Open AccessNovel CAPN1 missense variants in complex hereditary spastic paraplegia with early‐onset psychosis
Author(s) -
Alecu Julian E.,
Saffari Afshin,
Jumo Hellen,
Ziegler Marvin,
Strelko Oleksandr,
Brownstein Catherine A.,
GonzalezHeydrich Joseph,
Rodan Lance H.,
Gorman Mark P.,
Sahin Mustafa,
EbrahimiFakhari Darius
Publication year - 2022
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.51531
Subject(s) - missense mutation , hereditary spastic paraplegia , medicine , exome sequencing , spastic , psychosis , genetics , bioinformatics , psychiatry , gene , mutation , biology , phenotype , cerebral palsy
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.