Spastic Paraplegia 46 via the GBA2 Gene

Spastic Paraplegia 46 (SPG46) is a type of hereditary spastic paraplegia (HSP) characterized by early onset (1-20 years, median 7 years) of slowly progressive muscle stiffness and weakness and cerebellar signs. Some SPG46 patients may also have cognitive impairment, bladder dysfunction, cataract, and cerebral and corpus callosum atrophy on brain imaging (Boukhris et al. 2010; Martin et al. 2013; van de Warrenburg et al. 2016). Most SPG46 patients will need a cane in their 20s and become wheelchair-bound within 20-25 years of disease onset (Votsi et al. 2014).

SPG46 is inherited in an autosomal recessive (AR) manner. This disorder is caused by homozygous or compound heterozygous pathogenic variants in the GBA2 gene (Hammer et al. 2013; Sultana et al. 2015). To date, different types of variants (missense, nonsense, splicing and frameshift deletions/duplications) have been found in GBA2 to cause SPG46 (Human Gene Mutation Database). GBA2 encodes the enzyme non-lysosomal glucosylceramidase, which is localized at the cell surface and in the endoplasmic reticulum (Matern et al. 2001). The exact disease mechanism is still not clear; however the loss of function of glucocerebrosidase GBA2 is believed to impair the formation of motor neuron axons in SPG46 patients (Martin et al. 2013).

It is difficult to estimate the exact clinical sensitivity of this test due to the lack of large cohort studies. All the pathogenic variants in the GBA2 gene reported to date can be detected by sequencing.

This test provides full coverage of all coding exons of the GBA2 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).