Beneficiality of Combined Levetiracetam and Clonazepam for Myoclonus in MERRF Requires Further Confirmation
The study by Su et al. investigated the efficacy of antiepileptic drug (AED) treatments in patients with myoclonic epilepsy with ragged-red fibers (MERRF) syndrome, a mitochondrial disorder characterized by myoclonus, generalized epilepsy, ataxia, and myopathy. The research focused on the effectiveness of monotherapy versus combination therapy using four AEDs: levetiracetam (LEV), clonazepam (CZP), valproic acid (VPA), and topiramate (TPM). The findings suggested that combination therapies were more effective than monotherapy, with the combination of LEV and CZP being the most beneficial, showing positive results in 12 out of 17 patients.
However, the study raised several concerns and questions that warrant further investigation. One of the primary issues is the role of heteroplasmy rates of the m.8344A>G variant in the response to AED treatment. Heteroplasmy refers to the presence of more than one type of mitochondrial DNA (mtDNA) within a cell, and its rate can vary significantly between different tissues such as hair follicles, skin fibroblasts, muscle cells, blood lymphocytes, buccal mucosa cells, or urinary epithelial cells. The study did not provide information on the heteroplasmy rates in the included patients, which could significantly influence the treatment outcomes.
Another concern is the potential mitochondrion toxicity of VPA, particularly in patients with POLG1 mutations. VPA has been associated with liver toxicity and even fatalities in patients with mitochondrial disorders. In the study, two of the four patients with progressive disease after four months of monotherapy were on VPA. It is possible that the deterioration in these patients was due to VPA toxicity rather than the ineffectiveness of the drug or the natural progression of the disease.
The clinical diagnosis of MERRF requires the presence of four canonical features: myoclonus, generalized epilepsy, ataxia, and myopathy. However, in the study, only three out of the 17 patients presented with all four features. This discrepancy could be explained by variable heteroplasmy rates, which might influence the phenotypic expression of the disease. Additionally, the study did not report the results of muscle biopsies in the 11 patients who underwent the procedure, which could have provided further insights into the diagnosis and severity of the condition.
MERRF patients can present with a wide range of additional symptoms, including cognitive decline, migraine, psychiatric disease, stroke-like episodes, respiratory insufficiency, neuropathy, ptosis, ophthalmoparesis, optic atrophy, pigmentary retinopathy, hypoacusis, arrhythmias, cardiomyopathy, dysphagia, vomiting, gastrointestinal dysmotility, diabetes, hypothyroidism, short stature, and lipomatosis. The study did not provide detailed information on the presence of these additional phenotypic presentations in the included patients, which could have offered a more comprehensive understanding of the disease.
The family history of the patients was also not mentioned in the study. Since 75% of mitochondrial disorders associated with mtDNA variants are maternally transmitted, knowing the family history could provide valuable information on the inheritance patterns and the frequency of epilepsy and myoclonus in sporadic versus inherited cases.
Furthermore, the study did not mention any other drugs that the patients were taking in addition to AEDs. AEDs can interact with other medications, leading to either an enhancement or attenuation of their effects. Therefore, knowing the complete drug regimen of the patients is crucial for understanding the overall treatment outcomes.
In summary, while the study by Su et al. provides valuable insights into the treatment of MERRF syndrome with AEDs, several areas require further investigation. These include the role of heteroplasmy rates, the potential toxicity of VPA, a more comprehensive description of the phenotype, detailed family history, and information on other medications taken by the patients. Addressing these concerns could lead to a more effective and personalized treatment approach for patients with MERRF syndrome.
doi.org/10.1097/CM9.0000000000000042
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