Hereditary Spastic Paraplegia (HSP) via the ENTPD1 Gene

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 et al. 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 (Fink. 2014. PubMed ID: 25192507; Hedera et al. 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 starting 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 et al. 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).

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 et al. 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 et al. 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).

Biallelic variants in ENTPD1 have been reported in autosomal recessive spastic paraplegia type 64 (SPG64), which is an early-onset complex form of HSP. To our knowledge, no de novo variants have been reported in patients with SPG64 and all reported variants have been found in single patients or families. Variants reported to date include missense and nonsense variants (Novarino et al. 2014. PubMed ID: 24482476; Travaglini et al. 2018. PubMed ID: 29691679; Mamelona et al. 2019. PubMed ID: 30652007). To our knowledge, no large deletions or duplications have been reported in patients with SPG64; however, given the small number of patients reported to date, we cannot rule out the possibility that copy number variants could be clinically important. 

The ENTPD1 gene encodes ectonucleoside triphosphate diphosphohydrolase 1 (ENTPDase-1), a membrane protein that catalyzes dephosphorylation of extra-cellular nucleotides that are involved in the regulation of purinergic neurotransmission. ENTPDase-1 is comprised of two small cytoplasmic domains at the N- and C-termini and a large extra-cellular domain that spans amino acids 38 to 478 and includes the catalytic site (Mamelona et al. 2019. PubMed ID: 30652007). To date, all variants associated with SPG64 have been reported to occur in the extra-cellular domain of the protein (Novarino et al. 2014. PubMed ID: 24482476; Travaglini et al. 2018. PubMed ID: 29691679; Mamelona et al. 2019. PubMed ID: 30652007). ENTPD1 has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

To date, only a handful of families with SPG64 have been reported, indicating that the disorder is a rare form of HSP (Novarino et al. 2014. PubMed ID: 24482476; Travaglini et al. 2018. PubMed ID: 29691679; Mamelona et al. 2019. PubMed ID: 30652007).

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 ENTPD1 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).