Spastic Paraplegia 18 via the ERLIN2 Gene

Spastic Paraplegia 18 (SPG18) is a type of complex hereditary spastic paraplegia (HSP) with severe symptoms. Patients with SPG18 usually show early onset (before the age of 1 or 2 years) of features suggestive of spasticity, including ankle clonus, extensor plantar response, and hyperactive reflexes. Symptoms begin in the feet and spread in an ascending manner, and eventually affect the spine and neck. SPG18 patients typically have delayed motor development and intellectual disability, and are not able to speak, read or write. A few patients may also show seizures and epilepsy (Alazami et al. 2011; Yildirim et al. 2011). Some SPG18 patients may become wheelchair-bound in childhood (Alazami et al. 2011).

SPG18 is inherited as an autosomal recessive (AR) disorder. In a consanguineous Saudi family with SPG18, Alazami et al. (2011) identified a homozygous ~20 kb deletion that disrupts the coding region of ERLIN2 gene. Other studies identified a frameshift pathogenic variant (Yildirim et al. 2011) and a splicing pathogenic variant (Wakil et al. 2013), and confirmed that ERLIN2 loss of function could cause the SPG18 phenotype. ERLIN2 and its paralog ERLIN1 (SPG62) regulate the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs). The mechanism of ERLIN2-associated SPG18 is not clear, however, it has been postulated that loss function of ERLIN2 may lead to persistent activation of IP3 signaling and neuronal channel activity (Alazami et al. 2011).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. All the reported pathogenic variants in ERLIN2 are detectable by sequencing.

This test provides full coverage of all coding exons of the ERLIN2 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).