Is the MT-TN variant m.5703G>A truly causative for myoclonic epilepsy with ragged red fibers syndrome plus?
The article by Fu et al. discusses a 35-year-old male patient with late-onset myoclonic epilepsy with ragged red fibers syndrome (MERRF) plus syndrome, attributed to the MT-TN variant m.5703G>A. However, the pathogenicity of this variant has not been sufficiently confirmed, raising questions about its true causative role in the syndrome. The authors cite studies by Moraes et al. and Vives-Bauza et al. to support the variant’s pathogenicity, but the investigations carried out are deemed insufficient. The modified Yarham score, which validates eight items including the number of independent publications, heteroplasmy, segregation of the phenotype with the variant, proven biochemical defect, segregation of the variant with the biochemical defect on single-fiber studies, evidence of pathogenicity on cybrid studies or mutant mtDNA steady-state level studies, evolutionary conservation of the nucleotide, and abnormalities on histochemistry, is recommended for a more accurate assessment. Applying this score to the m.5703G>A variant results in a score value of 11, indicating that the variant is only probably pathogenic. Thus, further studies such as cybrid or mutant mtDNA steady-state level studies are required to definitively confirm its pathogenicity.
Valproic acid (VPA) is known to enhance myoclonus and can be mitochondrion-toxic. It is important to understand why VPA was administered to this patient and whether it was effective or caused side effects. Cardiac involvement is a common feature in MERRF, occurring in 18% of cases. One of the cardiac manifestations is late gadolinium enhancement (LGE), characterized by sub-endocardial, sub-epicardial, patchy, or transmural gadolinium enhancement 7 to 15 minutes after injection of the contrast medium. LGE can occur even in patients with normal echocardiography. Therefore, it is crucial to know if the reported patient underwent cardiac magnetic resonance imaging and if LGE was demonstrated.
The description “abnormalities of the visual pathway” on visually evoked potentials (VEPs) is non-specific and requires further specification. Any lesion along the visual pathways, from the cornea to the visual cortex, may result in prolonged latencies or reduced amplitudes of VEPs. Since the pigmentary retinal epithelium is frequently affected in patients with MERRF, manifesting as retinitis pigmentosa, rod and cone degeneration, pigmentary shifts, or optic atrophy, the results of the ophthalmologic investigations in the index case should be provided. Additionally, since patients with MERRF frequently present with white matter lesions, Leigh-like features, or stroke-like episodes, the findings on cerebral imaging should be detailed to more accurately interpret the VEPs.
In conclusion, while the m.5703G>A variant has been implicated in the development of MERRF plus syndrome, its pathogenicity has not been definitively confirmed. Further studies are required to establish its causative role. Additionally, the effects of VPA administration, the presence of cardiac involvement, and the specifics of visual pathway abnormalities need to be thoroughly investigated to provide a comprehensive understanding of the patient’s condition.
doi.org/10.1097/CM9.0000000000000337
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