Inspired by a patient
Rb R, Ajith A, Nayak A, Radhakrishnan A, Thomas B, Kesavadas C. Neuroimaging spectrum of GATOR1-related epilepsy (GATORopathies). Neuroradiology. 2026 May 18. doi: 10.1007/s00234-026-04036-2. Epub ahead of print. PMID: 42149211.
Abstract
Background: The mTOR pathway is important for neurodevelopment. The GATOR1 complex, composed of DEPDC5, NPRL2, and NPRL3, functions as a negative regulator of mTORC1 activity and pathogenic variants in the genes which comprise this complex cause focal epilepsy and malformation of cortical development, all named as GATORopathies. While focal cortical dysplasia is commonly reported, the full spectrum of associated neuroimaging findings remains incompletely defined.
Objective: To characterize the neuroimaging features associated with GATOR1 complex mutations and to explore potential associations between imaging phenotypes and specific genotypes.
Methods: MRI studies were retrospectively reviewed from January 2019 to December 2025 in patients with genetically confirmed GATOR1 mutations. Clinical, radiological, and genetic data were analyzed to identify imaging patterns and genotype-phenotype correlations.
Results: Twenty patients (median age : 6 years; range 1-25 years) were included. DEPDC5 mutations were most frequent (n = 12), followed by NPRL3 (n = 5) and NPRL2 (n = 3). MRI abnormalities were identified in 16 patients (80%). Focal cortical malformations were the most common finding (n = 8), followed by diffuse cortical malformations (n = 5) and generalized neuroparenchymal atrophy (n = 3); four patients had MRI-negative studies. Imaging findings varied considerably across genotypes. DEPDC5 and NPRL2 mutations showed a broad and heterogeneous radiological spectrum, whereas NPRL3 mutations showed a tendency toward cortical malformations, though the small subgroup size limits interpretation. Seizure onset spanned from infancy to adulthood; however, patients with diffuse cortical abnormalities or generalized neuroparenchymal atrophy tended to present earlier and experienced a greater seizure burden.
Conclusion: GATOR1-related epilepsy demonstrates substantial variability in neuroimaging and electroclinical features, extending beyond focal cortical malformations to include diffuse cortical malformations, generalized neuroparenchymal atrophy, and MRI-negative presentations. These findings highlight the value of integrated genetic, imaging, and electroclinical assessment in routine clinical practice.
Yang T, Banerjee R, Scheper M, Jiang M, Dai S, Aronica E, Wang Y. Ectopically overexpressed glycine transporter 2 contributes to epileptogenesis in DEPDC5-related epilepsy. Exp Neurol. 2026 May;399:115668. doi: 10.1016/j.expneurol.2026.115668. Epub 2026 Jan 24. PMID: 41587632.
Abstract
Loss-of-function mutations in DEPDC5 (DEP domain-containing protein 5), a critical negative regulator of mTORC1 (mechanistic Target of Rapamycin Complex 1), are often identified in patients with refractory epilepsy. To understand its underlying pathogenesis and develop novel therapeutics, we used a highly clinically relevant rat model of DEPDC5-related epilepsy and resected human patient tissues to profile the molecular architecture in the dysplastic cortex. We report here that Slc6a5 (solute carrier family 6 member 5 gene), a marker gene for glycinergic inhibitory neurons, is ectopically overexpressed in mutant excitatory neurons in both experimental animal and human tissues. Using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) in utero electroporation (IUE) to simultaneously knock out Depdc5 and Slc6a5 in forebrain excitatory neurons reduces seizure frequency and duration. These data suggest that SLC6A5 plays an important role in the epileptogenesis of DEPDC5-related epilepsy, although the underlying mechanisms remain unclear.
Samanta D. DEPDC5-related epilepsy: A comprehensive review. Epilepsy Behav. 2022 May;130:108678. doi: 10.1016/j.yebeh.2022.108678. Epub 2022 Apr 14. PMID: 35429726.
Abstract
DEPDC5-related epilepsy, caused by pathogenic germline variants(with or without additional somatic variants in the brain) of DEPDC5 (Dishevelled, Egl-10 and Pleckstrin domain-containing protein 5) gene, is a newly discovered predominantly focal epilepsy linked to enhanced mTORC1 pathway. DEPDC5-related epilepsy includes several familial epilepsy syndromes, including familial focal epilepsy with variable foci (FFEVF) and rare sporadic nonlesional focal epilepsy. DEPDC5 has been identified as one of the more common epilepsy genes linked to infantile spasms and sudden unexpected death (SUDEP). Although intelligence usually is unaffected in DEPDC5-related epilepsy, some people have been diagnosed with intellectual disabilities, autism spectrum disorder, and other psychiatric problems. DEPDC5 variants have also been found in 20% of individuals with various brain abnormalities, challenging the traditional distinction between lesional and nonlesional epilepsies. The most exciting development of DEPDC5 variants is the possibility of precision therapeutics using mTOR inhibitors, as evidenced with phenotypic rescue in many animal models. However, more research is needed to better understand the functional impact of diverse (particularly missense or splice-region) variants, the specific involvement of DEPDC5 in epileptogenesis, and the creation and utilization of precision therapies in humans. Precision treatments for DEPDC5-related epilepsy will benefit not only a small number of people with the condition, but they will also pave the way for new therapeutic approaches in epilepsy (including acquired epilepsies in which mTORC1 activation occurs, for example, post-traumatic epilepsy) and other neurological disorders involving a dysfunctional mTOR pathway.
Gu C, Wei X, Yan D, Cai Y, Li D, Shu J, Cai C. DEPDC5 plays a vital role in epilepsy: Genotypic and phenotypic features in cohort and literature. Epileptic Disord. 2024 Jun;26(3):341-349. doi: 10.1002/epd2.20223. Epub 2024 May 16. PMID: 38752894.
Abstract
Objective: DEPDC5 emerges to play a vital role in focal epilepsy. However, genotype-phenotype correlation in DEPDC5-related focal epilepsies is challenging and controversial. In this study, we aim to investigate the genotypic and phenotypic features in DEPDC5-affected patients.
Methods: Genetic testing combined with criteria published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), was used to identify pathogenic/likely pathogenic variants in DEPDC5 among the cohort of 479 patients with focal epilepsy. Besides, the literature review was performed to explore the genotype-phenotype correlation and the penetrance in DEPDC5-related focal epilepsies.
Results: Eight unrelated probands were revealed to carry different pathogenic/likely pathogenic variants in DEPDC5 and the total prevalence of DEPDC5-related focal epilepsy was 1.67% in the cohort. Sixty-five variants from 28 studies were included in our review. Combined with the cases reported, null variants accounted for a larger proportion than missense variants and were related to unfavorable prognosis (drug resistance or even sudden unexpected death in epilepsy; χ2 = 5.429, p = .020). And, the prognosis of probands with developmental delay/intellectual disability or focal cortical dysplasia was worse than that of probands with simple epilepsy (χ2 = -, p = .006). Besides, the overall penetrance of variants in DEPDC5 was 68.96% (231/335).
Significance: The study expands the variant spectrum of DEPDC5 and proves that the DEPDC5 variant plays a significant role in focal epilepsy. Due to the characteristics of phenotypic heterogeneity and incomplete penetrance, genetic testing is necessary despite no specific family history. And we propose to adopt the ACMG/AMP criteria refined by ClinGen Sequence Variant Interpretation Working Group, for consistency in usage and transparency in classification rationale. Moreover, we reveal an important message to clinicians that the prognosis of DEPDC5-affected patients is related to the variant type and complications.
Bacq A, Roussel D, Bonduelle T, Zagaglia S, Maletic M, Ribierre T, Adle-Biassette H, Marchal C, Jennesson M, An I; Genomics England Research Consortium; Picard F, Navarro V, Sisodiya SM, Baulac S. Cardiac Investigations in Sudden Unexpected Death in DEPDC5-Related Epilepsy. Ann Neurol. 2022 Jan;91(1):101-116. doi: 10.1002/ana.26256. Epub 2021 Nov 16. PMID: 34693554; PMCID: PMC9299146.
Abstract
Objective: Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the mammalian target of rapamycin (mTOR) repressor GATOR1 complex, cause focal epilepsies and increase the risk of sudden unexpected death in epilepsy (SUDEP). Here, we asked whether DEPDC5 haploinsufficiency predisposes to primary cardiac defects that could contribute to SUDEP and therefore impact the clinical management of patients at high risk of SUDEP.
Methods: Clinical cardiac investigations were performed in 16 patients with pathogenic variants in DEPDC5, NPRL2, or NPRL3. Two novel Depdc5 mouse strains, a human HA-tagged Depdc5 strain and a Depdc5 heterozygous knockout with a neuron-specific deletion of the second allele (Depdc5c/- ), were generated to investigate the role of Depdc5 in SUDEP and cardiac activity during seizures.
Results: Holter, echocardiographic, and electrocardiographic (ECG) examinations provided no evidence for altered clinical cardiac function in the patient cohort, of whom 3 DEPDC5 patients succumbed to SUDEP and 6 had a family history of SUDEP. There was no cardiac injury at autopsy in a postmortem DEPDC5 SUDEP case. The HA-tagged Depdc5 mouse revealed expression of Depdc5 in the brain, heart, and lungs. Simultaneous electroencephalographic-ECG records on Depdc5c/- mice showed that spontaneous epileptic seizures resulting in a SUDEP-like event are not preceded by cardiac arrhythmia.
Interpretation: Mouse and human data show neither structural nor functional cardiac damage that might underlie a primary contribution to SUDEP in the spectrum of DEPDC5-related epilepsies. ANN NEUROL 2022;91:101-116.
