, most of the variants are located in the AAA domain, and act by a haploinsufficiency mechanism (Beetz et al. 2006).

Pathogenic variants in SPAST gene account for almost 40% of hereditary spastic paraplegia (HSP) and about 18% of sporadic or apparent sporadic HSP (Lo Giudice et al. 2014).

This test provides full coverage of all coding exons of the SPAST gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).