Submission Details

CYP2U1 was first reported in relation to autosomal recessive hereditary spastic paraplegia (HSP) in 2012 (Tesson et al., PMID: 23176821). HSP (also referred to as familial spastic paraparesis), refers to a group of inherited disorders that are characterised by progressive weakness and spasticity of the lower limbs. Symptoms typically progress slowly and can sometimes present as a static clinical course. Age of onset is variable. HSP can co-occur with other conditions, including epilepsy, cognitive deficits, peripheral neuropathy, impaired vision, and deafness.

Twenty-four variants (missense, in-frame indel, nonsense, and frameshift) have been reported in 25 probands in 15 publications. We have included 9 probands and 12 variants in this curation (PMIDs: 23176821, 26914923, 24337409, 290354544, 28725025). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) had been reached (additional PMIDs include: 27679996, 26936192, 27292318, 28120039, 31281085, 31359954, 32006740, 32036589, 34316314, 33107650). Putative loss of function variants account for nearly 50% of observed variants (11/24), but missense variants have also been reported. Functional evidence including protein expression and enzymatic activity studies have been carried out for nine of the 24 variants, supporting the assumption that these variants act through a loss of protein/enzymatic activity.

Of note, vision impairment or other eye phenotypes were also observed in 11 of the 24 probands/families. A case study in 2021 (El Matri et al., PMID: 34828401) reported on an individual (aged 12) with p.Arg390* variant in CYP2U1, who presented with macular telangiectasia in the absence of an HSP phenotype. The GCEP did not include this proband in the curation; however, would like to point out that other individuals with the same variant (p.Arg390*) all presented with eye phenotypes and adult-onset HSP phenotypes. This may explain the absence of the phenotype in the individual reported by El Mitri (2021).

This gene-disease relationship is modestly supported by a CYP2U1 knockout murine model (PMID: 34546337). However, this knockout model does not recapitulate a locomotor phenotype, only a progressive short term memory loss (Y-maze) and photoreceptor cone degeneration (macular degeneration).

In summary, there is definitive evidence to support the relationship between CYP2UI and autosomal recessive HSP. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on October 6, 2022 (SOP Version 9). .