With interest we read the article by Maruo et al. about a 22yo male in whom Leigh syndrome was diagnosed upon endo-myocardial biopsy (EMB). Causative for Leigh syndrome was the mtDNA variant m.14453 A>G in MT-ND6 [1]. Biochemical investigations of the EMB revealed a complex-I defect. Biochemical investigations of the muscle homogenate were normal [1]. The patient manifested phenotypically with delayed psycho-motor development, seizures, lactic acidosis, hypertrophic cardiomyopathy, and muscle weakness [1]. We have the following comments and concerns. 

Leigh syndrome is usually diagnosed upon the clinical presentation, cerebvral MRI findings (bilateral basal ganglia, midbrain, brain stem, or cerebellar T2 hyperintens lesions), and confirmation of a mutation in one of the >75 currently known genes to cause Leigh syndrome. Since Leigh syndrome was suspected already prior to EMB, we shouold know why the patient nonetheless underwent EMB. Instead of EMB the patient should have undergone sequencing of the mtDNA. 

Phenotypes of pathogenic mtDNA variants may not only be determined by heteroplasmy rates [2] but also by mtDNA copy number, hyplotype, and polymorphisms. Thus, we should know the mtDNA copy number, the haplotype, and which polymorpshism of the mtDNA were detected. 

Biochemical investigations of the myocardial homogenate is unusual why we should know how the authors specified normal limits for respiratory chain complex acitivities. 

Since neuromuscular disorders (NMDs) are frequently associated with noncompaction, also known as left ventricular hypertrabeculation (LVHT), [3] and since mitochondrial disorders (MIDs) are the group of genetic disorders most frequently associated with LVHT [4], it is crucial to know if echocardiography was revised for LVHT. Since LVHT may be missed on echocardiography due to technical issues [5], we should know the results of cardiac magnetic resonance imaging (cMRI). Since LVHT is frequently associated with late gadolinium enhancement (LGE) [6], we should know if the index patient presented with LGE on cMRI.

Since several of the anti-seizure drugs (ASDs) are potentially mitochondriaon-toxic [7], it should be specified which ASDs the index patient particularly received and in which dosage. It is also crucial to know the quality of seizure control, if there were triggers of seizures, and if the ASDs exhibited any side effects. Since it is known that the ketogenic diet may exhibit a beneficial effect on epilepsy in MIDs, we should know if the ketogenic diet was ever tried in the index patient and if it was beneficial. 

Since mtDNA variants frequently manifest with multisystem disease and since the index patient manifested in the brain, heart, and muscle (myo-cardio-encephalopathy), we should know the results of prospective investigations for multisystem disease. Particularly, we should know which organs other than the brian, heart, and muscle were additionally involved. Particularly, we need to know which cells produced lactate in excess. Was it the myocardium, the brain or the muscle?

How do authors explain the discrpancy between normal muscle biposy and normal biochemical investigations of the muscle and muscle weakness on clinical neurologic exam. 

Overall, the study has several limitations which should be addressed before drawing final conclusions. Patients with suspected Leigh syndrome should not undergo EMB but rather sequencing of the mtDNA or whole exome sequencing (WES) for confirming the disgnosis Leigh syndrome. Genetic tests have less side effects than EMB.