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.
Missing are the results of the magnetic resonance spectroscopy (MRS). In MIDs MRS frequently shows a lactate peak. The elevated lactate in the cerebrospinal fluid (CSF) can be documented also by direct investigation of the CSF for lactate.
No explanation of the absent tendon reflexes was provided. We should be told if reduced tendon reflexes were due to a neuropathic or myopathic lesion. We also should know if the creatine-kinase, the aldolase, myoglobin, and lactate-dehydrogenase (LDH) were within the reference limits or increased.
The lactate stress test was highly abnormal, suggesting a MID. According to which protocol was the lactate stress carried out?
The negative family history does not exclude a MID. Mutations in either an mtDNA or nDNA located gene may occur spontaneously.
The term „abnormal hyperintensity “on DWI is misleading. There is no „normal hyperintensity “.
Overall, the interesting study has some limitations and inconsistencies which challenge the results and their interpretation. Addressing these issues would strengthen the conclusions, their clinical relevance, and could increase the status of the study.
Declarations
Funding sources: no funding was received
Conflicts of interest: none
Acknowledgement: none
Ethics approval: was in accordance with ethical guidelines. The study was approved by the institutional review board
Consent to participate: was obtained from the patient
Consent for publication: was obtained from the patient
Availability of data: all data are available from the corresponding author
Code availability: not applicable
Author contribution: JF: design, literature search, discussion, first draft, critical comments, final approval, DM: literature search, discussion, critical comments, final approval
Xie, F. et al. "A case report of neuronal intranuclear inclusion disease presenting with recurrent migraine-like attacks and cerebral edema: A mimicker of MELAS." Frontiers in Neurology, vol. 13, no. 1, 2022, pp. 837844. doi:10.3389/fneur.2022.837844.
Bonora, E. et al. "Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy." Brain, vol. 144, no. 5, 2021, pp. 1451–1466. doi:10.1093/brain/awab056.
Ho, C.Y. et al. "Longitudinal MRI brain findings in the R1349Q pathogenic variant of CACNA1A." Radiology Case Reports, vol. 16, no. 6, 2021, pp. 1276–1279. doi:10.1016/j.radcr.2021.02.052.
Malaquias, M.J. et al. "MYORG gene disease-causing variants in a family with primary familial brain calcification presenting with stroke-like episodes." Clinical Genetics, vol. 98, no. 5, 2020, pp. 517–519. doi:10.1111/cge.13836.
Malaquias, M.J. et al. "MYORG gene disease-causing variants in a family with primary familial brain calcification presenting with stroke-like episodes." Clinical Genetics, vol. 98, no. 5, 2020, pp. 517–519. doi:10.1111/cge.13836.
Conboy, E. et al. "Novel homozygous variant in TTC19 causing mitochondrial complex III deficiency with recurrent stroke-like episodes: Expanding the phenotype." Seminars in Pediatric Neurology, vol. 26, no. 1, 2018, pp. 16–20. doi:10.1016/j.spen.2018.04.003.
Conboy, E. et al. "Novel homozygous variant in TTC19 causing mitochondrial complex III deficiency with recurrent stroke-like episodes: Expanding the phenotype." Seminars in Pediatric Neurology, vol. 26, no. 1, 2018, pp. 16–20. doi:10.1016/j.spen.2018.04.003.
Yoo, D.H. et al. "Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome." Mitochondrion, vol. 35, no. 1, 2017, pp. 54–58. doi:10.1016/j.mito.2017.05.005.
Hikmat, O. et al. "ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: A POLG mimic?" European Journal of Neurology, vol. 23, no. 7, 2016, pp. 1188–1194. doi:10.1111/ene.13003.
Sagnelli, A. et al. "X-linked Charcot-Marie-Tooth type 1: Stroke-like presentation of a novel GJB1 mutation." Journal of the Peripheral Nervous System, vol. 19, no. 2, 2014, pp. 183–186. doi:10.1111/jns5.12070.
Finsterer, J. and Aliyev, R. "Metabolic stroke or stroke-like lesion: Peculiarities of a phenomenon." Journal of the Neurological Sciences, vol. 412, no. 1, 2020, pp. 116726. doi:10.1016/j.jns.2020.116726.
Finsterer, J. et al. "Stroke-like lesion in an m.3243A>G carrier presenting as hyperperfusion and hypometabolism." Cureus, vol. 13, no. 6, 2021, pp. e15487. doi:10.7759/cureus.15487.
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