With interest we read the review article by Senthilvelan et al. about the neuro-radiological findings in patients with a mitochondrial disorder (MID) [1]. It was concluded that cerebral imaging would render help in pointing towards a MID if a mutation escapes detection on exome sequencing. The study is appealing but has several limitations which raise the following comments and concerns.
The nature of stroke-like lesions (SLLs) is not sufficiently characterised. SLLs are a hallmark of MELAS but occur in other MIDs, such as MERRF, Saguenay-Lac St.-Jean cytochrome oxidase deficiency, Kearns-Sayre syndrome (KSS), OPA1-related disease, POLG1-related MIDs, ND3-related MID, Leigh syndrome, maternally inherited diabetes and deafness, ND4-related MID, MT-TV-related MID, and ND5-related MID [2]. SLLs are dynamic lesions which usually originate from the cortex and spread to adjacent cortical or subcortical regions within days, weeks, or even months. They usually regress in size thereafter, to reach a final stage. In the expanding phase SLLs are characterised by hyperintensity on T2/FLAIR, DWI, PWI, and hypointensity on oxygen-extraction fraction (OEF) MRI. FDG-PET shows hypometabolism. SLLs do not comply with a vascular territory and usually show a lactate peak on MR-spectroscopy. SLLs may end up with or without a structural cerebral lesion. Structural lesions as an endpoint of a SLL include white matter lesions, cortical or subcortical cysts, or laminar cortical necrosis.
Several abnormalities on imaging reported in MIDs were not addressed. These include basal ganglia calcification, laminar cortical necrosis as an endpoint of SLLs, subcortical cysts as an endpoint of a SLL, cortical cysts (toenail sign) as an endpoint of SLLs [3], empty sella, pituitary adenoma, aneurysm formation, ectasia of arteries, arterial dissection, remitting leucodystrophy due to mutations in FBP2 [4], progressive cerebellar atrophy in pyruvate-dehydrogenase deficiency [5], hypoplasia of the corpus callosum [6], unilateral periventricular leukomalacia in PDH deficiency [7], Wernicke encephalopathy due to vitamin B1 deficiency [8], and ponto-cerebellar hypoplasia.
We do not agree with the notion that LHON coexists with multiple sclerosis. The so called Harding syndrome is a misleading term, as LHON may mimic MS on imaging but the pathophysiology is different.
Not addressed were cerebral lesions secondary to cardiac involvement. These include cardio-embolic stroke, intracerebral bleeding, hypertensive encephalopathy in case of arterial hypertension, posterior reversible encephalopathy syndrome (PRES) in case of arterial hypertension, or vasoconstriction syndrome.
Cerebro-vascular abnormalities on imaging were not addressed either. MIDs may manifest with arteriopathy also affecting the cerebral arteries. Arteriopathy may manifest as aneurysm formation, ectasia, or as artery dissection [9,10].
Not addressed were congenital head deformities and dysmorphisms, such as microcephaly (FOX1 syndrome) in pyruvate-dehydrogenase deficiency [11] or macrocephaly (Penrose syndrome) [12].
Overall, the review has several limitations which challenge the results and their interpretation. These limitations sho`uld be addressed to substantiate the conclusions.
Senthilvelan, S. et al. “Neuromitochondrial disorders: genomic basis and an algorithmic approach to imaging diagnostics.” Clinical Neuroradiology, 2021. https://doi.org/10.1007/s00062-021-01030-4.
Finsterer, J. “Peculiarities of stroke-like lesions on MRI.” European Journal of Radiology Open, vol. 6, 2019, pp. 60–61. https://doi.org/10.1016/j.ejro.2019.01.001.
Ishigaki, H. et al. “Linear cortical cystic lesions: characteristic MR findings in MELAS patients.” Brain and Development, 2021. https://doi.org/10.1016/j.braindev.2021.05.002.
Gizak, A. et al. “A novel remitting leukodystrophy associated with a variant in FBP2.” Brain Communications, vol. 3, no. 2, 2021, article fcab036. https://doi.org/10.1093/braincomms/fcab036.
Nimmo, G.A.M. et al. “Bi-allelic mutations of LONP1 encoding the mitochondrial LonP1 protease cause pyruvate dehydrogenase deficiency and profound neurodegeneration with progressive cerebellar atrophy.” Human Molecular Genetics, vol. 28, no. 2, 2019, pp. 290–306. https://doi.org/10.1093/hmg/ddy351.
Sofou, K. et al. “MRI of the brain in childhood-onset mitochondrial disorders with central nervous system involvement.” Mitochondrion, vol. 13, no. 4, 2013, pp. 364–371. https://doi.org/10.1016/j.mito.2013.04.008.
Sharma, R. et al. “Unilateral periventricular leukomalacia in association with pyruvate dehydrogenase deficiency.” Developmental Medicine and Child Neurology, vol. 54, no. 5, 2012, pp. 469–471. https://doi.org/10.1111/j.1469-8749.2011.04108.x.
Jimoh, I.J. et al. “Wernicke–Korsakoff syndrome associated with mtDNA disease.” Therapeutic Advances in Neurological Disorders, vol. 13, 2020, article 1756286420938972. https://doi.org/10.1177/1756286420938972.
Finsterer, J. and Zarrouk-Mahjoub, S. “Mitochondrial vasculopathy.” World Journal of Cardiology, vol. 8, no. 5, 2016, pp. 333–339. https://doi.org/10.4330/wjc.v8.i5.333.
Kalashnikova, L.A. et al. “Mitochondrial arteriopathy as a cause of spontaneous dissection of cerebral arteries.” Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova, vol. 110, no. 4 Suppl. 2, 2010, pp. 3–11.
Akaba, Y. et al. “Phenotypic overlap between pyruvate dehydrogenase complex deficiency and FOXG1 syndrome.” Clinical Case Reports, vol. 9, no. 3, 2021, pp. 1711–1715. https://doi.org/10.1002/ccr3.3883.
Melis, D. et al. “Primrose syndrome: characterization of the phenotype in 42 patients.” Clinical Genetics, vol. 97, no. 6, 2020, pp. 890–901. https://doi.org/10.1111/cge.13749.
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