Stroke-Like Lesions Can Be a Manifestation of Variants in Ndna Located Mitochondrial Genes
We read with interest the article by Xie et al. about a 51yo female with nuclear inclusion disease (NID) due to a GGC expansion of 118 repeats in NOTCH2NLC detected upon a repeat-primed PCR [1]. The patient manifested phenotypically with migraine, lactic acidosis, and a stroke-like lesion (SLL) in the right occipito-temporal area at age 51y [1]. A mitochondrial disorder (MID) was considered as a differential but excluded upon sequencing of the mitochondrial DNA (mtDNA) and application of a gene panel for mutations in nuclear DNA (nDNA) located genes involved in mitochondrial function and morphology [1]. It was concluded that a NID should be considered as a differential of migraine and a SLL and that hyperintensity on diffusion weighted imaging (DWI) and cortical enhancement could be a biomarker of NID [1]. The study is appealing but raises concerns which should be extensively discussed۔We do not agree that a MID was entirely excluded as long it is unknown which nDNA genes were actually screened for pathogenic variants by means of the mitochondrial gene panel. SLLs have been reported in association with POLG1, LIG3, CACNA1A, MYORG, TTC19, MRM2, FASTKD2, ADCK3, GJB1, CSF1R, ARCA2, and COQ4 variants [2,3,4,5,6,7,8,9,10]. Pathogenic variants in these genes should be excluded before attributing the stroke-like lesion (SLL), the morphological equivalent of a SLE, to NIG. Arguments for a MID in the index patient are the elevated serum lactate, the abnormal lactate stress test, the reduced tendon reflexes suggesting neuropathy or myopathy, the SLL on MRI, and the history of migraine. We should be told if other phenotypic features of a MID, such as short stature, hypoacusis, sicca syndrome, cardiomyopathy, diabetes, or renal insufficiency were also present in the index patient. Since MIDs are usually multisystem disease, we should be informed about the results of investigations of organs potentially affected in MIDs. A further argument for the presence of a SLL in the index patent is the dynamic expansion of the left parieto-occipital lesion within three months [1]. Since SLL usually regress over time, we should be informed about the outcome of the SLL. Regarding the diagnosis SLL, DWI, and TIRM are not sufficient. A SLL is additionally characterised by a hyperintensity on perfusion weighted images (PWI), by a hypointensity on oxygen extraction MRI (OEF-MRI), and by hypometabolism on FDG-PET or SPECT [11,12]. Missing is the electroencephalography (EEG). Since SLLs can be triggered by seizures it is crucial to exclude or confirm the presence of epileptiform discharges.