Spectrum of Disease Caused By C191r, R157g, and A39v Tbc1d24 Mutations

Objective To describe the phenotypic spectrum of early-onset epilepsy associated with mutations in TBC1D24

Methods A retrospective review of all genetic testing performed at five centers since Jan 2018 was performed. All children with TBC1D24 variants were considered eligible. Patients were excluded if the mutations were non-pathogenic. Patient data, including details of clinical, laboratory, neurophysiological, and neuroimaging features, genetic mutations, and therapeutic interventions, were chronicled using a case record form.

Results Eleven patients (six female) belonging to eight families were included. The patients were homozygous to 571 T/C (n=3), 469 C/G (n=3), or 116 C/T (n=4) variants, giving the amino acid changes of C191R, R157G, and A39V, respectively, or compound heterozygotes for either of these three mutations (n=1). Irrespective of the genotype, the patients exhibited early-onset epileptic encephalopathy characterized by focal seizures (11/11), epilepsia partialis continua (n=11/11), and infantile spasms (n=7/11). The median age of onset of seizures was one month (IQR= 1 to 2 months). Brain MRI demonstrated cortical atrophy in 6/11 patients; no structural abnormality was identified for other patients. Electrographic features included slow background activity (n=8/11), multifocal paroxysmal inter-ictal epileptiform discharges (n=9/11), hypsarrhythmia (n=1), and focal migrating discharges (n=2). All patients had drug-resistant epilepsy, and 10/11 patients died at a median age of 14 months (IQR= 11 to 17 months).

Conclusion This study demonstrates that early-onset epileptic encephalopathy with predominantly focal seizures should raise the suspicion of TBC1D24 mutation. Patients with this disorder have drug-resistant epilepsy and are at high risk of early death from status epilepticus.