KCNT1 EPILEPSY SUMMARY

Clinical Characteristics: KCNT1-related epilepsy is most commonly associated with intractable seizures (40-100 per day) and severe developmental delay and impairment. Most patients never learn to walk or communicate. The two most common phenotypes are epilepsy of infancy with migrating focal seizures (EIMFS, reclassified from MMPSI/MPSI) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Less common seizure phenotypes include West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, leukodystrophy, focal epilepsy and multifocal epilepsy. The consequences of the variants can include cortical visual Impairment, neuroirritability, gastroesophageal reflux, constipation, neurogenic bladder, hip dysplasia, hypotonia, and dystonia. Some children develop pulmonary collaterals and cardiac arrhythmias which increase the risk of mortality. Children are also at risk for sudden unexpected death in epilepsy (SUDEP). 

Molecular Genetics: 

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here. 

Diagnosis: The diagnosis is established in a patient with intractable epilepsy and identification of a heterozygous pathogenic variant in KCNT1 by genetic testing. No formal clinical diagnostic criteria for KCNT1-related epilepsy have been published to date.

Prevalence:  The prevalence of KCNT1-related epilepsy is unknown. Based on published and pending reports, at least 300 cases have been identified worldwide, making this an ultra-rare disorder (fewer than 20 cases per million people). One prevalence model predicts that there are approximately 3000 worldwide cases. A lack of access to gene panel testing in much of the world is likely responsible for the 2800 undiagnosed cases. Fortunately, free genetic testing is available (in some countries) through the Behind the Seizure program originally established by Invitae and BioMarin. 

Existing Therapies: There are no FDA-approved therapies for KCNT1-related epilepsy. This is a patient population with a high unmet need. Seizures are treated with conventional anticonvulsant medications, but most patients show minimal improvement. Ketogenic diet is helpful in reducing seizure burden for some patients. Quinidine has been used as an off-label anticonvulsant with success in some individuals. Support such as physical therapy, speech therapy, and vision therapy is commonly utilized but rarely helps children achieve normal developmental milestones.

Experimental Therapies: 

Antisense Oligonucleotides (ASOs): There are currently several groups working on ASO drug development. ASO treatment for KCNT1 involves a “knockdown” strategy.

Available Preclinical Models:   

There are both iPSC derived neuronal models and multiple mouse models (including humanized mouse models) available for KCNT1 research and drug development.  2D and 3D models are also available. Contact us. info@kcnt1epilepsy.org

Registry/Natural History Study/Biobank: 

The Foundation sponsors a detailed, secure and re-contactable patient database with a list of known variants for KCNT1 mutations. We have over 100 persons with KCNT1 variants in the registry. We are building a biobank for iPSC development and trio genome testing. Contact info@kcnt1epilepsy.org

A digital natural history study using patient medical records and genetic reports for over 50 patients in the U.S. is available through Ciitizen.

Challenges of Ultra-rare disorders:  

Delay in diagnosis: Because of the extremely small number of children impacted by this disease, most physicians, including pediatric epilepsy specialists, have little experience with diagnosing and managing these complicated cases.  

The small population also creates barriers for drug development. Ultra-rare diseases typically attract less attention from researchers and drug developers.  

Identifying a sufficient number of cases to participate in a clinical trial can be challenging. Coordinating trials with a small number of patients spread across the country, or the world, creates additional barriers. 

Potentially Overlapping Areas: 

There is increased interest in the KCNT1 variants possibly due to the fact that the KCNT1 Slack channels in neurons are known to influence intellectual development and could potentially have implications for one of the largest causes of intellectual impairment (Fragile X) and autism.  In addition, researchers interested in hearing are interested in KCNT1 because these ion channels are involved in the function of hair cells within the cochlea.