Spastic Paraplegia 11 via the SPG11 Gene

Spastic paraplegia 11 (SPG11) is a type of hereditary spastic paraplegia (HSP) and is characterized by progressive spasticity and weakness of the lower limbs (Stevanin et al. 2008a). Most SPG11 cases are complex, i.e., the spastic paraparesis are associated with other features, such as cognitive impairments, thin corpus callosum (TCC), white and grey matter abnormalities (Stevanin et al. 2008b; Franca et al. 2012). Onset is typically early (age 1-31 years) and most SPG11 patients become wheelchair users 10-20 years after disease onset (Stevanin et al. 2008a).

Although cognitive impairments and TCC serve as phenotype predictors of SPG11, these features may also be present in other HSP patients with a different genetic basis. In addition, pathogenic variants in SPG11 can also cause Charcot-Marie-Tooth disease type 2X (Montecchiani et al. 2016) and juvenile Amyotrophic Lateral Sclerosis type 5 (ALS5) (Orlacchio et al. 2010), different neurological disorders with overlapping features. Molecular genetic testing is very useful in a precise diagnosis of this type of disease.

SPG11 is inherited as an autosomal recessive (AR) disorder and it is known to be the most common type of AR-HSP. SPG11 (also known as KIAA1840) is the only gene in which pathogenic variants cause SPG11 (Stevanin et al. 2007). The SPG11 gene encodes spatacsin (for spasticity with thin or atrophied corpus callosum syndrome protein), a protein expressed throughout the nervous system. The function of spatacsin is not well understood, but a recent study suggests that it may play roles in axonal maintenance and intracellular protein trafficking (Perez-Branguli et al. 2014). To date, with the exception of a few (<10) missense variants reported, all the identified pathogenic variants (>150) in SPG11 are either nonsense or deletions/duplications leading to a frameshift, strongly suggesting a loss-of-function mechanism (Human Gene Mutation Database).

SPG11 accounts for approximately 21% of all autosomal recessive (AR) hereditary spastic paraplegia (HSP) (Stevanin et al. 2008b). For patients with early-onset and cognitive impairments associated with thin corpus callosum (TCC), pathogenic variants in SPG11 may account for up to 59% of cases (Stevanin et al. 2008b; Denora et al. 2009).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the SPG11 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.