Exploring Ketogenic Diet Resistance in Glut1 Deficiency

Hello and a Happy 2025!

I would like to highlight a publication which was the product of a collaborative effort between a group in Italy led by Dr. Raffaele Falsaperla and Dr. Joerg Klepper in Germany.

The publication is “Exploring ketogenic diet resistance in glucose transporter type 1 deficiency syndrome: A comprehensive review and critical appraisal”. The aim of this review is to explore the characteristics of the ketogenic diet therapy failure when treating Glut1 Deficiency patients and identify the risk factors in those patients. The goal of the study team is to improve counseling and prognostication for those patients.

​​The study team performed a literature review focusing in studies done on pediatric Glut1 Deficiency patients who had drug-resistance epilepsy and did not respond to the ketogenic dietary therapy (KDT). 

KDT is the standard care treatment for patients with Glut1 Deficiency and ot has been shown to help most of the patients and in some cases most their symptoms. However, there is a percentage of patients who don’t respond to the diet, in some cases, due to diet intolerance and in other cases due to lack of compliance. Some patients, despite having good diet adherence, are not able to reach ketosis, while other who are able to reach good ketosis do not see any benefits from the diet. Currently, there is a lack of understanding about why these patients do not respond to the diet and how to best support them for their treatment. The publication discussed here aimed to identify the risk factors contributing to the lack of response to the diet by this patient population.

Through the literature search the study team found five female patients who had been diagnosed when they were between 10 days and 13 years of age and who did not respond to the KDT. The most common type of seizure experienced by these patients were absence seizures, with individual cases of clonic, tonic or myoclonic seizures. In addition, genetic testing results for some of these patients showed two patients had point mutations and another patient had a deletion.

A previous publication by Dr. Falsaperla that we featured in our blog reported a case of a female patient with Glut1 Deficiency who has resistance to KDT. The patient described developed intractable dystonic episodes which worsened with higher ketosis. Dr. Falsaperla and his team identified through in-silico genomic and proteomic analysis that the cause of the resistance to the diet was the patient’s variant on the SLC2A1 gene, a microdeletion on the first exon of the gene. The literature search indicated that variant or mutation type did not predict the therapeutic response to the diet. The authors think that there needs to be a better understanding of the role of noncoding RNA genes and downstream defects in all the processes involved in the production of the GLUT1 protein, this could help predict not only the disease severity, but also it could potentially help predict response to the diet.

The authors conclude that their research shows a significant gap in the literature related to data reported on KDT failure and the related risk factors. In addition, the number of cases reported in the literature is small, making it difficult to draw significant conclusions about the potential risk factors for KDT failure. Finally, the study team emphasizes the importance of multi-center studies to make a comprehensive exploration of the potential risk factors playing a role in this issue.

We would like to thank Dr. Falsaperla, Dr. Klepper and their teams for their work and their interest to help patients in our community.

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