Spastic Paraplegia 3A via the ATL1 Gene

Spastic paraplegia 3A (SPG3A) is a type of hereditary spastic paraplegia (HSP) characterized by progressive bilateral spasticity and weakness of lower limbs, and diminished vibration sensation. Over 80% of affected individuals manifest spastic gait before the age of 10 years and the rate of progression is slow. The average onset age is 4 years (Hedera 2010). In general, penetrance is high (80%-90%) in SPG3A patients and is not age-dependent (Durr et al. 2004). Typically, SPG3A with early-onset is characterized by a pure HSP phenotype, i.e., the symptoms are limited to lower limbs. However, complicated cases with others symptoms such as axonal motor neuropathy and distal amyotrophy, cerebellar ataxia and intellectual disability have also been reported (Scarano et al. 2005; Haberlová et al. 2008; Fusco et al. 2012).

Similar to other types of HSP, the genotype-phenotype correlation of SPG3A is not clear; therefore the diagnosis of SPG3A can be established only via molecular genetic testing.

SPG3A is caused by pathogenic variants in the ATL1 gene (Zhao et al. 2001). ATL1 is the only known causative gene for this type of HSP. SPG3A accounts for almost 7% of familial HSP, approximately 3.5% of sporadic HSP, and 10%-15% of autosomal dominant (AD) HSP (Lo Giudice et al. 2014; Fink et al. 1996). It is the most prevalent type of early-onset cases, accounting for approximately 40% of AD-HSP with onset before the age of 10 years (Abel et al. 2004; Durr et al. 2004). Although SPG3A is typically inherited in an AD manner, an extremely unusual recessive case has been reported (Khan et al. 2014).

ATL1 encodes protein atlastin-1, a member of the dynamin family predominantly expressed in the pyramidal neurons. ATL1 plays important roles in neurite outgrowth, intracellular membrane trafficking, and in the formation of the tubular ER network (Rismanchi et al. 2008; Hu et al. 2009). The protein contains two transmembrane domains and a GTP binding domain (Zhu et al. 2003). Most SPG3A-causing variants are missense variants in the GTPase binding domain, resulting in decreased catalytic activity (Hedera 2010).

SPG3A is allelic with another autosomal dominant disorder, hereditary sensory neuropathy type 1 (HSN1). Pathogenic variants in ATL1 have been identified in HSN1 patients (Guelly et al. 2011; Leonardis et al. 2012).

This test is predicted to detect pathogenic variants in ATL1 in approximately 7% of familial, and 3.5% of sporadic or apparent sporadic hereditary spastic paraplegia (HSP) patients (Lo Giudice et al. 2014). For autosomal dominant HSP, approximately 10%-15% of all patients and 40% of patients with early onset (< 10 years) will be found to have a pathogenic variant in ATL1 (Fink et al. 1996; Durr et al. 2004).

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 ATL1 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.