SYNGAP1 encephalopathy

Abstract

ObjectiveTo delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort.MethodsPatients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos.ResultsWe included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%).ConclusionsSYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.

SYNGAP1 mutations: Clinical, genetic, and pathophysiological features

“…In approximately 89% of cases, the mutation results in a pathogenic SYNGAP1 variant (Holder et al, 2019), which is a truncated version of the protein in approximately 60% of cases (due to frameshift or nonsense mutations). Pathogenic variants also arise due to missense mutations and splice site mutations (about 30% of cases) (Hamdan et al, 2011; O'Roak et al, 2014; Parker et al, 2015; Vlaskamp et al, 2019). In 11% of cases, 6p21.3 microdeletions are the cause of MRD5 (Holder et al, 2019; Vlaskamp et al, 2019).…”

Frequently Identified Genetic Developmental and Epileptic Encephalopathy: A Review Focusing on Precision Medicine

“…In a retrospective study with 57 patients, valproate (n = 45) and lamotrigine (n = 22) were the most commonly prescribed AEDs, with long-term treatment with lamotrigine in 77% and valproate in 64% of patients, respectively, suggesting effectiveness [98]. This is a reasonable result considering that generalized seizures occur in SYNGAP1-associated epilepsy patients and because there is currently no targeted therapy specifically for SYNGAP1.…”

“…SYNGAP1 mutations cause developmental epileptic encephalopathy characterized by generalized epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures that are often pharmacoresistant [98]. Seizures triggered by eating is also a characteristic feature [98]. SYNGAP1 encephalopathy is associated with a spectrum of mild to severe intellectual disability, with a large proportion of patients with severe ID and other comorbidi- Table 1.…”

“…Epilepsy with early onset tonic spasms (often immediately after birth) that are drug resistant, multifocal epileptic activity on EEG, developmental delay/intellectual disability, and involuntary movements such as spasms and jerks Levetiracetam, vigabatrin, and valproic acid have been reported to be beneficial in small number of case reports [81,82,[87][88][89][90][91]. ties such as behavioral problems, autism spectrum disorder, hypotonia, eating problems, and sleeping problems [98].…”

“…Generalized epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures that are drug resistant, seizures triggered by eating, and developmental delay/intellectual disability Valproate and lamotrigine are most frequently used[98].ALDH7A1, aldehyde dehydrogenase 7 family, member A1; CDKL5, cyclin-dependent kinase-like 5; KCNQ2, potassium channel, voltage-gated, KQT-like subfamily member 2; EEG, electroencephalogram; KCNT1, potassium channel subfamily T member 1; EIMFS, epilepsy of infancy with migrating focal seizures; ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; SCN2A, sodium channel, voltage-gated, type II, alpha subunit; SCN8A, sodium channel, voltage-gated, type VIII alpha subunit; STXBP1, syntaxin-binding protein 1; SYNGAP1, synaptic RAS-GTPase-activating protein 1.…”