Broadening the phenotype of m.5703G>A mutation in mitochondrial tRNAAsn gene

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Broadening the phenotype of m.5703G>A mutation in mitochondrial tRNAAsn gene from mitochondrial myopathy to myoclonic epilepsy with ragged red fibers syndrome

Mitochondrial diseases are among the most complex genetic disorders—they affect the tiny “power plants” of our cells (mitochondria) and can cause a dizzying range of symptoms, from muscle weakness to seizures. What makes them even trickier is that the same mutation can lead to completely different health issues in different people. Now, a new case study is shining a light on one such mutation: m.5703G>A in the mitochondrial tRNAAsn (MT-TN) gene. Previously linked only to mild muscle disease (mitochondrial myopathy), researchers have now found it in a patient with myoclonic epilepsy with ragged red fibers (MERRF) syndrome—a more severe condition involving seizures, coordination loss, and widespread muscle damage.

The Patient’s Journey: A Decade of Symptoms Before Diagnosis

The patient at the heart of the study is a 34-year-old Chinese man whose health declined slowly over 16 years. His first symptom, at 18, was a generalized tonic-clonic seizure (a full-body convulsion) that occurred once a year. By 23, he started having myoclonic seizures—sudden, uncontrollable jerks in his limbs, body, or head—several times a day. These were hard to manage with valproic acid and levetiracetam, two common epilepsy drugs.

Over the next decade, his symptoms worsened:

  • Muscle issues: At 31, he developed weakness and wasting (atrophy) in all four limbs, plus fatigue and trouble exercising.
  • Eye and facial problems: Bilateral eye fixation (inability to move his eyes freely), mild right eyelid droop (ptosis), weak facial/chewing muscles, slurred speech (dysarthria), and difficulty swallowing (dysphagia).
  • Nerve and coordination problems: At 32, he had numbness in his lower limbs that spread to his thighs, an unsteady gait, and mild hearing loss.

No family members had similar symptoms, so doctors initially struggled to pinpoint the cause.

Testing Reveals Classic MERRF Signs—And a Surprising Mutation

To diagnose him, doctors ran a battery of tests:

  • EEG: Showed generalized spike-and-wave complexes, confirming myoclonic epilepsy.
  • Muscle MRI: Revealed fatty infiltration (muscle damage) mostly in the back of his thighs and calves—rarely seen in MERRF.
  • Muscle biopsy: The “smoking gun” for mitochondrial disease: ragged red fibers (RRFs) (abnormal muscle fibers) and cytochrome c oxidase (COX)-deficient fibers (a sign of mitochondrial dysfunction).

But the biggest breakthrough came from next-generation sequencing (NGS), which analyzed his entire mitochondrial genome and hundreds of nuclear genes linked to muscle and epilepsy. The result? A heteroplasmic m.5703G>A mutation in the MT-TN gene—meaning the mutation was present in some (but not all) of his mitochondria. It was found in 61% of his blood mitochondria and 77% of his muscle mitochondria (higher levels in muscle explain his severe muscle symptoms).

Crucially, this mutation was not found in his mother’s blood—so it was a new (de novo) mutation, not inherited.

From Misdiagnosis to Targeted Treatment

For years, the patient’s myoclonus and seizures were poorly controlled with valproic acid—a drug not recommended for mitochondrial myoclonic seizures because it can worsen symptoms. Once diagnosed with MERRF, doctors switched him to a combination of levetiracetam and clonazepam—a regimen known to help MERRF patients. Within a month, his myoclonic seizures decreased.

Why This Case Changes Everything

Before this study, the m.5703G>A mutation was only reported in two patients with pure mitochondrial myopathy (muscle disease alone). This is the first time it’s been linked to full MERRF syndrome—defined by myoclonus, epilepsy, ataxia, and RRFs.

The findings are a big deal for two reasons:

  1. Expands MERRF’s genetic spectrum: Most MERRF cases (80%) are caused by the m.8344A>G mutation in the MT-TK gene. Now, doctors know to look for m.5703G>A in patients who don’t have the common mutation.
  2. Broadens the mutation’s “phenotype”: The same mutation can cause mild muscle disease or severe MERRF—depending on how many mitochondria are affected (heteroplasmy levels) and which organs are hit.

What This Means for Patients and Doctors

This case highlights three key takeaways:

  • Mitochondrial diseases are unpredictable: Symptoms can take years to fully appear, leading to delayed diagnosis.
  • Genetic testing is critical: Tools like NGS can find rare mutations that explain “mystery” symptoms.
  • Treatment must be personalized: Valproic acid is harmful for some mitochondrial seizures—switching to levetiracetam and clonazepam made a real difference for this patient.

The Bottom Line

For the first time, researchers have linked the m.5703G>A mutation to MERRF syndrome. This isn’t just a scientific curiosity—it’s a reminder that mitochondrial diseases are far more variable than we thought. For patients with unexplained seizures, muscle weakness, or coordination loss, this study offers new hope: a rare mutation could be the cause, and targeted treatment might help.

  1. Altmann J, Büchner B, Nadaj-Pakleza A, et al. Expanded phenotypic spectrum of the m.8344A>G “MERRF” mutation: data from the German mitoNET registry. J Neurol. 2016;263(5):961-972. doi: https://doi.org/10.1007/s00415-016-8086-3
  2. Moraes CT, Ciacci F, Bonilla E, et al. Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is the tRNA (Leu (UUR)) gene an etiologic hot spot? J Clin Invest. 1993;92(6):2906-2915. doi: https://doi.org/10.1172/JCI116913
  3. Vives-Bauza C, Del Toro M, Solano A, et al. Genotype-phenotype correlation in the 5703G>A mutation in the tRNA (ASN) gene of mitochondrial DNA. J Inherit Metab Dis. 2003;26(5):507-508. doi: https://doi.org/10.1023/A:1025133629685
  4. Su LJ, Wang YL, Han T, et al. Antimyoclonic effect of levetiracetam and clonazepam combined treatment on myoclonic epilepsy with ragged-red fiber syndrome with m.8344A>G mutation. Chin Med J (Engl). 2018;131(20):2433-2438. doi: https://doi.org/10.4103/0366-6999.243568
  5. Ban R, Guo JH, Pu CQ, et al. A novel mutation of mitochondrial T14709C causes myoclonic epilepsy with ragged red fibers syndrome in a Chinese patient. Chin Med J (Engl). 2018;131(13):1569-1574. doi: https://doi.org/10.4103/0366-6999.235120

Original Study Citation: Fu J, Ma MM, Pang M, et al. Broadening the phenotype of m.5703G>A mutation in mitochondrial tRNAAsn gene from mitochondrial myopathy to myoclonic epilepsy with ragged red fibers syndrome. Chin Med J (Engl). 2019;132(7):865-867. doi: https://doi.org/10.1097/CM9.0000000000000151

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