Abstracts

Rationale:
The GABRA1 gene encodes the alfa subunit of the GABA receptor. GABA is the major inhibitory neurotransmitter in the human brain. Pathogenic variants were first identified in patients with idiopathic generalized epilepsy. Recently the phenotypic spectrum, has been expanded to include a spectrum from mild genetic generalized epilepsies to severe phenotypes such as early onset developmental and epileptic encephalopathy (DEE), including Dravet syndrome. In the DEE group common symptoms include multiple treatment refractory seizure types, intellectual disability, fever-sensitive features and seizures onset before age of 12 months. Tonic clonic and myoclonic seizures are predominant.
Method:
A Next Generation Sequencing panel was performed as an analysis method. The features of clinical manifestation and evolution, electroencephalogram and neuroimaiging were analyzed. Seizures were classified according to the International League Against epilepsy recommendations. Results15 years old male patient with a de novo pathogenic variant in heterozygous state in the Gamma-aminobutyric acid (GABA) A receptor, alpha 1 (GABRA1) gene, described as c.335G >A, leading to the missense substitution p.(Arg112Gln).  The patient had simple febrile seizures onset at the age of 10 months and offset in the third year of life.  The first afebrile seizures onset at the age of 3.5 years with multiple seizures types: a). Focal impaired awareness seizures with behavioral arrest, b). Focal to bilateral tonic-clonic (type 1 with secondary generalization), c). Focal impaired awareness seizures with myoclonic jerks in the neck, shoulder and arm more often on the left side. EEG showed focal spike-wave discharges in bi-occipito-posttemporal region with anterior bi-frontal propagation. d). He also had a numerous focal motor aware seizures with myoclonic jerks in diaphragm, initially misdiagnosed as vocal tics, developed from the age of 7.  e). Focal sensory seizures appeared at the age of twelve as flickering in the eyes and a sensation of blindness, sometimes followed by eye blink. This sensation appears alone or as a visual aura with secondary generalisation.    Focal myoclonic seizures including myoclonic jerks in diaphragm and sensory visual seizures with or without generalisation are at present the only seizures types. The focal onset in bi-occipito-parietal region with anterior bi-frontal propagation was found in the ictal EEG pattern for all seizures types.  Seizures are drug-refractory. Current (poly)therapy include: brivaracetam and valproate acid. The patient is waiting for VNS implantation. From 7 years of age, memory and concentration problems appeared followed by increasing behavioral disorders with aggressiveness. Obsessive-compulsive disorder and infantile autism were diagnosed.
Conclusion:
Myoclonic seizures are one of the predominant seizure types among patient with pathogenic GABRA1 variants but sensory visual seizures may also occur. Diaphragm myoclonic seizures may be misdiagnosed as vocal tics. Intellectual disability is common but comorbidity with obsessive-compulsive disorder and infantile autism is also possible.
Funding:
:No funding was received