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Folia Neuropathologica
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vol. 59
Letter to the Editor

Valproic acid for myoclonic epilepsy in POLG1 carriers can be fatal

Josef Finsterer

Klinik Landstrasse, Messerli Institute, Vienna, Austria
Folia Neuropathol 2021; 59 (1): 17-18
Online publish date: 2021/03/31
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With interest we read the article by Tarka et al. about the autopsy findings of an 8-year-old female with mitochondrial disorder (MID) due to the compound heterozygous variants c.2243G>C and c.2542G>A in POLG1 [1]. The patient manifested clinically with mental retardation, developmental regression, and myoclonic epilepsy, for which she received valproic acid (VPA) [1]. Neuropathological studies after death from acute pancreatitis and liver failure revealed bilaterally symmetric degenerative lesions of the accessory olivary nuclei in addition to typical features of Alpers-Huttenlocher disease (AHD) [1]. It was concluded that pancreatitis prior to liver failure is unusual [1]. The study is appealing but raises comments and concerns.
The main shortcoming is that the patient received VPA. It is well known that VPA can cause acute liver failure in patients carrying POLG1 variants [2]. In some of these patients the outcome was even fatal [3]. Thus, VPA is contraindicated in patients carrying POLG1 variants. Missing in this respect is the dosage of VPA, seizure frequency, compliance, quality of seizure control, and the VPA serum levels. Since POLG1 carriers may manifest with hepato­pathy even in the absence of VPA, we should know if liver parameters were ever elevated prior to the application of VPA and if abdominal ultrasound ever detected liver enlargement, fatty infiltration, cysts, or fibrosis prior to starting VPA. Did the patient suffer from a coagulation disorder or from hypo-protei­nemia?
Since POLG1 may cause secondary mtDNA damage [4], we should know if there was a secondary mtDNA point mutation, mtDNA deletion/duplication, or if there was mtDNA depletion. Secondary damage may strongly determine the phenotype and thus the outcome of POLG1 carriers. We do not agree with the diagnosis of AHD. AHD is diagnosed upon the triad: mtDNA depletion, resistant epilepsy, and liver failure triggered by VPA [3]. However, the index patient met only 1 criterion. We do not agree with the statement that pancreatitis as a side effect of VPA is “extremely rare” [1]. On the contrary, pancreatitis is well appreciated as an adverse reaction to VPA [5].
Though the MRI of the brain was reported as normal, we should know which modalities were applied. Of particular interest is diffusion weighted imaging (DWI), apparent diffusion coefficient (ADC), perfusion weighted imaging (PWI,) and oxygen-extraction fraction (OEF) sequences. Furthermore, we should know if magnetic resonance spectroscopy (MRS) or direct measurement of cerebro-spinal fluid (CSF) lactate was ever carried out to see if there was lactic acidosis in the brain or not. Since the patient developed epilepsy, we should know if a neurodevelopmental defect was excluded as the cause of epilepsy by application of an epilepsy protocol according to the ILAE for the work-up of the etiology by means of imaging. Missing is if the patient was a mono- or di-zygotic twin. Missing is the information if the parents were consanguineous or non-consanguineous. Missing are clinical and genetic investigations of the parents and other first-degree relatives. Missing is a discussion about the phenotypic heterogeneity of POLG1 variants, which may not only cause syndromic MID, but also non-syndromic MID, as in the presented case. Overall, the interesting study has a number of limitations which should be met before drawing conclusions as those presented. Details about the family history and epilepsy are required and the results of clinical and genetic work-up of first-degree relatives are required. The effect of the POLG1 variants on mtDNA should be detailed. Details about cerebral imaging studies should be provided.


The author declares no conflict of interest.


1. Tarka S, Laure-Kamionowska M, Wierzba-Bobrowicz T, Witulska K, Ciara E, Szymańska K, Krajewski P, Stępień T, Acewicz A, Felczak P. POLG gene mutation. Clinico-neuropathological study. Folia Neuropathol 2020; 58: 386-392.
2. Bassett JT, Rodriguez B, Mulligan L, Fontana RJ. Acute liver failure in a military recruit treated with valproic acid and harboring a previously unrecognized POLG-1 mutation. Epilepsy Behav Rep 2019; 12: 100342.
3. Pronicka E, Weglewska-Jurkiewicz A, Pronicki M, Sykut-Cegiel­ska J, Kowalski P, Pajdowska M, Jankowska I, Kotulska K, Kalicinski P, Jakobkiewicz-Banecka J, Wegrzyn G. Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene. Med Sci Monit 2011; 17: CR203-9.
4. Roos S, Macao B, Fusté JM, Lindberg C, Jemt E, Holme E, Moslemi AR, Oldfors A, Falkenberg M. Subnormal levels of POL-A cause inefficient initiation of light-strand DNA synthesis and lead to mitochondrial DNA deletions and progressive external ophthalmoplegia [corrected]. Hum Mol Genet 2013; 22: 2411-2422.
5. Deschenes PC, Autmizguine J, Major P, Kleiber N. Valproic acid induced pancreatitis presenting with decreased level of consciousness in a child with tuberous sclerosis complex. J Pediatr Pharmacol Ther 2020; 25: 256-260.
Copyright: © 2021 Mossakowski Medical Research Centre Polish Academy of Sciences and the Polish Association of Neuropathologists. 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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