Reply to: A mono-organ POLG1-related mitochondrial DNA depletion syndrome must be confirmed by quantitative real-time polymerase chain reaction (PCR) or droplet digital PCR
We thank Finsterer and Zarrouk for their comments on the case report: “Living donor liver transplantation in a pediatric patient with mitochondrial DNA depletion syndrome caused by two novel POLG1 mutations: a case report and literature review” published in Translational Pediatrics (1,2).
Regarding the novelty of the POLG1 variants, we appreciate the authors directing our attention to the previous reports of the c.1735C>T and c.695G>A variants in adult patients with neurological phenotypes (3,4). We acknowledge the oversight in our literature review regarding these isolated adult cases. However, we would like to emphasize that the combination of these two specific variants as a compound heterozygous mutation, presenting exclusively as isolated acute liver failure and recurrent hypoglycemia in an infant without pre-existing neurological symptoms, remains a novel phenotypic expansion.
We agree with the authors that measuring mitochondrial DNA (mtDNA) copy number via quantitative real-time polymerase chain reaction (PCR) or digital droplet PCR is the gold standard for confirming mtDNA depletion. While direct quantification of mtDNA was a limitation in our center at the time of diagnosis, our biochemical evidence strongly supports the diagnosis. As detailed in Tab. 2 of our manuscript (2), the respiratory chain complex (RCC) assays revealed that the activities of mtDNA-dependent complexes (complex I and III) were markedly reduced to 32% and 28% of age-matched controls, respectively. In contrast, the activity of the purely nuclear-encoded complex II remained normal. This classic biochemical dissociation is highly indicative of an mtDNA-related defect, supporting our clinical diagnosis.
Regarding multisystem involvement, our patient underwent a rigorous formal pre-transplant assessment, including a developmental evaluation, electroencephalogram (EEG), and brain magnetic resonance imaging (MRI), all of which showed no evidence of neurological involvement at that time. Furthermore, in response to the authors’ specific question, the vomiting episodes completely ceased following the living donor liver transplantation (LDLT), as they were secondary to the acute metabolic crisis and liver failure rather than an independent gastrointestinal manifestation. We also wish to clarify that the pathogenicity of these variants was not assessed solely using in silico methods. In addition to the aforementioned biochemical assays, we provided ultrastructural evidence via electron microscopy. The liver biopsy revealed distinct morphological abnormalities in the mitochondria, including significant enlargement, abnormal ring-shaped morphology, and dense mitochondrial cristae, which corroborate the pathogenic impact of the identified mutations.
We agree that the potential mitochondrial toxicity of certain immunosuppressants requires careful consideration. Postoperatively, the patient was maintained on a standard pediatric immunosuppressive regimen consisting of tacrolimus, with trough levels regularly monitored and maintained within the target therapeutic range. Methylprednisolone was also administered initially and subsequently tapered gradually until complete discontinuation. To date, the patient has tolerated this regimen excellently, maintaining stable allograft function without clinical or laboratory signs of drug-induced mitochondrial toxicity.
Finally, we confirm that the patient’s parents are of non-consanguineous Han descent, and there is no family history of inherited metabolic disorders. Regarding the reference values for the RCC activities, we acknowledge that the absolute reference ranges were not explicitly listed. Because absolute specific activities can vary significantly depending on tissue processing, our methodology prioritized a more robust approach using 10 age-matched pediatric controls. The patient’s results were normalized to citrate synthase (CS) activity—a reliable marker of mitochondrial mass. The profound dissociation, showing drastically reduced mtDNA-encoded complexes alongside preserved nuclear-encoded complex II activity, demonstrates the specific biochemical defect, rendering the absolute reference limits less critical for the final diagnostic conclusion.
Acknowledgments
None.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article did not undergo external peer review.
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0527/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Finsterer J, Zarrouk S. A mono-organ POLG1-related mtDNA depletion syndrome must be confirmed by quantitative real-time PCR or droplet digital PCR. Transl Pediatr 2026; [Crossref]
- Li Y, Xie F, Wei L, et al. Living donor liver transplantation in a pediatric patient with mitochondrial DNA depletion syndrome caused by two novel POLG1 mutations: a case report and literature review. Transl Pediatr 2026;15:161. [Crossref] [PubMed]
- Algahtani H, Shirah B, Alsaggaf K, et al. Chronic progressive external ophthalmoplegia in a Saudi patient with a mutation in the POLG gene successfully managed with bilateral frontalis sling. Journal of Genetic Medicine 2021;18:121-6.
- Harrower T, Stewart JD, Hudson G, et al. POLG1 mutations manifesting as autosomal recessive axonal Charcot-Marie-Tooth disease. Arch Neurol 2008;65:133-6. [Crossref] [PubMed]
