Developmental outcome of electroencephalographic findings in SYNGAP1 encephalopathy

SYNGAP1 haploinsufficiency results in a developmental and epileptic encephalopathy (DEE) causing generalized epilepsies accompanied by a spectrum of neurodevelopmental symptoms. Concerning interictal epileptiform discharges (IEDs) in electroencephalograms (EEG), potential biomarkers have been postulated, including changes in background activity, fixation-off sensitivity (FOS) or eye closure sensitivity (ECS). In this study we clinically evaluate a new cohort of 36 SYNGAP1-DEE individuals. Standardized questionnaires were employed to collect clinical, electroencephalographic and genetic data. We investigated electroencephalographic findings, focusing on the cortical distribution of interictal abnormalities and their changes with age. Among the 36 SYNGAP1-DEE cases 18 presented variants in the SYNGAP1 gene that had never been previously reported. The mean age of diagnosis was 8 years and 8 months, ranging from 2 to 17 years, with 55.9% being male. All subjects had global neurodevelopmental/language delay and behavioral abnormalities; 83.3% had moderate to profound intellectual disability (ID), 91.7% displayed autistic traits, 73% experienced sleep disorders and 86.1% suffered from epileptic seizures, mainly eyelid myoclonia with absences (55.3%). A total of 63 VEEGs were revised, observing a worsening of certain EEG findings with increasing age. A disorganized background was observed in all age ranges, yet this was more common among older cases. The main IEDs were bilateral synchronous and asynchronous posterior discharges, accounting for ≥50% in all age ranges. Generalized alterations with maximum amplitude in the anterior region showed as the second most frequent IED (≥15% in all age ranges) and were also more common with increasing age. Finally, diffuse fast activity was much more prevalent in cases with 6 years or older. To the best of our knowledge, this is the first study to analyze EEG features across different age groups, revealing an increase in interictal abnormalities over infancy and adolescence. Our findings suggest that SYNGAP1 haploinsufficiency has complex effects in human brain development, some of which might unravel at different developmental stages. Furthermore, they highlight the potential of baseline EEG to identify candidate biomarkers and the importance of natural history studies to develop specialized therapies and clinical trials.


GROSS MOTOR ABILITIES
with the assistance of a mobility device (ex -walker, cane).Climbs stairs using handrails or with assistance.Cannot walk long distances.o Level IV (moderate to severe limitations): Using mobility assistance, such as wheelchair, more so than before.o Level V (severe limitations): Children are transported in a manual wheelchair in all settings.Children are limited in their ability to maintain antigravity head and trunk postures and control arm and leg movements.Transfers require complete physical assistance of an adult.At home, children may move short distances on the floor or may be carried by an adult.Children may achieve selfmobility using powered mobility with extensive adaptations for seating and control access.
Fine Motor ○ Level I (mild limitations): Handles objects easily and successfully but slight limitation with precision and hand coordination.May need adult assistance when handling objects compared to other children of the same age.Limited in holding very small, very heavy, or fragile objects.
○ Level II (mild to moderate limitations): Handles most objects, but with somewhat reduced quality or speed.May use alternative strategies, such as using only one hand instead of both or switching hands, or use a hard surface for support instead of both hands.
○ Level III (moderate limitations): Handles objects with difficulty and slowly; often needs help by having objects placed in front of him/her.
Level IV (moderate to severe limitations): Handles a limited selection of objects; needs constant adult help; at best, can perform simple actions: grasping or releasing objects.
○ Level V (severe limitations): Does not handle objects and has severely limited ability to perform even simple actions.At best, can push, touch, press, or hold on to a few simple items.

BEHAVIOUR AND PSYCHIATRIC SYMPTOMS
Diagnosis (choose one): Age at diagnosis of SYNGAP1 mutation (i.e when diagnosis was confirmed by a lab study) o Prenatal (first month of life); age: _____days o Newborn (first month of life); age: _____days o Infant (2 nd to 18 th month of life); age: _____months o Child (>18 month to 11 years); age: _____years o Adolescent/adult (>11 years); age: _____years o Yes If yes, age of onset (in y) _________________________ o Yes If yes, age of onset (in y) _________________________ o No BEHAVIOUR 35.Sleep Disorders o Yes If yes, age of onset (in y) _________________________ o Yes If yes, age of onset (in y) _________________________ o No 40.Friendliness o Yes If yes, age of onset (in y) _________________________ o No 41.Autism Spectrum Disorder o Yes If yes, age of onset (in y) _________________________ o No 42.Deficits in social communication o Yes If yes, age of onset (in y) _________________________ Level III (moderate limitations): Walking requires assistance, either from an adult or a mobility assistance device.Sits with trunk support, lifts self up while holding onto something sturdy; can climb stairs with assistance.oLevelIV (moderate to severe limitations): Children sit on a chair but need adaptive seating for trunk control and to maximize hand function.Children move in and out of chair sitting with assistance from an adult or a stable surface to push or pull up on with their arms.Children may at best walk short distances with a walker and adult supervision but have difficulty turning and maintaining balance on uneven surfaces.Children are transported in the community.Children may achieve selfmobility using a powered wheelchair.o Level V: Physical impairments restrict voluntary control of movement and the ability to maintain antigravity head and trunk postures.All areas of motor function are limited.Functional limitations in sitting and standing are not fully compensated for through the use of adaptive equipment and assistive technology.At Level V, children have no means of independent movement and are transported.Level I limitations): Speed, balance, and coordination are reduced.Runs, jumps, climbs stairs, and walks without assistance.o Level II (mild to moderate limitations): Minimal ability to run and jump.Needs assistance when climbing steps (needs railing) or walking on uneven surfaces or an incline.Otherwise able to walk indoors and outdoors with little to no help.o Level III (moderate limitations): Able to walk indoors and outdoors Unable to skip, hop, or jump.Able to sit in a chair without assistance and climb stairs with assistance (railing).o Continuous (>90% of record) o Abundant (50-89% of record) o Frequent (10-49% of record) o Occasional (1-9% of record) o Rare (< 1 % of record) Patient (ID): ……………………………………... Date: …… /……./…….. (DD/MM/YYYY)