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Letter to the Editor

Low Heteroplasmy Rates Argue Against the m.3243A>G Variant as the Cause of Auditory Agnosia

Finsterer, Josef MD, PhD

Author Information
doi: 10.1097/NRL.0000000000000247
  • Open

To the Editor:

We read with interest the article by Smith et al1 about a 61-year-old woman who presented with auditory hallucinations being attributed to bitemporal T2-weighted apparent diffusion coefficient-weighted, and diffusion-weighted imaging hyperintense lesions on magnetic resonance imaging. These lesions were interpreted as stroke-like lesions (SLLs), the morphologic equivalent of a stroke-like episode. Genetic workup revealed the m.3243A>G variant manifesting not only as SLLs but also as epilepsy, migraine, hypoacusis, cerebral lactate elevation, lactic acidosis, and short stature. We have the following comments.

The main shortcoming of the study is that the heteroplasmy rate of the m.3243A>G variant was determined only in lymphocytes.1 A heteroplasmy rate of 6% is too low to explain the phenotypic features of the presented patient. Thus, it is crucial that the heteroplasmy rate is determined in tissues more severely affected than lymphocytes.

We do not agree with the statement that the patient did not have clinical seizures.1 Why did the authors not consider the auditory hallucinations as seizures? As epilepsy is a frequent manifestation of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS),2 the clinical presentation can be most easily interpreted as seizure activity. We should know whether electroencephalograms (EEGs) were recorded during an episode of auditory agnosia. If the authors regarded the patient as seizure free, why was levetiracetam initialized. Treating EEGs is not what is recommended by the International League Against Epilepsy (ILAE).

Missing is also an extensive family history. It is not sufficient to state that the family history was positive for hearing loss. If this was the case, it is quite likely that it was a manifestation of a mitochondrial disorder. To assess whether the clinical presentation was attributable to a hereditary disease, we should know how many of the first-degree relatives carried the m.3243A>G variant, which phenotypic features other family members exhibited, and whether any of them had a history of SLLs. It should also be reported whether the parents were consanguineous or not. First-degree family members, particularly those with hearing loss and the one with intractable epilepsy, should have been genetically tested for the m.3243A>G variant. As the mitochondrial DNA variants are inherited from the mother’s side in 75% of the cases,3 it is quite likely that she was also affected and carried the m.3243A>G variant.

As the m.3243A>G variant frequently manifests with mitochondrial myopathy,4 we should be informed about the results of nerve conduction studies and needle electromyography in the index patient. Even if needle electromyography was normal, we should know whether creatine kinase was elevated and whether the patient ever underwent muscle biopsy, to see whether ragged-red fibers, frequently present in MELAS patients,5 could be found.

As the patient obviously had experienced bitemporal SLLs, and as SLLs are typically associated with hyperperfusion in the acute stage,6 we should be informed whether perfusion-weighted imaging was carried out if the bitemporal lesions showed hyperperfusion. It would also be interesting to know whether oxygen extraction magnetic resonance imaging was carried out and whether oxygen extraction was typically reduced within the SLLs.6

Overall, this interesting case could be more meaningful if the heteroplasmy rates of affected tissues were provided, if EEGs during acoustic agnosia were reported, if the patient was investigated for mitochondrial myopathy, and if the family history was provided.

Josef Finsterer, MD, PhD

Neurological Department, City Hospital Rudolstiftung, Messerli Institute, Vienna, Austria

REFERENCES

1. Smith K, Chiu S, Hunt C, et al. Late-onset mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes presenting with auditory agnosia. Neurologist. 2019;24:90–92.
2. Whittaker RG, Devine HE, Gorman GS, et al. Epilepsy in adults with mitochondrial disease: a cohort study. Ann Neurol. 2015;78:949–957.
3. Poulton J, Finsterer J, Yu-Wai-Man P. Genetic counselling for maternally inherited mitochondrial disorders. Mol Diagn Ther. 2017;21:419–429.
4. Suzuki J, Iwata M, Moriyoshi H, et al. Gastro-intestinal involvement in m.3243A>G-associated mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Intern Med. 2018;57:771.
5. Zierz CM, Joshi PR, Zierz S. Frequencies of myohistological mitochondrial changes in patients with mitochondrial DNA deletions and the common m.3243A>G point mutation. Neuropathology. 2015;35:130–136.
6. Yu L, Xie S, Xiao J, et al. Quantitative measurement of cerebral oxygen extraction fraction using MRI in patients with MELAS. PLoS One. 2013;8:e79859.
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