Before biliary atresia is claimed as a phenotypic manifestation of the m.3243A>G variant, the causal relationship must be proven

I read with interest the article by Sun et al. about a 7-month-old female with the m.3243A>G variant in MT-TL1 who developed a biliary atresia phenotype at 2 months of age and was initially treated with the Kasai procedure (1). Despite this measure, she developed recurrent, therapy-resistant cholangitis, which is why she underwent a successful liver transplant at the age of 7 months (1). It was concluded that the m.3243A>G variant can lead to recurrent cholangitis and that mitochondrial dysfunction can cause inflammation (1). The study is interesting, but some points need clarification and should be discussed.

The first point is that I disagree with the view that the m.3243A>G variant can be phenotypically associated with recurrent cholangitis (1). No such cases have been reported to date. Since cholangitis can be a common complication of the Kasai procedure (2), recurrent cholangitis is more likely to be due to the previous surgery than to the underlying mitochondrial DNA (mtDNA) variant. Liver involvement in mitochondrial disorders has been reported particularly in patients with mtDNA depletion due to mutations in nuclear genes, but not in patients with mtDNA mutations. However, in a study of mtDNA variants in 14 patients with biliary atresia, 34 common non-synonymous variations were detected in mtDNA protein-coding genes in critical regions of complexes I to V involved in subunit assembly, proton pump activity, and/or supercomplex formation (3). It was concluded that mtDNA mutations can exacerbate the severity of liver failure in patients with biliary atresia (3).

The second point is that the index patient was not prospectively examined for multisystem disease (1). Mitochondrial disorders caused by the m.3243A>G variant are usually multisystem diseases (4). The organs predominantly affected are the brain, muscles, eyes, ears, gastrointestinal tract, endocrine organs, heart, and kidneys. Which of the common manifestations of mitochondrial disorders, apart from hepatopathy, did the index patient present with? Was lactate ever measured in serum or cerebrospinal fluid (CSF), and was it elevated? Lactic acidosis is a common feature of m.3243A>G carriers (4,5).

The third point is that the heteroplasmy rates of m.3243A>G were not specified (1). What do the authors mean by “with a frequency of 9,195/(9,195+2,432) (79.08%)”? Is 79.08% the heteroplasmy rate? Furthermore, neither the mtDNA copy number nor the haplotype is mentioned. Since both parameters are important determinants of the phenotype, it would be important to know whether these parameters influenced the phenotypic expression of the m.3243A>G variant in such a way that it manifested itself in hepatopathy.

The fourth point is that the explanted liver was not examined for respiratory chain function or heteroplasmy rates. Assuming that biliary atresia was a phenotypic expression of the m.3243A>G variant, it can be assumed that the heteroplasmy rates in the liver were particularly high and the mtDNA copy number particularly low. It would also be interesting to know which complexes of the respiratory chain were dysfunctional in the liver cells.

The fifth point is that no long-term results were reported (1). Since some of the immunosuppressants administered to patients with transplanted organs can be mitochondrial toxic, it would be interesting to know whether the rate of deterioration of the phenotype has increased, as the patient must take immunosuppressants to prevent organ rejection.

Finally, I disagree with the statement that the pedigree in Fig. 3 shows maternal inheritance (1). Although the caption mentions that the mother of the index patient also carried the m.3243A>G variant, the pedigree does not show that the mother carried the mutation or that she was clinically affected. This should be clarified.

Overall, before attributing biliary atresia to the m.3243A>G variant, the most important genetic determinants, the entire spectrum of phenotypic expressions, and the long-term outcome after transplantation must be specified, and a causal relationship must be proven.

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