GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: A possible gradient in severity?

BACKGROUND: Variants of GATOR1-genes represent a recognised cause of focal cortical dysplasia (FCD), the most common structural aetiology in paediatric drug-resistant focal epilepsy. Reports on familial cases of GATOR1-associated FCD are limited, especially with respect to epilepsy surgery outcomes. METHODS: We present phenotypical manifestations of four unrelated patients with drug-resistant focal epilepsy, FCD and a first-degree relative with epilepsy. All patients underwent targeted gene panel sequencing as a part of the presurgical work up. Literature search was performed to compare our findings to previously published cases. RESULTS: The children (probands) had a more severe phenotype than their parents, including drug-resistant epilepsy and developmental delay, and they failed to achieve seizure freedom post-surgically. All patients had histopathologically confirmed FCD (types IIa, IIb, Ia). In Patient 1 and her affected father, we detected a known pathogenic NPRL2 variant. In patients 2 and 3 and their affected parents, we found novel likely pathogenic germline DEPDC5 variants. In family 4, we detected a novel variant in NPRL3. We identified 15 additional cases who underwent epilepsy surgery for GATOR1-associated FCD, with a positive family history of epilepsy in the literature; in 8/13 tested, the variant was inherited from an asymptomatic parent. CONCLUSION: The presented cases displayed a severity gradient in phenotype with children more severely affected than the parents. Although patients with GATOR1-associated FCD are considered good surgical candidates, post-surgical seizure outcome was poor in our familial cases, suggesting that accurate identification of the epileptogenic zone may be more challenging in this subgroup of patients.

Implications of genetic diagnostics in epilepsy surgery candidates: A single-center cohort study.

OBJECTIVE: Genetic causes are increasingly identified in patients with focal epilepsy. These genetic causes may be related to the effectiveness of epilepsy surgery. We aimed to assess the use and yield of genetic testing in a large cohort of patients who were evaluated for epilepsy surgery. METHODS: We performed a retrospective single-center consecutive cohort study of patients who were evaluated for surgery between 1990 and 2016. Within this cohort, we assessed the use of genetic testing-either before or after presurgical decision-making. We evaluated genetic results as well as the outcome of presurgical decision-making and surgery, and compared these end points for different subgroups-especially MRI-positive vs MRI-negative patients. Patients with tuberous sclerosis (TSC) and KRIT1 mutations were excluded from analysis. RESULTS: Of the 2385 epilepsy patients who were evaluated for surgery, 1280 (54%) received surgical treatment in our center. Of the entire cohort, 325 (14%) underwent genetic testing, comprising 156 of 450 MRI-negative patients (35%) vs 169 of 1935 MRI-positive patients (9%). A genetic cause of epilepsy was found in 40 of the 325 patients (12%, 2% of the entire cohort), mainly consisting of mutations in ion channel function and synaptic transmission genes, and mTOR pathway gene mutations. Three of the seven patients with mTOR pathway gene mutations underwent surgery; two achieved complete seizure freedom. One of the 17 patients with germline mutations in ion channel function and synaptic transmission genes received resective surgery but was not rendered seizure-free; two other patients underwent invasive intracranial EEG-monitoring before being rejected. SIGNIFICANCE: This study shows that genetic testing is increasingly applied in focal epilepsy patients who are considered for epilepsy surgery. The diagnostic yield of genetic testing is highest in next generation sequencing techniques, and the outcome of genetic testing assists selecting eligible patients for invasive intracranial monitoring and resective surgery.