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

• Published in: Annals of clinical and translational neurology Vol. 9; no. 4; pp. 570 - 576
• Main Authors: Alecu, Julian E., Saffari, Afshin, Jumo, Hellen, Ziegler, Marvin, Strelko, Oleksandr, Brownstein, Catherine A., Gonzalez‐Heydrich, Joseph, Rodan, Lance H., Gorman, Mark P., Sahin, Mustafa, Ebrahimi‐Fakhari, Darius
• Format: Journal Article
• Language: English; Spanish
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2022; John Wiley & Sons, Inc; Wiley
• Subjects: Adolescent; Age; Amino acids; Brief Communication; Brief Communications; Calpain - genetics; Enzymes; Fibroblasts; Humans; Hydrogen bonds; Mutation; Paralysis; Pedigree; Proteins; Psychosis; Psychotic Disorders - genetics; Spastic Paraplegia, Hereditary - genetics; Spasticity; United States > US
• ISSN: 2328-9503; 2328-9503
• DOI: 10.1002/acn3.51531

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.