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

ABSTRACT: 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.

SUBMITTER: Alecu JE 

PROVIDER: S-EPMC8994985 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Alecu Julian E JE   Saffari Afshin A   Jumo Hellen H   Ziegler Marvin M   Strelko Oleksandr O   Brownstein Catherine A CA   Gonzalez-Heydrich Joseph J   Rodan Lance H LH   Gorman Mark P MP   Sahin Mustafa M   Ebrahimi-Fakhari Darius D  

Annals of clinical and translational neurology 20220316 4

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.  ...[more]

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