Clinical characteristics: DEPDC5-related epilepsy encompasses a range of epilepsy syndromes, almost all of which are characterized by focal seizures, with seizure onset in a discrete area of the brain. While most individuals with DEPDC5-related epilepsy have a normal brain MRI, some have epilepsy associated with a cortical malformation, usually focal cortical dysplasia or hemimegalencephaly. Seizure syndromes include familial focal epilepsy with variable foci (FFEVF), autosomal dominant sleep-related hypermotor epilepsy (ADSHE), familial mesial temporal lobe epilepsies (FMTLE), autosomal dominant epilepsy with auditory features (ADEAF), infantile spasms, and severe developmental encephalopathy. Although psychomotor development is usually normal, developmental delays, intellectual disability, or autism spectrum disorder have been reported in some individuals.

Diagnosis/testing: The diagnosis of DEPDC5-related epilepsy is established in a proband with suggestive findings and at least one heterozygous pathogenic variant in DEPDC5 identified by molecular genetic testing. Some affected individuals have biallelic variants in DEPDC5, and some have a second mosaic (or postzygotic) DEPDC5 variant within the brain.

Management: Treatment of manifestations: The response to anti-seizure medication (ASM) is variable. While some individuals respond well to first-line ASMs, others are more refractory to treatment. There is currently no evidence that seizures respond better to one specific ASM. In individuals with hemimegalencephaly or focal cortical dysplasia and refractory epilepsy, resective epilepsy surgery should be explored early in the disease course. Standard treatment for developmental delay / intellectual disability and autism spectrum disorders.

Surveillance: Assess for new or ongoing neurologic manifestations (such as new-onset seizures or changes in seizure symptoms), predictive factors for sudden unexpected death in epilepsy, and developmental progress at each visit. Repeat EEG as appropriate when seizure frequency increases or when seizures of new symptomatology occur. Repeat brain MRI with a higher-resolution technique in individuals with treatment-resistant seizures whose first brain MRI was normal to rule out subtle cortical dysplasia.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those who are at risk for developing seizures as early as possible. This typically entails targeted molecular genetic testing for the known pathogenic variant(s) in the family.

Pregnancy management: Pregnant women should receive counseling regarding the risks and benefits of using ASM during pregnancy; the advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily; the effects of pregnancy on ASM metabolism; and the effect of pregnancy on maternal seizure control.

Genetic counseling: DEPDC5-related epilepsy is an autosomal dominant disorder; however, affected individuals with germline biallelic missense variants have been rarely reported. All probands reported to date with biallelic DEPDC5 variants inherited variants from their heterozygous parents. In these families, heterozygous parents may or may not have manifestations of DEPDC5-related epilepsy. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If one parent of the proband has a DEPDC5 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. If both parents of a proband have a DEPDC5 pathogenic variant, sibs have a 75% chance of inheriting one or two pathogenic variants and a 25% chance of inheriting neither pathogenic variant and not being affected. Once the DEPDC5 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.