Early Seizure Onset Linked to Increased Disease Severity in DEPDC5-Related Epilepsy

Early seizure onset is strongly associated with greater disease severity in individuals with DEP domain-containing 5 (DEPDC5)-related epilepsy, according to findings published in Neurology.

Pathogenic variants in the DEPDC5 gene are a frequent genetic cause of focal epilepsy. Researchers conducted a pooled cohort analysis and scoping review to refine penetrance estimates, define genotype-phenotype correlations, and assess treatment outcomes in patients with DEPDC5-related epilepsy. They systematically reviewed PubMed for studies published up to August 2024. Eligible publications included families with heterozygous DEPDC5 variants and excluded sporadic or recessive cases.

A total of 33 studies, comprising 170 families and 586 individuals carrying DEPDC5 variants, were included. Most families were of European (63.5%) or Asian (35%) ancestry. Overall, 64.9% (95% CI, 60.8%-68.7%) of carriers developed epilepsy, and penetrance was similar between multiplex and nonmultiplex families. By age 10 years, 76.1% of carriers had developed seizures, with a median onset of 5 years.

The positive outcomes after epilepsy surgery observed in our review underscore the critical role of early evaluation for epilepsy surgery in individuals with DEPDC5 variants, particularly for children with early-onset epilepsy.

Focal epilepsy accounted for 83.9% of cases, most commonly involving the frontal lobe (46% of those with a reported focus). Drug resistance occurred in 48.3% of affected individuals. Lesions were seen in 33.1% of those with available magnetic resonance imaging (MRI) data, 85.7% of which were malformations of cortical development. Early seizure onset (≤1 year) was significantly associated with drug resistance (P =2.4 × 10⁻⁸), intellectual disability (P =2.1 × 10⁻⁸), and MRI lesions (P =2.2 × 10⁻⁸).

Among those with drug-resistant epilepsy, 34.7% underwent surgical resection, and 88% achieved favorable postoperative outcomes (Engel class I or II). Those with MRI-detected malformations were 17.9 times more likely to undergo surgery compared with those with normal imaging (61.3% vs 7.8%; P =2.5 × 10⁻¹¹). Focal cortical dysplasia type IIa was the most common histopathologic finding (60.6%).

Intellectual disability occurred in 20.6% of affected individuals, while psychiatric comorbidities, including anxiety, depression, and autism spectrum disorder, were reported in 23.2%. Sudden unexpected death in epilepsy accounted for 16% of all deaths among those with available data.

Study limitations include reliance on previously published genotype and phenotype data, potential reporting bias toward severe or surgical cases, and underrepresentation of non-European populations.

The authors noted that early seizure onset may indicate a more severe phenotype and warrant earlier intervention. “The positive outcomes after epilepsy surgery observed in our review underscore the critical role of early evaluation for epilepsy surgery in individuals with DEPDC5 variants, particularly for children with early-onset epilepsy, especially because surgery may offer cognitive benefits in the long term,” the researchers concluded.

Disclosures: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.