SYNGAP1-related developmental and epileptic encephalopathy (ORPHA:544254)
A rare genetic developmental and epileptic encephalopathy (DEE) characterized by developmental delay, generalized epilepsy consisting of eyelid myoclonia with absences and myoclonic-atonic seizures, intellectual disability and autism spectrum disorder (ASD).
Epidemiology
This disorder has an estimated prevalence of <1/1 000 000.
Clinical description
Presentation is of developmental delay, identified in the first months of life, associated with hypotonia and subsequent neurodevelopmental plateauing or regression. Generalized epilepsy is present in most with seizure onset typically at 2-3 years (ranges from 4 months to 7 years) with a distinctive epilepsy syndrome, combining eyelid myoclonia with absences and myoclonic-atonic seizures. Drop attacks due to eyelid myoclonia evolving to myoclonic-atonic or atonic seizure can be present. Other generalized seizure types, variably combined, and reflex seizures triggered by eating or eyes closure may occur. The spectrum of seizure severity varies, with drug-resistant seizures in about half of patients. Moderate to severe intellectual disability becomes progressively evident in most, associated with ASD in about half of the patients. Behavioral disorders, including oppositional and defiant behavior with aggression, self-injury, and temper tantrums, are seen in most. Subtle dysmorphic facial features may be present in some, including slightly prominent eyebrows with medial flaring, hypertelorism, full nasal tip, slightly upturned nasal tip, short philtrum, cupid bow upper lip, broad mouth with diastemata of the upper teeth, and small pointed chin. Other associated features comprise high pain threshold, eating and sleeping problems, ataxia or gait abnormalities, and orthopedic abnormalities. Brain imaging is usually normal with possible nonspecific findings.
Etiology
The SYNGAP1 gene (6p21.32) encodes the synaptic Ras-GTPase-activating protein 1, mainly expressed in the synapses of excitatory neurons. Loss of function mutations in SYNGAP1 impairs neuronal homeostasis and development. This disorder is caused by heterozygous pathogenc SYNGAP1 variants or chromosome 6p21.32 microdeletions encompassing the SYNGAP1 gene.
Diagnostic methods
The diagnosis is suspected in a patient with developmental delay or intellectual disability, ASD and generalized epilepsy with generalized epileptiform abnormalities on EEG. The genetic identification of pathogenic SYNGAP1 variants (next generation sequencing) or chromosome 6p21.32 microdeletions (aCGH ) confirms the diagnosis.
Differential diagnosis
The phenotype of SYNPAG1-related encephalopathy might overlap with that of other neurodevelopmental disorders and DEEs. Seizures semiology, trigger factors and EEG patterns can help to differentiate this syndrome and orient the genetic testing.
Antenatal diagnosis
Once a pathogenic SYNGAP1 variant has been identified, prenatal testing is possible for a pregnancy at increased risk.
Genetic counseling
The pattern of inheritance is autosomal dominant. Whilst pathogenic variants occur de novo in almost all cases, parental mosaicism is possible. In such cases, genetic counseling is recommended as the risk of recurrence in affected families is higher than the general population.
Management and treatment
Management requires a multidisciplinary approach and tailored treatments addressing the specific symptoms. Anti-seizure medications and ketogenic diet are used for the management of seizures. Non-pharmacological interventions comprise physical, occupational, speech, and feeding therapy, as well as individualized educational plans.
Prognosis
Life expectancy is unknown due to under diagnosis in adult age. However, adult patients are known, demonstrating that survival into adulthood is possible. Prognosis is poor, resulting in severe cognitive deficits in most, associated with behavioral disorders of variable degree, and persisting seizures in half of the cases.

                            Last update: 
                            January 2021


                            - Expert reviewer(s): 
                            Dr Sara MATRICARDI  - Pr Rima NABBOUT | EpiCARE*


                                * European Reference Network