Pure Hereditary Spastic Paraplegia Panel

Hereditary spastic paraplegia (HSP) is a group of clinically and genetically diverse diseases, characterized by bilateral lower extremity spasticity (rigid muscles) and weakness (Fink. 2014. PubMed ID: 25192507; Hensiek et al. 2015. PubMed ID: 25480570; Hedera. 2018. PubMed ID: 20301682). HSP is classified as “pure” or “uncomplicated” when symptoms are confined to lower extremity spasticity and weakness and hypertonic urinary bladder. In contrast, HSP is classified as “complex” or “complicated” if the impairments in the lower limbs are also accompanied by other systemic or neurologic abnormalities such as seizures, ataxia, intellectual disability, dementia, peripheral neuropathy, and vision and hearing impairment (Hedera. 2018. PubMed ID: 20301682). The incidence of all forms of HSP is estimated to be less than one in 10,000 individuals or 0.01% (Hensiek et al. 2015. PubMed ID: 25480570).

Symptoms of the disease may begin at any age, with early onset HSP beginning in early childhood and often resembling spastic diplegic cerebral palsy and late onset HSP beginning later in childhood or early adulthood (Fink. 2014. PubMed ID: 25192507; Hedera. 2018. PubMed ID: 20301682). In addition to variation in the age of onset, the severity and rate of progression are highly variable among different subtypes of complex HSPs, and even within a specific subtype (Tesson et al. 2015. PubMed ID: 25758904). Patients with pure HSP typically maintain normal function of the upper limb and have no abnormalities in speech or swallowing. In addition, pure HSP does not shorten lifespan (Hedera. 2018. PubMed ID: 20301682).

Advantages of genetic testing for HSP include confirmation of diagnosis, identification of other health risks associated with complicated HSP, allowing for targeted testing of other family members, and assistance with reproductive planning (Hedera. 2018. PubMed ID: 20301682).

To date, more than 90 genetic loci and over 70 genes have been shown to be involved in HSP (Tesson et al. 2015. PubMed ID: 25758904; de Souza et al. 2017. PubMed ID: 27271711). HSP may be inherited in an autosomal dominant (AD) (75% to 80% of cases), autosomal recessive (AR) manner (25% to 30%); or X-linked (XL) (1% to 2%) manner (Hensiek et al. 2015. PubMed ID: 25480570; Hedera. 2018. PubMed ID: 20301682). The genotype-phenotype correlation is poor, and some genes are associated with both complex and pure HSP (Fink. 2013. PubMed ID: 23897027). This multi-gene panel contains causative genes solely for pure HSP as well as the ones that can cause both pure and complex HSP.

See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

This multi-gene panel includes almost all the currently known causative genes for pure Hereditary Spastic Paraplegia (HSP). It is difficult to estimate the clinical sensitivity of this test due to the lack of data. Based on the frequencies of some causative genes in this panel (Hedera. 2018. PubMed ID:  20301682), we predict that this test should detect causative variants in at least 50% of patients with a pure HSP phenotype.

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

This panel typically provides 99.9% coverage of all coding exons of the genes 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 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).