Asymmetric parietal and temporal lobe atrophy due to the variant m.8363G>A in transfer ribonucleic acid (Lysine)

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Asymmetric parietal and temporal lobe atrophy due to the variant m.8363G>A in transfer ribonucleic acid (Lysine)

Mitochondrial disorders are complex, multisystem conditions that often reveal new insights into how genetic mutations affect the body. A 2019 study by Xu et al. in the Chinese Medical Journal highlighted a 54-year-old man with a mitochondrial disorder (MID) impacting his brain, ears, and muscles—all linked to a specific genetic change: the m.8363G>A variant in the transfer ribonucleic acid for lysine (tRNA(Lys)). As a neurologist studying mitochondrial diseases, I read this case with interest—and several key questions about the patient’s presentation and care.

The man’s diagnosis included mitochondrial myopathy (muscle weakness from faulty mitochondria) affecting his limb muscles. But mitochondrial myopathies often spread to other muscles—facial, eye-moving (extraocular), core (axial), swallowing (bulbar), or breathing muscles. Did these areas become involved at diagnosis or later? This matters because it tells us how the mutation progresses in different muscle groups.

We also need to know more about his muscle biopsy. Mitochondrial tRNA mutations like m.8363G>A typically cause “combined respiratory chain defects”—problems with multiple parts of the mitochondrial machinery that makes energy for cells. Did the biopsy show reduced activity in one or more of these energy-producing complexes? This data would confirm the mutation’s direct impact on muscle function.

The patient had dysarthria (slurred speech). Is this from weak bulbar muscles (which control swallowing and speech) or damage to the brainstem (the brain region that regulates these muscles)? The answer changes how we approach treatment. Similarly, mitochondrial disorders often cause neuropathy (nerve damage)—did nerve tests show axonal damage (nerve fiber loss) or demyelination (damage to the nerve’s protective covering)? This detail shapes our understanding of the mutation’s effect on the nervous system.

Lactate, a byproduct of energy production, is a red flag for mitochondrial disease. Elevated lactate in the blood—either at rest or during mild exercise (a “lactate stress test”)—is common in mitochondrial myopathy. Did this patient have high lactate levels, and did they rise when he exercised below his anaerobic threshold (the point where muscles switch to less efficient energy production)? This would strengthen the link between his symptoms and the mutation.

Since the brain was involved (asymmetric parietal and temporal lobe atrophy), we should check cerebrospinal fluid (CSF) lactate. Mitochondrial brain disorders often cause cerebral lactic acidosis—can magnetic resonance spectroscopy (MRS) or direct CSF testing confirm this? This would tie his brain atrophy to mitochondrial dysfunction.

Heteroplasmy—the mix of normal and mutated mitochondrial DNA (mtDNA) in cells—is critical to mitochondrial disease severity. The more mutated mtDNA a cell has, the worse the symptoms. We know the patient had the mutation in muscle, but what about other tissues: hair follicles, skin cells, cheek lining, urine cells, or blood? Heteroplasmy rates vary by organ, so this data would explain why some areas (like the brain) were more affected than others.

Family history is key too: 75% of mtDNA mutations are inherited from mothers. Was the patient’s mother affected, and did she carry the m.8363G>A variant? This would tell us if the mutation was inherited or spontaneous.

Brain atrophy in MIDs often starts as focal (limited to one area, like the cerebellum or basal ganglia) and becomes diffuse over time. Did this patient’s parietal/temporal atrophy start as focal and spread? Understanding this progression helps predict long-term outcomes.

Finally, treatment: MIDs are hard to treat, and vitamins, lipoic acid, or cofactors usually don’t work. Did any of the patient’s symptoms improve with treatment? If so, was it real improvement—or could it have been spontaneous or a placebo effect? And did his brain atrophy get better with symptom improvement? This would tell us if treatment targets the right pathways.

Why do these details matter? Mitochondrial disorders are highly variable—each case adds to our map of how mutations like m.8363G>A behave. For patients with unusual symptoms (like asymmetric brain atrophy), comprehensive data is essential to refine diagnoses, predict progression, and develop treatments.

The original case is valuable, but filling these gaps would help us better understand this specific variant and improve care for others with similar mutations.

References

  1. Xu HL, Lian YJ, Chen X. Brain atrophy in a patient with mitochondrial DNA G8363A mutation. Chin Med J 2019;132:2141–2142. doi: doi.org/10.1097/CM9.0000000000000395
  2. Smits P, Mattijssen S, Morava E, van den Brand M, van den Brandt F, Wijburg F, et al. Functional consequences of mitochondrial tRNA Trp and tRNA Arg mutations causing combined OXPHOS defects. Eur J Hum Genet 2010;18:324–329. doi: doi.org/10.1038/ejhg.2009.169
  3. Finsterer J. Mitochondrial neuropathy. Clin Neurol Neurosurg 2005;107:181–186.
  4. Finsterer J, Shorny S, Capek J, Cerny-Zacharias C, Pelzl B, Messner R, et al. Lactate stress test in the diagnosis of mitochondrial myopathy. J Neurol Sci 1998;159:176–180. doi: doi.org/10.1016/s0022-510x(98)00170-1
  5. Weerasinghe CAL, Bui BT, Vu TT, Nguyen HT, Phung BK, Nguyen VM, et al. Leigh syndrome T8993C mitochondrial DNA mutation: heteroplasmy and the first clinical presentation in a Vietnamese family. Mol Med Rep 2018;17:6919–6925. doi: doi.org/10.3892/mmr.2018.8670
  6. Finsterer J. Asymmetric parietal and temporal lobe atrophy due to the variant m.8363G>A in transfer ribonucleic acid (Lysine). Chin Med J 2021;134:243–244. doi: doi.org/10.1097/CM9.0000000000001118

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