Asymmetric Parietal and Temporal Lobe Atrophy Due to the Variant m.8363G>A in Transfer Ribonucleic Acid (Lysine)
The case report by Xu et al. describes a 54-year-old male patient with a multisystem mitochondrial disorder (MID) attributed to the mitochondrial DNA (mtDNA) variant m.8363G>A in the transfer ribonucleic acid (tRNA) for lysine. This variant was associated with clinical manifestations affecting the brain, ears, and muscles. The patient exhibited mitochondrial myopathy, which primarily affected the limb muscles. However, the report did not specify whether other muscle groups, such as facial, extra-ocular, axial, bulbar, or respiratory muscles, were involved at diagnosis or during follow-up. These muscle groups are frequently affected in MIDs, and their involvement could provide further insights into the disease’s progression and severity.
Mitochondrial myopathy caused by mtDNA tRNA variants typically results in combined respiratory chain defects. Therefore, it is essential to know the results of biochemical investigations of the muscle biopsy. Specifically, the report should clarify whether there was reduced activity of a single or multiple respiratory chain complexes. Such information would help in understanding the biochemical basis of the myopathy and its correlation with the clinical phenotype.
The patient also presented with dysarthria, but it remains unclear whether this was due to bulbar muscle involvement or brainstem pathology. Additionally, nerve conduction studies could reveal whether the patient had axonal or demyelinating polyneuropathy, which is frequently associated with MIDs. These details would provide a more comprehensive picture of the neurological manifestations in this case.
Mitochondrial myopathy is often associated with elevated serum lactate levels, either at rest or during mild exercise. A lactate stress test, which measures lactate levels below the anaerobic threshold, could provide valuable diagnostic information. The report should include the patient’s serum lactate levels and whether they increased upon mild exercise. Furthermore, since central nervous system involvement in MIDs is frequently associated with elevated cerebrospinal fluid (CSF) lactate, it would be beneficial to know if magnetic resonance spectroscopy (MRS) showed an increased lactate peak or if direct CSF measurement revealed cerebral lactic acidosis.
The phenotypic manifestations of mtDNA variants depend on the heteroplasmy rate, which refers to the proportion of mutated mtDNA within a mitochondrion or cell. The report should specify the heteroplasmy rates in the patient’s muscle tissue. Since heteroplasmy rates can vary across different tissues, it would also be informative to know the rates in other tissues, such as hair follicles, skin fibroblasts, buccal mucosa cells, urinary epithelial cells, or blood lymphocytes. This information could help explain the variability in organ involvement and disease severity.
The family history of the index patient is unclear. Given that 75% of mtDNA variants are maternally inherited, it is important to know whether the patient’s mother was clinically affected and whether she carried the m.8363G>A variant. This information could provide insights into the inheritance pattern and the potential risk for other family members.
Brain atrophy is a common feature of MIDs, often affecting the cerebellum or basal ganglia. In this case, the patient exhibited asymmetric parietal and temporal lobe atrophy. It is unclear whether this focal atrophy represents the end-stage of a stroke-like lesion or if it developed progressively. The report should provide details on the development of focal atrophy and whether it became more diffuse as the disease progressed.
Treatment of MIDs typically involves vitamins, lipoic acid, and cofactors, although these interventions are usually ineffective. The report should specify which clinical manifestations improved with treatment and whether the improvement was spontaneous or a placebo effect. Additionally, it would be interesting to know if the focal cerebral atrophy improved alongside the clinical manifestations.
Since MIDs are often multisystem disorders, either at onset or during the disease course, prospective investigations for subclinical or mildly manifesting organ involvement are crucial. Early detection of organ affection, particularly of the heart, can improve patient outcomes. The report should include results from such prospective multisystem investigations to provide a comprehensive understanding of the disease’s impact on various organs.
In conclusion, this case highlights the complexity of MIDs and the importance of thorough and comprehensive investigations to understand their phenotypic spectrum. Detailed information on family history, heteroplasmy rates in various tissues, results of prospective multisystem investigations, and the effectiveness of treatment would enhance our understanding of this disorder. The case also underscores the need for early detection and management of organ involvement to improve patient outcomes.
doi.org/10.1097/CM9.0000000000001118
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