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Response to: The tRNA(Ile) variant m.4309G>A may not cause Kearns Sayre syndrome.

W thank Dr. Finsterer for his insightful remarks about the case of a 16-year-old male with KearnsSayre syndrome (KSS) who underwent heart transplantation (HTx) because of intractable dilated cardiomyopathy and appreciate the opportunity to clarify some details not previously addressed due to space constraints. Unlike nDNA variants, a common framework for mitochondrial DNA variant classification is yet to be agreed upon by international scientific societies. At the very least, if we apply the conservative classification method of Wang and coworkers, the m.4309G>A variant should be considered as unclassified. However, multiple lines of current, nonconflicting evidence point to a pathogenic role of the m.4309G>A variant: it has not been observed in healthy individuals (HmtVar), it has been independently reported as associated with progressive external ophthalmoplegia and exercise intolerance with ragged-red fibers; in vitro assays demonstrate negative functional and structural effects on tRNA(Ile); and in silico predictions (PON-mt-tRNA, MitoTIP, and HmtVar) range from “possibly pathogenic” to “pathogenic.” Furthermore, in our case, the m.4309G>A mutation is associated to the cardinal phenotypic features of KSS, such as retinopathy, onset <20 years, progressive external ophthalmoplegia, short stature, and cognitive impairment; so, it also confirmed the pathogenetic role of the questioned variant. Besides, the variant has a de novo origin in our patient and no mtDNA deletions have been found. Considering the additional features of the KSS, our patient showed several highlights of the disease, reinforcing the clinical aspect of the aforementioned genetic variant: it had a history of epilepsy, treated with levetiracetam, and white matter lesions in nucleus caudate were evident in a brain MRI. Although the known retinopathy, our patient showed a good preserved level of vision. No facial dysmorphism was noted. Similarly, the subtle myopathy and the lactic acidosis have not prevented a good ability in exercise performance. He did not show hypoacusia. Laboratory tests have confirmed a mild grade of renal insufficiency and anemia, while no thrombocytopenia, diabetes, or hypothyroidism have been never detected. Concerning the heart, the diagnosis of left ventricular hypertrabeculation/noncompaction was excluded through a cardiac magnetic resonance before the HTx, and the histopathological features agreed with the diagnosis of idiopathic dilated cardiomyopathy, where the cardiac muscle was primarily affected by the disease. Nowadays, the long-term follow-up of this patient is ongoing, and surely it will give us answers about the potential role of immunosuppression in the evolving aspects of the noncardiac manifestations of the phenotype. Nine months after the HTx, his current immunosuppressive regimen is based on steroids, mycophenolate mofetil, and cyclosporin. Centers always struggle with making decisions on whether to offer a scarce resource to patients with a systemic and progressive disease: long-term followup of this case will be essential to assess if KSS patients truly benefit from HTx in the long-term.