LAUSR

With interest we read the article by Miyahara and colleagues about a 17-year-old female with a mitochondrial disorder (MID) due to the variant m.8344A>G in tRNA(Lys), being classified as myoclonus epilepsy with ragged red fibers / mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MERRF/MELAS) overlap syndrome. We have the following comments and concerns. We disagree with the classification of the condition as MERRF/MELAS overlap syndrome. Occurrence of a stroke-like lesion (SLL) in MERRF patients is not uncommon and has been previously reported. According to two retrospective investigations of cohorts of MERRF patients carrying the m.8344A>G variant, the frequency of strokelike episodes (SLEs), the clinical equivalent of a SLL, is 4%, respectively 3% in m.8344A>G carriers. Since the patient did not manifest with the four canonical phenotypic features of MERRF (myoclonus, generalized epilepsy, mitochondrial myopathy, and ataxia), she should be classified as MERRF plus syndrome. MERRF plus is characterized by phenotypic manifestations not only in the brain and skeletal muscle but also the eyes, ears, the heart, the gastrointestinal tract, endocrine organs, and the skin. Missing in this report is the mutation load of the m.8344A>G variant. Knowing the heteroplasmy rate is crucial, as it may correlate with the disease severity. Thus, we should be informed about heteroplasmy rates in all affected tissues determined after autopsy. It is also crucial to report the phenotype and genotype of the mother to assess if MERRF plus occurred sporadically or was inherited via the maternal line. In 75% of the cases transfer RNA variants are maternally inherited. Missing is also the presentation of the magnetic resonance imaging (MRI) apparent diffusion coefficient (ADC) map. Since it is assumed that the patient had a SLE at age 17 years, it is crucial that the corresponding SLL is documented on multimodal MRI. This includes not only T2-weighted images (T2WI) and diffusion-weighted images (DWI) but also ADC maps, perfusion-weighted imaging, and oxygen extraction MR. Provision of these modalities is crucial as SLLs in the acute phase show up on MRI as hyperintensity on DWI and ADC, as hyper-perfusion and as reduced oxygen extraction not confined a vascular territory. Since the reason for admission of the described patient was a SLE, it is surprising that treatment of the SLE included “vasopressors, antibiotics, and steroids”. The standard therapy of SLEs includes nitric oxide-precursors, such as Larginine or L-citrulline, and antiepileptic drugs. Additionally, some patients may profit from the ketogenic diet or steroids. Concerning steroids, the therapeutic effect is highly variable. In some patients a beneficial effect and in some patients a negative or detrimental effect has been reported. The patient was suspected to have died from heart failure. However, no cardiac compromise was reported prior to age 17 years. If heart failure developed acutely, Takotsubo syndrome (TTS) has to be considered. Thus, we should be informed about the echocardiographic findings, serum catecholamine levels, pro-B-type natriuretic peptide values, routine electrocardiogram (ECG) and the 24 hECG. Heart failure may also occur in noncompaction, which is why we should know if noncompaction was detectable. Since seizures are the second most common trigger of TTS, we should know if the SLE at age 17 years was associated with seizures. If seizures occurred prior to TTS, it is conceivable that heart failure resulted from TTS triggered by the seizure. Importantly, the study confirms that SLLs may also occur in a non-classical distribution, as has been recently reported. Overall, this interesting study could be more meaningful if the points raised above were adequately addressed. It should be also stressed that laminar cortical necrosis can be the histological equivalent of a non-classical SLL.