GENETIC EPILEPSY: EVALUATION,
MANAGEMENT, AND TREATMENT
Dietary Therapy in
Genetic Epilepsies
The ketogenic diet has been used to achieve remission from seizures in a variety
of drug-resistant genetic epilepsies.
Deana Bonno, MD
Ketogenic diets (KDs) are formulated to con-
sist of high fat intake combined with restrict-
ed carbohydrate and adequate protein intake
to yield a state of nutritional ketosis. In the
strictest form—classic KD—foods are weighed
and measured to conform to the prescribed
ratio for the individual. The KD ratio refers to the grams of
fat in relation to the grams of carbohydrate plus protein of
each meal. Therefore, an individual on a 3:1 diet consumes
3 grams fat for every 1 gram of carbohydrate plus protein.1
Less restrictive diets have been developed that allow indi-
viduals to enter the state of nutritional ketosis by restricting
carbohydrates to specific daily targets and adding fat to each
meal. For example, in a modified Atkins diet, an individual
may have a net carbohydrate goal of 20 grams per day.1 If
using a low glycemic index diet, the goal is 40 to 60 grams of
carbohydrates per day, with the focus on consuming lower
glycemic index carbohydrates.2 The glycemic index is a mea-
sure of how quickly various carbohydrates are broken down
and metabolized, and the effect they have on blood glucose
levels2 (Figure).
KDs were used widely to treat epilepsy beginning in the
early 1920s through the 1930s, prior to FDA approval of phe-
nytoin in 1939.3 Thereafter, medication discovery and approv-
al displaced KDs as a major treatment for epilepsy until KDs
returned to public attention through media portrayals of an
infant named Charlie who experienced freedom from seizures
after treatment with KD at Johns Hopkins Medicine.3 In the
past 20 to 30 years, interest in and use of KDs for drug-resis-
tant epilepsy has risen, and KDs have been adapted for broad-
er use outside of the pediatric population. Drug-resistant
epilepsy is defined as failure to achieve seizure freedom after
adequate trials of at least 2 appropriately chosen antiseizure
medications (ASM).4 This article reviews the evidence for use
of KDs in various genetic conditions, including Angelman syn-
drome (AS), glucose transporter type 1 deficiency syndrome
30 PRACTICAL NEUROLOGY NOVEMBER 2023
(GLUT1-DS), tuberous sclerosis complex (TSC), and early-
onset epileptic encephalopathy with burst suppression.
Angelman Syndrome
AS, caused by loss or reduction of maternal UBE3A (15q11-
q13) function, is characterized by developmental delay, ataxic
gait, and limited expressive speech.5 More than 80% of indi-
viduals with AS develop epilepsy, and the majority of cases
(~70%) are medically refractory. The typical onset of seizures
is between age 1 and 3 years. Generalized seizure types are the
most common, but individuals often have multiple seizure
types. EEG tests can have characteristic findings, including
notched occipital delta rhythms and rhythmic theta patterns.6
A small prospective study of the low glycemic diet included
6 children with AS between ages 1 and 18 who had never been
treated with dietary therapy.6 A baseline EEG test was obtained,
and seizure diaries were kept. Participants were followed up at 1
and 4 months, including a repeat EEG test at 4 months. At base-
line, participants had between 0.4 and 30.9 seizures per week.
Three participants became seizure-free, 2 had greater than 80%
seizure reduction, and 1 had no response. In a retrospective case
series of 23 participants with AS treated with the low-glycemic
diet,7 22% achieved seizure freedom and 43% were seizure-free
except during illness or episodes of nonconvulsive status epilep-
ticus. An additional 30% of participants had decreased seizure
frequency, nearly all of whom achieved 50% to 90% reduction
in seizures. The average duration of treatment was 3 ± 2.5 years.
Most recently, supplementation of exogenous ketones in 13
children with AS was shown to be safe, though study size and
duration limited conclusions about efficacy.8 A large propor-
tion of patients with Angelman syndrome respond favorably to
dietary therapy.
GLUT1-DS
Glucose is transported across the blood–brain barrier by
the glucose transporter protein (GLUT1), which is encod-

Classic KD MAD
3%
7%
25%
5%
90%
n Fats n Carbohydrates
Figure. Comparison of classic ketogenic diets (KD), and their modifications and macronutrient ratios. LGIT, low glycemic index therapy;
MAD, modified Atkins diet. Adapted with permission from Pietrzak D, Kasperek K, Rękawek P, Piątkowska-Chmiel I. The therapeutic
role of ketogenic diet in neurological disorders. Nutrients. 2022;14(9):1952. doi:10.3390/nu14091952
ed by the SLC2A1 gene on chromosome 1.9,10 In GLUT1-
DS, this transport is faulty, leading to low glucose levels in
the cerebrospinal fluid. A diagnosis of classic GLUT1-DS
is based on low levels of glucose in the cerebrospinal fluid
in the presence of normal serum glucose (hypoglycor-
rhachia) and/or a pathogenic variant in the SLC2A1 gene;
missense, nonsense, and structural variants all presum-
ably causing haploinsufficiency have been described.10
GLUT1-DS is a heterogeneous disease. In the classic form,
individuals present with encephalopathy and seizures.
However, individuals also can present with movement
disorders (eg, ataxia, chorea, dystonia), varying degrees of
intellectual and developmental disability, and eye move-
ment abnormalities, including aberrant gaze saccades.10
KD can provide an alternate fuel source for the central
nervous system in the form of ketone bodies, which do
not rely on GLUT1 for movement across the blood–brain
barrier; rather, they enter the brain by a monocarboxylic
acid transporter.9
A retrospective case series11 looked at 20 children with
GLUT1-DS who were diagnosed between age 4 weeks and
18 months and treated with classic KD. All had epilepsy and
were refractory to multiple ASM. Seizure types included gen-
eralized tonic-clonic, absence, focal, myoclonic, and astatic
or atonic. All caregivers of these 20 infants and children
reported resolution or reduction in seizures on classic KD.
A small prospective study12 included 15 children pre-
scribed a 3:1 KD. There were between 2 and 5 years of fol-
low-up for each participant. Ten of 15 participants remained
GENETIC EPILEPSY: EVALUATION,
MANAGEMENT, AND TREATMENT
LGIT
28%
45%
70%
27%
n Proteins
seizure-free on KD in monotherapy. Two of 15 participants
had seizures recur after 2 years despite adequate levels of
ketosis, and these seizures were controlled with ethosuxi-
mide. One participant experienced seizure reduction but
not seizure freedom. No seizure adverse effects occurred and
parental satisfaction with the diet was good. Two partici-
pants discontinued the diet.
Information also is available on the long-term safety of
KDs in GLUT1-DS. A prospective, multicenter case series
looked at the long-term cardiovascular safety of KDs in
GLUT1-DS,13 including 10 participants followed over 10
years. Outcome measures included body mass index and
total cholesterol, high-density lipoprotein, low-density lipo-
protein, and triglyceride levels at baseline, 6 months, and 2,
5, and 10 years. There was no significant difference in cardio-
vascular risk for participants on long-term KDs compared
with a reference population.
In 2014, a case series of 3 individuals provided information
on long-term bone health and body composition in indi-
viduals with GLUT1-DS on KDs. Fourteen participants were
adults between age 24 and 25 who had been on a 3:1 KD for
more than 5 years. Outcome measures included anthropo-
metric and body composition measurements, bone mineral
content, and bone mineral density at baseline and annually.
Two individuals had slight fat mass loss; 1 had slight fat mass
gain. All 3 had reductions in bone mineral content (–5.5% to
–10.8%) at 3 years, which was stable thereafter. Both bone
mineral content and bone mineral density were within the
normal range at 5 years.
NOVEMBER 2023 PRACTICAL NEUROLOGY 31
 GENETIC EPILEPSY: EVALUATION,
MANAGEMENT, AND TREATMENT
Tuberous Sclerosis Complex
TSC is an inherited multisystem disorder that is typically
caused by pathogenic variants in TSC1 or TSC2. It is char-
acterized by pleomorphic features involving several organ
systems. Hallmark central nervous system features include
the presence of cortical tubers, subependymal nodules, and
subependymal giant cell astrocytomas. People with TSC
can experience epilepsy, behavioral disorders, and cognitive
defects, with epilepsy being the most common, reported in
up to 90% of individuals. Many individuals with TSC can go
on to develop medically refractory epilepsy.15,16
A retrospective review15 of individuals with TSC-
associated medically refractory epilepsy treated with KD at a
single center over a period of 7 years demonstrated that 10
of 12 participants (83%) experienced 50% or greater reduc-
tion in seizures after 3 months of treatment. Four of those
individuals (33%) were seizure-free. Two participants discon-
tinued the diet because of worsened seizures. At 6 months,
60% of individuals continuing on the diet were seizure-free,
and 80% had greater than 50% reduction in seizures. Six of
the initial 12 individuals maintained the diet for more than
12 months, and 4 had a 90% or greater reduction in seizures,
with 2 of these individuals being seizure-free.
An observational study16 of 31 children with TSC-
associated epilepsy treated with KDs demonstrated that
45% of participants had greater than 50% reduction in sei-
zures at 18 months, with this percentage dropping to 32% at
24 months. Approximately 20% of individuals were seizure-
free after 24 months on KDs. This study also looked at the
time to response (defined as greater than 50% reduction in
seizures) and found that the majority of participants who
would be responders had response within the first month
on KDs. No additional individuals obtained greater than 50%
reduction in seizures after 3 months on KDs.
Early-Onset Epileptic Encephalopathy With Burst
Suppression
Early-onset epileptic encephalopathy with burst suppres-
sion, also known as Ohtahara syndrome, is often associated
with structural or metabolic etiologies. Varying genetic
factors are increasingly being implicated in this disorder. A
retrospective chart review17 included individuals with seizure
onset at 3 months or younger, EEG tests showing burst-
suppression pattern, a full etiologic workup completed,
and follow-up available for at least 1 year. Individuals with
hypoxic-ischemic encephalopathy were excluded. Forty-
eight individuals were included and a genetic diagnosis
was established in 31 (64%). A total of 27% were found to
have STXBP1 sequence variations; 10%, KCNQ2 sequence
variations; and 10%, SCN2A sequence variations. A variety
of other sequence variations accounted for the remain-
ing cases. Among people in whom KD was attempted, all
32 PRACTICAL NEUROLOGY NOVEMBER 2023
of those with a KCNQ2 sequence variation (n=4) and 7 of
10 with an STXBP1 sequence variation were responders.
However, only 1 of 5 with an SCN2A sequence variation had
response.
Infantile Spasms
Infantile spasms (IS) are an age-dependent form of epi-
lepsy which usually present between 3 and 10 months of
age. The incidence is 2 to 3 per 1000 live births, and IS may
be associated with structural, metabolic, or genetic abnor-
malities. However, in many cases, the etiology is unknown.
A systematic review18 of 13 observational studies examined
the efficacy of KDs as an adjunctive therapy in 341 patients
with IS and found that ~65% experienced >50% reduction in
spasms. Median spasm-free rate was ~35%, with those with
IS of unknown etiology having an increased probability of
achieving this status.
Conclusion
A variety of dietary therapies are available throughout
the lifespan for people with difficult-to-control epilepsy.
Although data delineating the efficacy of KDs on the major-
ity of genetic epilepsies are not yet available, certain genetic
epilepsies (ie, AS and GLUT1-DS) are suggested to be par-
ticularly responsive to dietary therapy. Response to dietary
therapy in TSC-associated epilepsy seems to be more mod-
est but is still likely better than the 6-month to 1-year sei-
zure-freedom outcomes reported for additional medication
trials beyond 2 failed ASM, which range from 11% to 28%.19-21
In infants with catastrophic onset of epilepsy in whom
genetic etiologies can be identified, those with STXBP1 or
KCNQ2 sequence variations should have classic KDs consid-
ered early in the course of their treatment. In some individu-
als, KDs can and should be continued for years, and evidence
suggests the overall long-term risks from a cardiovascular
and bone health perspective are acceptable. n
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doi:10.1055/s-2005-872843 Deana Bonno, MD
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NOVEMBER 2023 PRACTICAL NEUROLOGY 33