Is the MT-TN variant m.5703G>A truly causative for MERRF plus?

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Is the MT-TN variant m.5703G>A truly causative for myoclonic epilepsy with ragged red fibers syndrome plus?

Mitochondrial diseases like Myoclonic Epilepsy with Ragged Red Fibers (MERRF) syndrome are notoriously hard to diagnose—connecting a specific genetic change to a patient’s symptoms requires rock-solid evidence. In 2019, a study by Fu et al. suggested the MT-TN variant m.5703G>A caused a late-onset “MERRF plus” syndrome in a 35-year-old man. But does the research hold up to scrutiny?

Josef Finsterer, a neurologist at Krankenanstalt Rudolfstiftung in Vienna, Austria, raised key questions about the study in a correspondence to the Chinese Medical Journal. Here’s why the link between m.5703G>A and MERRF plus isn’t yet proven—and what’s missing to confirm it.

The Study: A 35-Year-Old Man with Late-Onset MERRF Plus

Fu et al.’s report described a man who developed myoclonus (involuntary muscle jerks), epilepsy, and muscle abnormalities later in life—symptoms labeled “MERRF plus” because they extended beyond classic MERRF. The team blamed the m.5703G>A variant, found in the mitochondrial tRNAAsn gene (MT-TN), and cited earlier work to support its role in disease. But Finsterer argues the evidence is incomplete.

1. Pathogenicity: The Variant Is “Probably” Causative—But Not Definitive

To prove a mitochondrial DNA (mtDNA) variant causes disease, experts use the modified Yarham score, a tool that rates 8 critical factors:

  • How many independent studies report the variant
  • Whether it’s present in affected tissues (heteroplasmy)
  • If symptoms “track” with the variant in families
  • Proven biochemical defects (e.g., faulty mitochondrial function)
  • Single-fiber studies linking the variant to cell damage
  • Cybrid studies (testing the variant in lab-grown cells)
  • Evolutionary conservation (if the genetic spot is vital across species)
  • Abnormal muscle tissue (histochemistry)

When Finsterer applied this score to m.5703G>A, it scored 11 points—enough for “probably pathogenic” but not “definitive.” The missing pieces? Cybrid studies (to see if the variant damages cells) or tests of mutant mtDNA levels. Without these, we can’t rule out other causes.

2. Valproic Acid: A Drug That Could Worsen Symptoms

The patient was prescribed valproic acid (VPA), an antiepileptic drug. But VPA is risky for MERRF patients: it can worsen myoclonus and is toxic to mitochondria—the very structures already damaged in MERRF. Finsterer asks: Why was VPA used? Did it help the epilepsy, or did it make symptoms worse? Without this context, the link between the variant and the patient’s condition is muddled.

3. Missing Cardiac MRI: A Key Gap in MERRF Care

MERRF doesn’t just affect the brain and muscles—18% of patients develop heart problems. A telltale sign is late gadolinium enhancement (LGE), where contrast dye builds up in damaged heart tissue on MRI. LGE can appear even if an echocardiogram (heart ultrasound) looks normal. But Fu et al. didn’t report a cardiac MRI for their patient. Finsterer notes this is a critical omission: without checking for LGE, we don’t know if the heart was involved—a common MERRF feature.

4. Vague Visual Tests: What’s Really Causing the “Abnormal Pathways”?

The study mentioned “abnormalities of the visual pathway” from visually evoked potentials (VEPs)—tests that measure brain responses to light. But Finsterer says this is too broad. VEPs can be abnormal for any problem along the visual chain: a scratched cornea, retinal damage, or a brain lesion. MERRF often harms the eyes (e.g., retinitis pigmentosa, optic atrophy) or brain (white matter lesions, stroke-like episodes). To interpret the VEP results, we need two things:

  • Ophthalmologic exams to check for eye damage
  • Cerebral imaging (like MRI) to look for brain lesions

The study didn’t include either, making the visual findings hard to link to the variant.

What This Means for MERRF Research

Finsterer’s critique highlights a bigger challenge in mitochondrial disease research: proving a genetic variant causes symptoms requires multiple lines of evidence. The m.5703G>A variant might play a role in MERRF plus—but right now, the data is incomplete. To confirm it, researchers need:

  • Cybrid studies or mtDNA level tests
  • Clarity on VPA’s role in the patient’s symptoms
  • Cardiac MRI to check for LGE
  • Ophthalmologic and brain imaging to explain VEP results

References

  1. Fu J, Ma MM, Pang M, Yang L, Li G, Song J, Zhang JW. Broadening the phenotype of m.5703G>A mutation in mitochondrial tRNAAsn gene from mitochondrial myopathy to myoclonic epilepsy with ragged red fibers syndrome. Chinese Medical Journal. 2019;132(7):865-867. doi.org/10.1097/CM9.0000000000000151
  2. Finsterer J, Zarrouk-Mahjoub S, Shoffner JM. MERRF classification: implications for diagnosis and clinical trials. Pediatric Neurology. 2018;80:8-23. doi.org/10.1016/j.pediatrneurol.2017.12.005
  3. Finsterer J. Toxicity of antiepileptic drugs to mitochondria. Handbook of Experimental Pharmacology. 2017;240:473-488. doi.org/10.1007/164_2016_2
  4. Catteruccia M, Sauchelli D, Della Marca G, Primiano G, Cuccagna C, Bernardo D, et al. Myo-cardiomyopathy is commonly associated with the A8344G “MERRF” mutation. Journal of Neurology. 2015;262(3):701-710. doi.org/10.1007/s00415-014-7632-0
  5. Zsurka G, Becker F, Heinen M, Gdynia HJ, Lerche H, Kunz WS, et al. Mutation in the mitochondrial tRNA(Ile) gene causes progressive myoclonus epilepsy. Seizure. 2013;22(4):483-486. doi.org/10.1016/j.seizure.2013.03.003

Original correspondence by Josef Finsterer, Krankenanstalt Rudolfstiftung, Vienna, Austria. Published in Chinese Medical Journal. 2019;132(14):1752. doi.org/10.1097/CM9.0000000000000337

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