REEP1-Related Disorders via the REEP1 Gene

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of disorders in which progressive spasticity of the lower limbs is the major clinical feature. This is mainly caused by the dying-back degeneration at the distal end of the corticospinal tract axons. HSP is divided into “pure” and “complicated” subtypes, with complicated cases having additional findings such as ataxia, seizures, dementia, and cognitive impairment (Fink 2015). There is considerable variability in age of onset, disease course, and severity. REEP1 pathogenic variants can cause hereditary spastic paraplegia type 31 (SPG31), which is typically a “pure” type of HSP (Zuchner et al. 2006; Beetz et al. 2008); however complicated phenotypes have also been observed in some patients. Patients have proximal weakness of the lower extremities, brisk reflexes, and spastic gait abnormalities. Age of onset ranges from late childhood to early thirties. Pathogenic variants in REEP have recently been found to also cause distal hereditary motor neuropathy (dHMN) type VB (Beetz et al. 2012). In the described family with dHMN due to a REEP1 presumed gain-of-function variant, onset occurred in the first or second decade and clinical features included distal muscle weakness and atrophy, primarily affecting the intrinsic hand muscles, but also affected the lower legs resulting in abnormal gait and pes cavus. None had increased muscle tone or spasticity.

SPG31 and distal motor neuropathy Type VB are autosomal dominant disorders caused by defects in the REEP1 gene (Beetz et al. 2012; Zuchner et al. 2006). The REEP1 gene has 7 coding exons that encode a receptor expression-enhancing protein 1 (REEP1), which is found in neurons of the brain and spinal cord. Beetz et al. (2012) hypothesize that loss-of-function variants lead to upper motor neuron disease, while possible gain-of-function variants lead to lower motor neuron disease. Genetic defects of REEP1 found to date include missense, nonsense, splicing, microRNA target site alterations (3’UTR), and small deletion/insertions (Human Gene Mutation Database). A few gross (whole exon or larger) deletions and duplications involving REEP1 have also been reported.

Clinical sensitivity for the distal motor neuropathy phenotype is unknown, since only a few patients have been reported. In a large French cohort of 175 unrelated Hereditary Spastic Paraplegia (HSP) individuals consistent with autosomal dominant inheritance, 12 of the patients were found to harbor pathogenic REEP1 variants (~6.9%) (Goizet et al. 2011). In another large cohort study, 16 of 535 (~3.0%) HSP patients were found to have REEP1 pathogenic variants. When only the “pure” HSP patients were considered (134 patients), REEP1 pathogenic variants were found in 8.2% of samples (Beetz et al. 2008).

This test provides full coverage of all coding exons of the REEP1 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).