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A success story: the ketogenic diet for Glut1 deficiency syndrome
In this brief article Larissa describes the history of Glut1 and how the ketogenic therapy became the go-to solution to treat the condition.
Larissa's Profile
Name: Larissa De Clauser
Profession: Medical Affairs Manager
Education: PhD in Neurosciences (University Collage London)
Favorite Food: Pistacchio Ice, Tempeh
The discovery of Glut1 deficiency syndrome
35 years ago, in 1991, the paediatric neurologist Dr. De Vivo was faced with two young patients. Martin and Lisa (names are invented) both had seizures beginning in the third month of life. Treatment with several antiseizure medications had been ineffective. The children exhibited reduced glucose levels in the cerebrospinal fluid (a substance surrounding the brain and spinal cord), compared to their blood. After excluding a bunch of other causes that might lead to this observation, Dr. Vivo and his team suspected that the children had a deficit in the transport of glucose to the brain. Indeed, they found a genetic alteration in the glucose transporter type 1 (in short Glut1), a protein that is required to bring glucose to the brain. Since glucose is normally the source of energy used by our body, including the brain, the team thought about using a different type of fuel. A ketogenic diet can provide this fuel to the brain in form of ketones (Owen et al., 1967). Within one week of therapy Martin and Lisa were seizure free (De Vivo et al., 1991). After this success story the effectiveness of the ketogenic dietary therapy has been demonstrated in many more people with Glut1 deficiency syndrome (Glut1 DS) (Klepper & Leiendecker, 2007), and today the ketogenic dietary therapy remains the gold standard treatment (Klepper et al., 2020).
Symptoms and their change over time
Seizures are the hallmark symptom of Glut1 deficiency syndrome (short Glut1 DS). They occur in 90% of patients (Pong et al., 2012) and they don’t respond to antiseizure medication. Other common symptoms are movement disorders, which can be either persistently ongoing or sudden and intense, varying also in their severity (Klepper et al., 2020). In children sudden, repeated and brief head-eye movements are typical for Glut1 DS (Pearson et al., 2017). When growing up the seizures tend to decrease or disappear and movement disorders become more prevalent (Alter et al., 2015) and change in their manifestation. While growing up difficulties in gate and speech become evident (Pons et al., 2010), driven by a poor muscle control. In more than 70% of patients sudden and intense repetitive movements are observed (Klepper et al., 2016) and triggered by fasting (e.g., when waking up), after exercise, or through stress (De Giorgis et al., 2015). Compared to their peers individuals with Glut1 DS may have poorer cognitive skills that can result in intellectual disabilities and vary in severity, correlating with the overall clinical picture (Leen et al., 2010). The ketogenic dietary therapy has been shown to be effective in treating the full range of symptoms (Klepper et al., 2020). Importantly, the earlier the dietary therapy is started, the better the long-term outcomes are for the patients (Alter et al., 2015), and hence an early diagnosis is key!
Types of ketogenic dietary therapy for Glut1 DS
Since the clinical picture of Glut1 DS changes over the individual’s lifetime, and the data availability on adults is limited, recommendations for the type of ketogenic therapy based on clinical experience have been made (Klepper et al., 2020). In infants and young children, a classic ketogenic dietary therapy leading to high ketone levels is preferred, since the developing brains requires more energy (Kim et al., 2016). In adults and adolescents, where the correlation between ketone levels and the ketogenic ratio is less strong (Porper et al., 2021), the Modified Atkins Diet (short MAD) might be more appropriate to increase compliance and quality of life, since it is less restrictive (Kim et al., 2016).
Since MCTs are highly ketogenic (Harvey et al., 2018), they could be integrated in a ketogenic dietary therapy to boost ketosis and make the overall diet for children and adult Glut1 DS patients less restrictive. A recent case report showcases the successful use of MCTs in an adult patient, Lidia (name invented), who had suffered from drug-resistant epilepsy as a child and who is still experiencing seizures in the early morning. At the age of 47 she is diagnosed with Glut1 DS. Lidia also has problems walking long distances, speaking clearly, and she suffers from sudden uncontrolled movements. The doctors were able to significantly reduce her symptoms with a diet low in carbohydrates (60g/day) and rich in MCTs (20% of total calorie intake). Lidia demonstrates that even adults receiving a late diagnosis of Glut1 DS can benefit from the ketogenic dietary therapy (Nabatame et al., 2024).
There are three different categories of neurological symptoms in Glut1 DS: epilepsy, movement disorders, and cognitive disturbances. The classic Glut1 DS presentation covers all three categories, whereas milder forms might not involve all categories and the range of symptoms can change over time (Adapted from (Pearson et al., 2013). The ketogenic dietary therapy is useful to treat the full range of symptoms, having the highest effectiveness in treating epilepsy with a reduction of seizures by over half in 95% of Glut1 DS patients (Kass et al., 2016).
Bibliography:
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