SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy

Abstract

Objective: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort.

Methods: Patients 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.

Results: We 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%).

Conclusions: SYNGAP1 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.

Figure 1. Schematic presentation of SYNGAP1 mutations and microdeletions (A) in patients of our cohort or (B) previously published in the literature

Chromosome 6p21.32 microdeletions including SYNGAP1, are presented as gray bars with << and >> indicating that their breakpoints were outside the region presented here. Truncating (◆) and splice-site (→) mutations are presented above the gene, and missense and in-frame (•) mutations are shown underneath the gene. Bold variants concern recurrent variants that were identified in our cohort but also previously published in the literature. Colors of the lines represent the epilepsy syndrome phenotype: moderate to severe developmental and epileptic encephalopathy (red), moderate to severe developmental encephalopathy with epilepsy (orange), moderate to severe developmental encephalopathy with no epilepsy (blue), mild developmental and epileptic encephalopathy (light green), mild developmental encephalopathy with no epilepsy (dark green), and unknown/unclassified epilepsy (gray). Chromosomal coordinates were based on National Center for Biotechnology Information Build 37 [hg19] and SYNGAP1 mutations, protein domains, and exons on the longest isoform 1 (NM_006772.2).

Figure 2. Ictal EEG registration during eyelid myoclonia–myoclonic–atonic seizure

Red arrows indicate the different phases of the seizure associated with a generalized spike wave (eyelid myoclonia) and a further spike wave correlating with the myoclonic (spike) and atonic (wave) components.

Figure 3. SYNGAP1 dysmorphology

Portrait photographs from 31 of 56 patients with SYNGAP1 mutations or microdeletions including SYNGAP1. (A) Patient 4, (B) patient 6, (C) patient 7, (D), patient 8 (sibling of patient 9), (E) patient 9 (sibling of patient 8), (F) patient 12, (G) patient 13, (H) patient 14, (I) patient 16, (J) patient 18, (K) patient 19, (L) patient 20, (M) patient 21, (N) patient 23, (O) patient 25, (P) patient 27, (Q) patient 28, (R) patient 29, (S) patient 31, (T) patient 32, (U) patient 33, (V) patient 34, (W) patient 35, (X) patient 37, (Y) patient 45, (Z) patient 47, (AA) patient 50, (AB) patient 51, (AC) patient 52, (AD) patient 54 (monozygotic twin with patient 55), and (AE) patient 55 (monozygotic twin with patient 54).

Figure 4. Brain pathology in a patient with an SYNGAP1 mutation

(A) Glial fibrillary acidic protein (GFAP)–stained section of the cerebellar cortex showing a single surviving Purkinje cell (arrow points toward this cell) in a field of Purkinje cell loss and mild internal granular layer and cerebellar molecular layer astrocytosis. (B) GFAP staining of dentate gyrus showing no neuronal loss but mild reactive astrocytosis in the dentate granular layer and the dentate molecular layer of the hippocampus. (C) Vertex view of the cerebral hemispheres showing leptomeningeal fibrosis.

Figure 5. SYNGAP1 encephalopathy

This conceptual diagram highlights that the most common epilepsy phenotype in our cohort was an overlapping syndrome combining the features of 2 well-recognized epilepsy syndromes: epilepsy with eyelid myoclonia with absences (EMA) and epilepsy with myoclonic-atonic seizures (MAE). About one-third of the cohort did not fit into either of these syndromes and had nonsyndromic developmental and epileptic encephalopathy (DEE). One case had West syndrome. Other individuals with SYNGAP1 encephalopathy may have developmental encephalopathy (intellectual disability) without epilepsy.

Figure 6. Comorbidities of SYNGAP1 encephalopathy

The figure shows the percentage of each comorbidity associated with SYNGAP1 encephalopathy in our cohort. Dark red denotes moderate to severe intellectual disability; light red denotes mild intellectual disability.