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Polish Journal of Pathology
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vol. 70
Letter to the Editor

Liver pathology in hepato-cerebral mitochondrial depletion syndromes due to POLG1, DGUOK, 146or MPV17 variants

Josef Finsterer

Neurological Department, Krankenanstalt Rudolfstiftung, Messerli Institute, Vienna, Austria
Pol J Pathol 2019; 70 (2): 146-147
Online publish date: 2019/09/04
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With interest we read the article by Pronicki et al. about a histopathological study of liver specimens (biopsy n = 5, autopsy n = 8) from 13 children with the hepato-cerebral form of mitochondrial depletion syndrome due to pathological variants in POLG1, DGUOK, and MPV17 [1]. The authors found depletion of mtDNA in the liver, ranging from 0.01 to 11% [1]. Five of the 13 patients had epilepsy [1]. All patients died from liver failure [1]. We have the following comments and concerns.
We do not agree with the notion that mitochondrial depletion syndromes exclusively follow an autosomal recessive (AR) trait of inheritance as mentioned in the introduction [1]. Particularly mitochondrial depletion syndrome due to RRM2B mutations may be inherited in an autosomal dominant (AD) way [2]. Also transmission of mutations in TWINKLE may follow an AD trait of inheritance [3].
Since mitochondrial depletion syndrome may go along with reduced activity of a single or multiple respiratory chain complexes [4], we should be informed about the results of biochemical investigations of the presented liver or muscle specimens of the included patients. Which of the respiratory complexes were reduced in activity? Was there reduction of single or multiple complex activity?
Ultrastructural investigations of mitochondria in mtDNA depletion syndromes show that mitochondria may be abnormal in number, size, structure, and dynamics [5]. Thus, we should be informed about the ultrastructural findings in the 13 included patients. It would be also helpful to know the results of the Gomori trichrome stain, and of the NADH-, SDH-, and COX stainings.
Since blood, muscle, and liver were used for genetic analysis, we should be informed if the amount of mitochondrial DNA (mtDNA) depletion was different between these tissues. Particularly we would like to know if there was depletion also in clinically non-affected tissues.
Since five patients had epilepsy we should be informed about the antiepileptic drugs these patients received. Particularly from valproic acid, phenytoin, carbamazepine, and phenobarbital it is known that they are potentially mitochondrion-toxic [6]. Was deterioration of the phenotype in these five patients associated with the antiepileptic drug therapy? Since epilepsy in mitochondrial depletion syndrome may also respond to ketogenic diet, we should know how many of the included patient received it.
Overall, this interesting study could be more meaningful if depletion rates from the liver were compared with depletion rates from other tissues, if detailed information about the antiepileptic regimen were provided, if results of immune-histochemical investigations of the specimens were provided, and if electron microscopy findings were presented.


1. Pronicki M, Piekutowska-Abramczuk D, Rokicki D, et al. Histopathological liver findings in patients with hepatocerebral mitochondrial depletion syndrome with defined molecular basis. Pol J Pathol 2018; 69: 292-298.
2. Gorman GS, Taylor RW. RRM2B-Related Mitochondrial Disease. 2014 Apr 17. In: Adam MP, Ardinger HH, Pagon RA, et al. (eds.). GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from http://www.ncbi.nlm.nih.gov/books/NBK195854/
3. Goffart S, Cooper HM, Tyynismaa H, et al. Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling. Hum Mol Genet 2009; 18: 328-340.
4. Hakonen AH, Goffart S, Marjavaara S, et al. Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion. Hum Mol Genet 2008; 17: 3822-3835.
5. Stiles AR, Simon MT, Stover A, et al. Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion. Mol Genet Metab 2016; 119: 91-99.
6. Finsterer J, Zarrouk Mahjoub S. Mitochondrial toxicity of antiepileptic drugs and their tolerability in mitochondrial disorders. Expert Opin Drug Metab Toxicol 2012; 8: 71-79.
Copyright: © 2019 Polish Association of Pathologists and the Polish Branch of the International Academy of Pathology This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
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