Spastic Paraplegia and Psychomotor Retardation with or without Seizures (SPPRS) via the HACE1 Gene

Hereditary spastic paraplegia (HSP) is a group of clinically and genetically diverse diseases, characterized by spasticity (rigid muscles) and lower extremity weakness (Fink. 2014. PubMed ID: 25192507; Hensiek et al. 2015. PubMed ID: 25480570). Historically, some HSPs are classified as “complex” if the impairments in the lower limb are also accompanied by other systemic or neurologic abnormalities such as seizures, ataxia, intellectual disability, dementia, and vision and hearing impairment (Hedera. 2018. PubMed ID: 20301682).

Pathogenic variants in HACE1 have been implicated as a monogenic cause of SPPRS (spastic-paraplegia-psychomotor-retardation -seizures syndrome, or spastic paraplegia and psychomotor retardation with or without seizures), a rare type of complex HSP with onset in infancy. SPPRS affects diverse ethnic groups, with a prevalence estimated at less than 1 in 1,000,000. Most patients present as newborns with muscular hypotonia followed by global developmental delay, intellectual disability, progressive lower limb spasticity, and often seizures. Minor features of SPPRS are highly variable, and may include ocular abnormalities such as strabismus and/or retinal dystrophy, cerebral atrophy, and hypoplasia of the corpus callosum (Hollstein et al. 2015. PubMed ID: 26424145)

While there are currently no treatments reported for SPPRS, patients and their families may benefit from a molecular diagnosis for prognostic information, symptom management, and reproductive planning.

The majority of variants in HACE1 reported as causative for SPPRS are biallelic truncating loss-of-function variants in a compound heterozygous or homozygous state, consistent with autosomal recessive inheritance (Akawi et al. 2015. PubMed ID: 26437029; Hollstein et al. 2015. PubMed ID: 26424145; Nagy et al. 2019. PubMed ID: 31321300).

HACE1 encodes HECT Domain and Ankyrin Repeat Containing E3 Ubiquitin Protein Ligase 1 (HACE1), an E3 ubiquitin ligase that catalyzes the covalent attachment of ubiquitin moieties to cellular GTPases to target them for degradation by the proteasome, thus antagonizing cellular GTPase activity to regulate a variety of cellular processes (Tang et al. 2011. PubMed ID: 21988917; Torrino et al. 2011. PubMed ID: 22036506).

HACE1 has two known functional domains: the ankyrin repeat region responsible for substrate recognition proximal to the N-terminus (AA 64-257) and the catalytic HECT domain critical for ubiquitin conjugation at the very C-terminus (AA 572-909). Most pathogenic HACE1 variants reported in patients with SPPRS are predicted to result in nonsense-mediated mRNA decay or a truncated protein product with no catalytic activity (Nagy et al. 2019. PubMed ID: 31321300). A homozygous variant predicted to result in the in-frame deletion of a highly conserved residue within the catalytic HECT domain has also been reported in patients with SPPRS (Akawi et al. 2015. PubMed ID: 26437029), suggesting that loss of HACE1 catalytic activity rather than loss of HACE1 protein is important for development of SPPRS.

Heterozygous de novo missense variants in the molecular pathway downstream of HACE1 in RAC1 (encodes a substrate of HACE1) and TRIO (Rac1-GEF) are reported to result in clinical manifestations that overlap with SPPRS, including hypotonia, global developmental delay, and intellectual disability (Reijnders et al. 2017. PubMed ID: 28886345). However, these patients do not exhibit progressive spasticity, a hallmark feature of SPPRS. Thus, HACE1-deficiency appears to be the major cause of SPPRS.

Primary neonatal cardiomyocytes and embryonic fibroblasts derived from homozygous Hace1 knock-out mice are viable in cell culture (Zhang et al. 2014. PubMed ID: 24614889), suggesting HACE1 is not an essential gene for cell survival. Importantly, homozygous Hace1 knock-out mice exhibit brain morphologies and phenotypes similar to patients with SPPRS, including hypoplasia of the corpus callosum, as well as movement and learning deficiencies (Nagy et al. 2019. PubMed ID: 31321300).

Clinical sensitivity is difficult to estimate because only a small number of patients with SPPRS have been reported. Due to phenotypic heterogeneity and rarity of SPPRS, as well as phenotypic overlap with other complex HSPs, clinical sensitivity may be low. Analytical sensitivity should be high because all pathogenic variants reported to date are detectable by sequencing.

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 HACE1 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.