Mitochondrial Cardiomyopathy Due to the MT-TI Variant m.4300A>G Requires Comprehensive Clinical and Genetic Workup

Editor:

With interest we read the article in the April 2023 issue of Radiology: Cardiothoracic Imaging by Dr Schoonvelde and colleagues (1) on three siblings with mitochondrial hypertrophic cardiomyopathy due to the homoplasmic variant m.4300A>G in mitochondrially encoded tRNA isoleucine (MT-TI) (1). The study is excellent but has limitations that are a cause of concern and should be discussed.

Because mitochondrial disorders (MIDs) are usually multisystemic diseases either already at onset or with progression of the disease, it is mandatory to systematically examine these patients for asymptomatic or mildly symptomatic multiorgan involvement. Therefore, we should know whether any of the three siblings presented with typical phenotypic features of a MID, such as short stature, dysmorphism, hypoacusis, visual impairment, gastrointestinal compromise, muscle weakness, easy fatigability, exercise intolerance, endocrine disturbances, skin changes, anemia, thrombocytopenia, bone abnormalities, kidney failure, lactic acidosis, or immunologic abnormalities (1).

Because patient 2 had rheumatoid arthritis, we should know how it was diagnosed. Did the patient meet the American College of Rheumatology criteria for rheumatoid arthritis? Because MIDs commonly manifest with polyarthralgias due to affection of the cartilage (2), we should know whether or not arthralgias were due to involvement of the joints in MID rather than rheumatoid arthritis.

There is scarce discussion of the cause of late gadolinium enhancement (LGE) (1). Was it due to scarring, inflammation, edema, or hyperperfusion? LGE has been previously reported in patients with mitochondrial cardiomyopathy (3), which is most likely due to fibrosis of the left ventricular myocardium.

Mitochondrial hypertrophic cardiomyopathy can be associated with noncompaction, also known as left ventricular hypertrabeculation (LVHT) (4). Were there any indications at cardiac MRI or echocardiography for LVHT? Panels C and D of Figure 1 are highly suggestive of LVHT in all three siblings. LVHT is commonly associated with subendocardial LGE (5).

Missing is the family history and investigation of other first-degree relatives, particularly the mother. Since presence of mitochondrial hypertrophic cardiomyopathy in three siblings is highly suggestive of hereditary disease, it is mandatory that particularly the mother is examined clinically and genetically.

In summary, MIDs require examination for multisystem disease. Mitochondrial hypertrophic cardiomyopathy requires confirmation or exclusion of LVHT. Mitochondrial hypertrophic cardiomyopathy in three siblings requires examination of the mother and other first-degree relatives.