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 read with interest the article by Li et al. about an 11-month-old boy with a monoorganic mitochondrial disease (MID) due to the compound heterozygous variants c.1735C>T (maternally inherited) and c.695G>A (paternally inherited) in the POLG1 gene (1). The variants manifested phenotypically exclusively in the liver with recurrent hypoglycemia and acute liver failure (1). The patient successfully received a living donor liver transplant and made a near-complete recovery (1). The study is interesting, but some points warrant discussion.

First, we disagree with the assertion that the POLG1 variants have not been previously described (1). The c.1735C>T variant has already been described in a 38-year-old Saudi man with bilateral ptosis, strabismus, and chronic progressive external ophthalmoplegia (CPEO) (2). This patient was compound heterozygous and also carried the c.2246T>C variant (2). The c.695G>A variant has been described in a patient with autosomal recessive axonal Charcot-Marie-Tooth disease type 2 (3). In addition to neuropathy, this patient exhibited head tremor, slowed saccades, nystagmus, dysmetria, dysdiadochokinesia, dysarthria, dysphagia, and myopathy (3).

The second point concerns the diagnosis of mitochondrial DNA (mtDNA) depletion syndrome (1). Although POLG1 mutations can cause secondary mtDNA depletion (4), they can also lead to hepatopathy without secondary mtDNA depletion (5). Therefore, it is crucial to demonstrate, through appropriate testing, that the mtDNA copy number was indeed reduced in the index patient. A reduced mtDNA copy number can be most reliably detected using quantitative real-time polymerase chain reaction (PCR) or digital droplet PCR (6).

Thirdly, the patient was not systematically screened for multisystem disease (1). POLG1 mutations often manifest not only in a single organ, but in multiple organs, tissues, or systems—either at the onset of the disease or as it progresses to a multisystem MID (7). Common neurological manifestations of POLG1 variants include epilepsy, ataxia, neuropathy, cognitive impairment, stroke-like episodes, movement disorders, or myopathy (8). Has the index patient ever been examined by a neurologist? Cerebral magnetic resonance imaging (MRI) and electroencephalography (EEG) may not be sufficient to detect neurological involvement. In addition to hepatopathy, non-neurological manifestations may include gastrointestinal symptoms (vomiting, dysphagia, gastrointestinal motility disorders), optic atrophy, hearing impairment, external ophthalmoplegia, and cardiomyopathy. Did the vomiting cease after liver transplantation (8)?

The fourth point concerns the pathogenicity of the detected variants, which was assessed solely using in silico methods (1). To assess the actual pathogenicity of a variant, biochemical and functional assays, studies in model organisms, determination of population frequency, family segregation, and comparison of the patient phenotype with previously described phenotypes are essential (9).

Fifth, the patient’s immunosuppressive therapy was not documented in detail (1). Since immunosuppressants can be mitochondrially toxic (10), it is crucial to know which therapy the patient received and whether he tolerated it well in the long term without adverse effects.

Finally, neither the long-term course nor the parents’ blood relationship was documented. Furthermore, no reference values for respiratory chain complex functions were provided, although the methodology mentions the calculation of reference values for ten healthy controls.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0516/coif). The authors have no conflicts of interest to declare.

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