Ketogenic Diet Resistance

Hello and welcome to Science with Sandra!

For this installment, I would like to highlight a recent publication by Professor Raffaelle Falsaperla in Italy in collaboration with Professor Joerg Klepper in Germany. The current publication “Toward a Working Definition of Ketogenic Diet Resistance in GLUT1 Deficiency Syndrome” is a follow up of the study “GLUT-1DS resistant to ketogenic diet: from clinical feature to in silico analysis. An exemplificative case report with a literature review, which I highlighted in March 2024 and you can find following this link.

What the study is about?

As it’s widely known, the ketogenic diet (KD) is the standard of care treatment for GLUT1 Deficiency Syndrome. The diet benefits most of the patients for most of the symptoms, reducing seizures and improving cognition and movement in some instances.

However, a small number of patients don’t benefit from it, even when the diet is done correctly. The study by Prof. Falsaperla et al. introduces a “working definition” of KD resistance to help clinicians identify and study these cases in a consistent way.

Proposed Definition of KD Resistance

The authors of the publication propose to establish a systematic evaluation of different domains, which could assist clinicians in identifying subgroups of patients who may benefit from individualized interventions. The authors suggest that a patient could be considered resistant to the ketogenic diet when all of the following are true: 

1. Therapeutic ketosis is achieved: Blood β-hydroxybutyrate levels stay at ≥2.0–2.5 mmol/L on repeated tests.
2. Dietary adherence is confirmed by a dietitian or validated tools.
3. Trial duration: The diet has been followed for at least 3 months, longer—at least 6 months for cognitive or motor goals.
4. No meaningful improvement in the main symptoms (seizures, movement, or cognitive function) is observed using standardized measures. Interictal epileptiform discharges (IEDs) burden may be used as an adjunctive marker where available but is not required for classification.

Why is this study important?

Despite the ketogenic diet benefiting a high percentage of patients in our community, for about 15% of our loved ones the diet does not work. This is known as ketogenic diet resistance and there is currently a big gap in understanding the reasons behind this phenomenon. The current study defines a set of domains that can be used to evaluate patients who don’t see benefit from the diet, with the aim of helping clinicians determine whether a patient has resistance to the ketogenic diet treatment.

The evaluation could serve as a guide to help:

• Clinicians decide when to modify treatment or add medication.
• Researchers compare results across studies.
• Families understand when the diet truly isn’t working versus when it may need more time or adjustments.

Possible Reasons for KD Resistance

Professor Falsaperla et al. outline several biological and practical factors that might explain poor response:

• Genetic differences in SLC2A1 mutations or in other metabolic pathway related genes.
• Problems with ketone transport or use in the brain (e.g., reduced monocarboxylate transporter (MCT) function).
• Mitochondrial dysfunction or issues with enzymes that process ketones.
• Inflammation or oxidative stress interfering with energy use.
• Hormonal/sex-related differences, possibly more common in female patients.
• Dietary or medication factors, like low energy intake or use of valproate. According to the authors, valproate interferes with ketosis.

Authors suggestions

Ketogenic diet resistance should be considered when all of the following are present:

• Confirmed therapeutic ketosis (serial blood β-hydroxybutyrate ≥2.0–2.5 mmol/L, interpreted in context)
•  Adequate adherence to the prescribed KD (dietetic assessment, with validated questionnaires when available)
•  ≥3 months of continuous KD (longer for primarily cognitive/motor goals)
• Lack of meaningful clinical improvement on symptom-relevant standardized measures. IED burden on EEG may be used as an adjunct marker of network instability but is not required for classification.

Highlights:

• This paper provides the first proposal to define and evaluate ketogenic diet resistance in GLUT1 Deficiency.
• It emphasizes a multidimensional approach, combining clinical, biochemical and cognitive information to determine wither or not a patient presents KD resistance.
• This paper provides the first structured proposal to define and evaluate “ketogenic diet resistance” in GLUT1DS.
• Finally, the authors suggest to have a multicenter collaboration to validate and refine these criteria, helping ensure patients receive the most effective and individualized care possible.

Finally, Dr. Falsaperla emphasized a concept that he sees emerging from his line of research: since these patients exhibit resistance to the Ketogenic Diet, our current efforts are focused on strengthening the GLUT1-mediated transport and enhancing its functional relationship with the MCT system. The final goal is to optimize cerebral energy availability and potentially improve the neurological outcomes where the diet alone is not sufficient.

We thank Professor Falsaperla for and Klepper for their work in this study and for their interest in our community. And I would also like to thank Dr. Falsaperla for reviewing the post and sharing some additional thoughts.

Thank you for visiting our blog and please do not hesitate to contact me at sojeda@g1dfoundation if you have any questions.