Spastic Paraplegia 6 via the NIPA1 Gene

Spastic Paraplegia 6 (SPG6) is a type of hereditary spastic paraplegia (HSP) characterized by a severe and progressive spasticity and weakness of the lower limbs (Lo Giudice et al. 2014). Typically, SPG6 exhibits a pure HSP phenotype, i.e., the symptoms are limited to the lower limbs. However, rare cases “complicated” with peripheral neuropathy, cognitive impairment or epilepsy have also been reported (Klebe et al. 2007; Du et al. 2011; Svenstrup et al. 2011). Onset in late teenage or early adulthood is common, but with a range from 8 to 40 years (Denora et al. 2013). SPG6 typically presents with relatively aggressive progression, leading to wheelchair dependency in most patients (Botzolakis et al. 2011).

SPG6 is inherited in an autosomal dominant (AD) manner and is caused by pathogenic variants at the 15q11.2 locus of the NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome region protein 1) gene (Rainier et al. 2003). NIPA1 gene encodes a potential Mg²⁺ transporter, which is highly expressed in the nervous system. NIPA1 protein localizes to plasma membrane, endosomes and Golgi apparatus (Rainier et al. 2003; Goytain et al. 2007). NIPA1 is an inhibitor of BMP (bone morphogenic protein) signaling (Tsang et al. 2009), which is very important for distal axonal function (Zhong et al. 2014). To date, at least 4 different causative variants (c.134C>G, c.298G>A, c.316G>C and c.316G>A) have been reported in SPG6 patients and all of them are missense (Human Gene Mutation Database). c.316 might be a mutational hot spot in the NIPA1 gene, and studies from unrelated families have proved c.316G>A as a recurrent de novo mutation (Hedera et al. 2013).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. In a study of 110 White autosomal dominant HSP families who are negative for SPG4 (spast), SPG6 accounts for <1% (1/110) patients (Klebe et al. 2007).

This test provides full coverage of all coding exons of the NIPA1 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).