Ketogenic diet. The ketogenic diet (KD) has been formally used to treat epilepsy for the past 100 years. Its history of use dates to Hippocrates who realized that while people with epilepsy fasted their seizures improved. The ketogenic diet mimics a long-term fasting state by having the body enter ketosis with a high fat low carbohydrate + protein diet.

Effectiveness of the ketogenic diet. KD has been tried across various genetic DEEs. By comparing it against other treatment options, we can assess how effective KD is in different conditions. When looking at individuals with disease-causing variants in SCN8A, STXBP1, and SCN2A, it was most successful for STXBP1.

The obvious keto-genetic candidates. Pyruvate Dehydrogenase Complex Deficiency (PDCD) occurs from pathogenic variants in PDHA1 (most common), PDHX, PDHB, DLAT, PDP1, and DLD. In PDCD, pyruvate from carbohydrates cannot be used appropriately which can lead to an increase in lactate. By introducing KD, cells can obtain energy from fatty acids instead. Glucose transporter type 1 deficiency syndrome (GLUT1 DS) occurs from pathogenic variants in SLC2A1. SLC2A1 encodes for the protein GLUT1 which helps transport glucose into the brain. The ketogenic diet is used to provide the brain with an alternative fuel source, ketones.

Common syndromic candidates. Prior to an influx of knowledge of genetic causes of epilepsy with myoclonic atonic seizures (EMAS), Lennox-Gastaut Syndrome (LGS), and West Syndrome, KD was a well-known treatment for these specific epilepsy syndromes. Many epilepsy syndromes, especially EMAS, are thought/known to have a genetic component to them.

Ko A et al. reported on 155 total patients who were on a form of a KD and divided them into responders (≥ 90% seizure reduction from baseline at 3 months after KD initiation) and non-responders (< 90% seizure reduction). The responder rate is high as many would argue a ≥ 50% in seizures from baseline would qualify as a responder. When they looked at LGS there were 31 patients and 9 (29%) responded and 22 (71) did not respond to a KD. They had 67 patients with West Syndrome with 24 (35.8%) responders. The number of EMAS patients was low at 5 and surprisingly only 1 (20%) was a responder. The KD’s used were 4:1, 3:1, and modified ketogenic diet (MKD).

Ketosis and mitosis. The most common question when pursuing a ketogenic diet is- how does it work? It will be a bittersweet day when we finally have those answers as there is some aspect of “magic” to using a ketogenic diet. Last year, Pedersen et al. published a decrease in DNA methylation in adults with epilepsy after they were on a MKD for twelve weeks. Regardless of the responder response to MKD, there were not any significant differences in DNA methylation changes between the two groups.

The not-so obvious keto-genetic candidates. Going back to Ko A et al.: they reported out KD responder rates (≥90% reduction) in those with genetic epilepsy diagnoses compared to those without a known genetic cause. The best response rates at 12 months were seen in KCNQ2 (n=6, responder rate=83.3%, p=0.014), SCN1A (n=18, responder rate=61.6%, p=0.014), SCN2A (n=3, responder rate=100%, p=0.030), and STXBP1 (n=4, responder rate=100%, p=0.010).

Keto Karma. Should I try keto for genetic epilepsy even though there has not been any success to date for that specific syndrome? YES (with the exclusion of some disorders which a ketogenic diet would be contraindicated)! Ingo recently quoted Nike when talking about ketogenic diets- “Just do it”.

Sarah Tefft

Sarah is a nurse practitioner in the ENGIN program at CHOP.