From the Guidelines
The DEPDC5 heterozygous gene variant c.4779T>A (p.Ser1593Arg) is likely significant in epilepsy development, particularly in familial focal epilepsy, due to its potential disruption of the mTOR pathway, which is crucial for cell growth and brain development. This specific variant changes the amino acid serine to arginine at position 1593 in the protein, potentially altering its normal function as part of the GATOR1 complex that inhibits mTOR signaling 1. When mutated, DEPDC5 can lead to hyperactivation of the mTOR pathway, causing abnormal brain development and epileptic seizures.
Clinical Implications
- Patients with this variant may develop focal epilepsy, which could respond to standard antiepileptic medications like levetiracetam, carbamazepine, or lamotrigine.
- In cases where seizures are drug-resistant, mTOR inhibitors such as everolimus might be considered as targeted therapy, though this approach remains experimental and requires further investigation 1.
- Genetic counseling is recommended for affected individuals and their families, as DEPDC5 mutations follow an autosomal dominant inheritance pattern, meaning each child of an affected person has a 50% chance of inheriting the variant.
Diagnostic Considerations
- The diagnosis of epilepsy associated with the DEPDC5 gene variant involves a combination of clinical evaluation, genetic testing, and imaging studies to identify any structural brain abnormalities.
- Given the potential for variable expressivity and penetrance, a comprehensive diagnostic work-up is essential for individuals with suspected DEPDC5-related epilepsy, as outlined in recent consensus recommendations on the diagnostic work-up for malformations of cortical development 1.
Management and Treatment
- Management of epilepsy associated with the DEPDC5 gene variant focuses on controlling seizures and may involve a multidisciplinary approach, including medication, lifestyle modifications, and in some cases, surgical intervention.
- The choice of antiepileptic medication should be tailored to the individual's specific seizure type and syndrome, with consideration of the potential benefits and risks of each treatment option.
From the Research
Significance of DEPDC5 Heterozygous Gene Variant
The DEPDC5 gene is associated with various forms of epilepsy, including familial focal epilepsy and sporadic non-lesional focal epilepsy 2, 3. The heterozygous gene variant c.4779T>A (p.Ser1593Arg) is a specific mutation that has been identified in individuals with epilepsy.
Relationship to Epilepsy
- DEPDC5-related epilepsy is characterized by enhanced mTORC1 pathway signaling, which can lead to abnormal brain development and function 2, 4.
- The DEPDC5 gene is an inhibitory component of the mTOR pathway, and mutations in this gene can disrupt normal brain function, leading to epilepsy 5.
- Heterozygous loss-of-function mutations in DEPDC5, such as the c.4779T>A variant, can lead to increased mTORC1 signaling and abnormal morphology in human iPSC-derived cortical neurons 4.
Clinical Implications
- Individuals with DEPDC5-related epilepsy may experience a range of symptoms, including seizures, intellectual disabilities, and psychiatric problems 2.
- The identification of DEPDC5 variants can help clinicians make a definitive diagnosis and develop targeted treatment plans, such as the use of mTOR inhibitors 2, 6.
- Further research is needed to understand the functional impact of diverse DEPDC5 variants and to develop precision therapies for DEPDC5-related epilepsy 2, 3.