SERPINI1 pathogenic variants: An emerging cause of childhood‐onset progressive myoclonic epilepsy

Abstract

Progressive myoclonic epilepsies are rare neurodegenerative diseases with a wide spectrum of clinical presentations and genetic heterogeneity that render their diagnosis perplexing. Discovering new imputable genes has been an ongoing process in recent years. We present two pediatric cases of progressive myoclonic epilepsy with SERPINI1 pathogenic variants that lead to a severe presentation; we highlight the importance of including this gene, previously known as causing an adult-onset dementia-epilepsy syndrome, in the genetic work-up of childhood-onset progressive myoclonic epilepsies.

Early-onset rapidly progressive myoclonic epilepsy associated with G392R likely pathogenic variant in SERPINI1

“…Additionally, EEGs revealed no photoparoxysmal response on intermittent photic stimulation also at low (1−3 Hz) frequencies. Behavioral abnormalities and failure at school were the first signs before seizure onset in our case, as in the case reported by Ranza et al [3] Therefore, neuroserpinosis should be included in the differential diagnosis of children with behavioral abnormalities and learning disabilities preceding PME in the first decade.…”

“…The parents did not carry this variation. Coutelier et al [2] and Ranza et al [3] reported the same aminoacid change (G392R) in the SERPINI1 gene in an 11-year-old girl with medication-refractory electrical status epilepticus of slow-wave sleep, and in a 12-year-old male with early-onset PME with assistance in all activities of daily living, respectively. Although the variation in the protein level is same as the previous two cases, the G to C transversion in nucleotide level has not been reported as a disease causing mutation to date.…”

Gene expression effects of lithium and valproic acid in a serotonergic cell line

“…Of these serpins, which are involved in many regulatory processes, SerpinI1 (neuroserpin) is primarily secreted by axons in the brain, and may play a role in axonal growth and synaptic plasticity [66]. In humans, mutation in SERPINI1 lead to childhood-onset progressive myoclonic epilepsy [67] or familial dementia [68]. Amongst genes downregulated by exposure to VPA in our study was Ap2b1, which encodes an essential component of vesicle function, including synaptic vesicles [69].…”

Gene expression effects of lithium and valproic acid in a serotonergic cell line

“…Of these serpins, which are involved in many regulatory processes, SerpinI1 (neuroserpin) is primarily secreted by axons in the brain and may play a role in axonal growth and synaptic plasticity (68). In humans, mutation in SERPINI1 leads to childhood-onset progressive myoclonic epilepsy (61) or familial dementia (18). Among genes downregulated by exposure to VPA in our study was Ap2b1, which encodes an essential component of vesicle function, including synaptic vesicles (43).…”