Keto Diet Resolves Non-convulsive Seizures in 2 Girls With New Variant
A ketogenic diet safely and rapidly controlled treatment-resistant prolonged non-convulsive seizure activity in two girls with Angelman syndrome caused by a new mutation in the UBE3A gene, a study shows.
These therapeutic benefits were observed before the detection of ketone bodies, the fat-derived molecules produced by the liver to serve as an energy source when glucose or sugar — the body’s go-to energy source — is not readily available.
These cases highlight the ketogenic diet as an effective approach to manage prolonged non-convulsive seizures related to Angelman and suggest that carbohydrate restriction may, by itself, have an effect on these seizures.
The study, “Novel UBE3A pathogenic variant in a large Georgian family produces non-convulsive status epilepticus responsive to ketogenic diet,” was published in the journal Seizure.
Angelman is most often caused by a de novo deletion of a region of the maternally inherited chromosome 15 containing the UBE3A gene. De novo genetic changes are mutations not inherited from a person’s parents, but instead developed for the first time during embryonic development.
In about 10% of cases, the disease is caused by mutations in the maternal UBE3A gene that is passed on through generations. These mutations are typically associated with a milder disease relative to chromosome 15 deletions affecting other genes besides UBE3A.
A growing number of studies suggests that the ketogenic diet — one that is high in fat and low in carbohydrates (sugars and starches) — is effective at controlling Angelman-related seizures, most of which are resistant to standard anti-epileptic medication.
While it is not entirely known why this diet is beneficial, a number of hypotheses have suggested that producing ketone bodies and using them as fuel leads to a metabolic shift that ultimately dampens overall neuron excitability and reduces seizure activity.
Now, a team of researchers in Georgia, along with colleagues in France, described the case of two sisters with Angelman caused by a new UBE3A mutation and whose non-convulsive status epilepticus (NCSE) was effectively resolved with the ketogenic diet.
NSCE, affecting half of all Angelman patients, refers to prolonged periods of unresponsiveness caused by seizures without convulsions.
Part of a large Georgian family, the two girls, 10 and 9 years old, were the oldest of four family members affected by Angelman and carrying the same UBE3A mutation (c.2365del/p.Glu798Serfs*32). All had inherited the mutation from their respective mothers, who showed no symptoms of the disease.
The team found that the mutation resulted in an early stop in protein production, leading to a shorter, non-working UBE3A enzyme, thereby being deemed a disease-causative mutation.
To date, the sisters were the only ones to experience seizures, which started at age 2 in the form of brief, jerking spasms in the older sister and at age 3.5 in the form of fever-triggered seizures in the youngest.
Between the ages of 4 and 5, both girls showed cognitive deterioration, with reduced alertness and poor communication/eye contact.
Also, the oldest was constantly in a “bad” mood, did not respond to any commands, and showed poor sleep, while the youngest lost interest in her surroundings and stopped having Angelman’s characteristic laughing bursts.
An electroencephalogram (EEG) on both girls revealed continuous, abnormal brain activity spikes that confirmed that these behavioral changes were due to NCSE. Despite administration of recommended anti-seizure medication, including pyridoxine, benzodiazepines, and valproic acid, the non-convulsive seizures remained unchanged.
A non-fasting ketogenic diet, with a 4:1 fat-to-non-fat ratio, was implemented using blended food that was given orally.
Both girls showed cognitive and behavioral improvements, as well as pronounced reductions or complete elimination of NCSE-related brain spiking activity, after two to three days on the diet.
Ketone bodies were first detected in the urine on the fourth to fifth day of the diet, which is consistent with other reports showing that seizure activity stops before the appearance of ketone bodies.
While it is possible that there was a “subcellular ketone body-related metabolic shift that may have accounted for the antiepileptic activity, reports on the low glycemic index diet efficacy underline the possible effects of glucose restriction by itself on seizure control,” the researchers wrote.
Both sisters discontinued the ketogenic diet after one year due to difficulty in adhering to such a stringent diet and initiated the low glycemic index diet, which eliminates starchy and sugary carbs.
After five years, the girls continued to show no clinical or EEG signs of NCSE, but the parents said their levels of alertness and behavior were best while on the ketogenic diet.
Given that a small amount of glucose in the brain “is sufficient to ensure a few minutes of major activity needed for seizure onset,” glucose depletion caused by the ketogenic diet could hamper such seizure-triggering brain activity, the team wrote.
This could also explain the anti-seizure effects of the low glycemic index diet, they added.
“Whatever the mechanism, our case study shows that [ketogenic diet] is safe and efficient for the treatment of NCSE due to [Angelman syndrome],” the researchers wrote.
A previous, small clinical trial (NCT03644693) showed that a dietary supplement meant to mimic the effects of a ketogenic diet was generally safe and well-tolerated in children with Angelman.
Given that the small study did not have the statistical power to detect meaningful changes in seizure frequency or other efficacy-related outcomes, a larger, placebo-controlled trial is needed to confirm the safety and assess the efficacy of this type of supplement, the study noted.
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