Authors :
Presenting Author: Manuela Ochoa-Urrea, MD – University of Texas Health Science Center at Houston
Elizabeth Butler, PA-C – Cleveland Clinic
Tobias Bruenger, PhD – University of Texas Health Science Center at Houston
Costin Leu, PhD – University of Texas Health Science Center at Houston
Christian M Bosselmann, MD – University Hospital Tübingen
Imad Najm, MD – Cleveland Clinic
Samden Lhatoo, MD, FRCP – University of Texas Health Science Center at Houston
Dennis Lal, PhD – University of Texas Health Science Center at Houston
Rationale:
Pathogenic variants in DEPDC5 are the most frequent cause of genetic focal epilepsies (10% of all focal epilepsy cases) and subjects with these variants have increased risk of sudden unexpected death in epilepsy (SUDEP). Prior family studies have shown incomplete penetrance (66%), with data originally from European descent countries. The absence of up-to-date penetrance estimates and the incomplete pooling of knowledge across diverse populations highlights the critical need to disseminate updated information on this developing area of research.
Methods:
We conducted a literature review of families with DEPDC5-related epilepsy, considering all studies listed on PubMed until August 2024. We extracted genotype and phenotype information and performed penetrance calculation, including obligate carriers. Clinical characteristics were analyzed across subjects with a confirmed or inferred DEPDC5 variant and epilepsy.
Results:
Thirty-three publications were identified comprising 595 individuals from 170 families carrying DEPDC5 variants. Out of the DEPDC5 variant carriers, 387/595 individuals had a diagnosis of epilepsy resulting in an estimated penetrance of 65% (95% CI 61.05-68.89). The median seizure onset was 4.9 years, with focal epilepsy reported as the most common epilepsy type (82%). Among individuals in whom treatment response was reported, 49.5% of individuals had drug-resistant epilepsy. Twenty nine percent of subjects with reported MRI had a lesion, 94% of which were malformations of cortical development. Twenty three percent underwent epilepsy surgery, most of which attained good outcome. Notably, our analysis revealed that earlier seizure onset is strongly associated with increased disease severity. Individuals with drug-resistant epilepsy (DRE) had a significantly earlier median age of seizure onset (1.41 years) compared to those without DRE (7 years, P = 7.9e-09). Similarly, earlier onset was observed in those who underwent epilepsy surgery (1 year vs. 7 years, P = 2.8e-07) and those with intellectual disability (0.22 years vs. 5 years, P = 1.8e-08). Additionally, drug resistance was associated with lesional MRI (OR = 3.32, P = 0.007). From the proportion of subjects who had DEPDC5-related epilepsy and death was reported, 22.7% had died of SUDEP (3 definite, 2 probable).
Conclusions:
This study not only corroborates previous penetrance estimates but also identifies early seizure onset as a critical prognostic marker for disease severity in DEPDC5-related epilepsy. Our findings, derived from the largest dataset to date, including recent data from Asian populations, offer valuable insights into the clinical management and prognosis of this condition.
Funding: No external funding was obtained for this research. The study was conducted independently without financial support from any grants, institutions, or organizations.