Intractable epilepsy in m.1630A>G carriers should be treated with a ketogenic diet on a trial basis

We read with interest the article by Wang et al. about a 3-year-old boy with a mitochondrial disorder (MID) due to the m.1630A>G variant in mitochondrial tRNAVal (MT-TV), which had appeared de novo and could not be detected in the patient’s mother (1). The patient presented phenotypically with intractable epilepsy (1). The study is noteworthy, but several points should be discussed.

The first point is the discrepancy between the low heteroplasmy rate of 7.3% and the severe encephalopathy (1). Such a low heteroplasmy rate suggests that the corresponding carrier of the mutation is asymptomatic rather than symptomatic. Have attempts been made to determine the heteroplasmy rate in neuronal tissue or cerebrospinal fluid (CSF)? The discrepancy could be explained by high heteroplasmy rates in the brain but low heteroplasmy rates in clinically unaffected tissues. However, such an assumption remains speculative as long as a high heteroplasmy rate in the brain has not been confirmed.

The second point is that the mitochondrial DNA (mtDNA) copy number was not determined in the index patient (1). It is known that mtDNA copy numbers can also determine the phenotype of mtDNA variants (2). Reduced mtDNA copy number has been shown to be associated with many health-related phenotypes of metabolically active tissues, such as brain, cardiovascular disease and liver damage (1).

The third point is that the patient had severe encephalopathy but a normal magnetic resonance imaging (1). However, the patient did not undergo any other imaging studies, nor did he undergo CSF testing. CSF studies could have documented an elevated CSF lactate, which is common in mitochondrial encephalopathies (3). Elevated brain lactate could also have been detected with magnetic resonance spectroscopy (MRS). Fluorodeoxy-glucose positron emission tomography (FDG-PET) could have demonstrated hypometabolism in the bifrontal areas where epileptiform discharges were recorded on the video-electroencephalography (4).

The fourth point is that the index patient has not been systematically examined for multisystem involvement. MIDs are known to frequently affect not just a single organ but multiple organs, with particular affinity for the brain, eyes, ears, endocrine organs, heart, gastrointestinal tract, skeletal muscles and peripheral nerves (5).

The fifth point is that the patient was not treated with L-arginine, glutamine, antioxidants, vitamins or co-factors, which are known to be of particular benefit to affected patients in at least some cases (6). There is also no mention of whether or not the patient has attempted treatment with the ketogenic diet. The ketogenic diet is known to significantly improve epilepsy in patients with MIDs (7). In a 20-year-old woman with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) due to the m.3243A>G variant, a long-term ketogenic diet reduced seizure frequency by >50 (7).

The sixth point is that the m.1630A>G variant was not only found in three patients, including the index case mentioned in the article (1). At least a fourth patient was described by Wong et al. (8). This patient presented phenotypically with renal failure, stroke-like episodes and gastrointestinal dysmotility (8).

Finally, it was not reported in detail which antiepileptic drugs were tried.

In summary, this interesting study has limitations that put the results and their interpretation into perspective. Addressing these limitations could reinforce the conclusions and support the study’s message. Intractable epilepsy in m.1630A>G carriers should be treated with the ketogenic diet and mitochondrial cocktails.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-194/coif). The author has no conflicts of interest to declare.

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References

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