Novel CAPN1 missense variants in complex hereditary spastic paraplegia with early-onset psychosis

CAPN1-associated hereditary spastic paraplegia (SPG76) is a rare and clinically heterogenous syndrome due to loss of calpain-1 function. Here we illustrate a translational approach to the case of an 18-year-old patient who first presented with psychiatric symptoms followed by spastic gait, intention tremor, and neurogenic bladder dysfunction, consistent with a complex form of HSP. Exome sequencing showed compound-heterozygous missense variants in CAPN1 (NM_001198868.2: c.1712A>G (p.Asn571Ser)/c.1991C>T (p.Ser664Leu)) and a previously reported heterozygous stop-gain variant in RCL1. In silico analyses of the CAPN1 variants predicted a deleterious effect and in vitro functional studies confirmed reduced calpain-1 activity and dysregulated downstream signaling. These findings support a diagnosis of SPG76 and highlight that the psychiatric symptoms can precede the motor symptoms in HSP. Our results also suggest that multiple genes can potentially contribute to complex neuropsychiatric diseases.

Automated summary

CAPN1-associated hereditary spastic paraplegia (SPG76) is a rare and clinically heterogeneous syndrome caused by the loss of calpain-1 function. In this study, we present a translational approach to a case of an 18-year-old patient who initially showed psychiatric symptoms followed by spastic gait, intention tremor, and neurogenic bladder dysfunction, which are characteristic of a complex form of HSP. Genetic analysis revealed compound-heterozygous missense variants in CAPN1 and a previously reported heterozygous stop-gain variant in RCL1. In silico and in vitro functional studies confirmed the deleterious effect of the CAPN1 variants on calpain-1 activity and downstream signaling. These findings support the diagnosis of SPG76 and highlight the possibility of multiple gene involvement in complex neuropsychiatric diseases.