With interest we read the article by Perrone et al. (2020)Perrone E, Cavole TR, Oliveira MG, Virmond LDA, Silva MFB, Soares MFF, Iglesias SBO, Falconi A, Silva JS, Nakano V et al. (2020) Leigh syndrome in apatient with a novel C12orf65 pathogenic variant: Case report and literature review. Genet Mol Biol 43:e20180271. about a 2 years old female with Leigh syndrome (LS) due to the homozygous 14bp frameshift deletion in C12orf65 encoding COXPD7. It was concluded that the mutated protein domain GGQ is responsible for a conservative peptidyl-hydrolase function and that loss of function mutations in this domain play a pathogenetic role for the development of LS (Perrone et al., 2020Perrone E, Cavole TR, Oliveira MG, Virmond LDA, Silva MFB, Soares MFF, Iglesias SBO, Falconi A, Silva JS, Nakano V et al. (2020) Leigh syndrome in apatient with a novel C12orf65 pathogenic variant: Case report and literature review. Genet Mol Biol 43:e20180271.). We have the following comments and concerns.

We do not agree with the notion that LS is exclusively an early onset disease (Perrone et al., 2020Perrone E, Cavole TR, Oliveira MG, Virmond LDA, Silva MFB, Soares MFF, Iglesias SBO, Falconi A, Silva JS, Nakano V et al. (2020) Leigh syndrome in apatient with a novel C12orf65 pathogenic variant: Case report and literature review. Genet Mol Biol 43:e20180271.). Though presenting with an onset <2y of age in 80% of the cases (Hong et al., 2020Hong CM, Na JH, Park S and Lee YM (2020) Clinical characteristics of early-onset and late-onset Leigh syndrome. Front Neurol 11:267.), the remaining portion of LS patients has an onset >2y of age (Hong et al., 2020Hong CM, Na JH, Park S and Lee YM (2020) Clinical characteristics of early-onset and late-onset Leigh syndrome. Front Neurol 11:267.).

We also do not agree with the statement that “brain changes are almost identical in all patients” with LS (Perrone et al., 2020Perrone E, Cavole TR, Oliveira MG, Virmond LDA, Silva MFB, Soares MFF, Iglesias SBO, Falconi A, Silva JS, Nakano V et al. (2020) Leigh syndrome in apatient with a novel C12orf65 pathogenic variant: Case report and literature review. Genet Mol Biol 43:e20180271.). Though cerebral lesions are usually symmetric with regard to distribution, different structures may be affected. These include the caudate nucleus, the putamen, the globus pallidus, the thalamus, the brainstem, or the cerebellum (Finsterer, 2008Finsterer J (2008) Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol 39:223-235.). Though these miscellaneous presentations on imaging do not allow establishing close genotype-phenotype correlations, they represent to some extent the extensive genetic heterogeneity of the syndrome.

We should know if respiratory distress episodes were attributed to the brainstem lesion in the medulla oblongata, to affection of peripheral nerves affecting respiratory muscles, to myopathy of axial including respiratory muscles, or to lactic acidosis.

Though the C12orf65 deletion was present in the homozygous state and though DNA from the parents was extracted it is not mentioned if either parent carried the mutation in the heterozygous state, as could be expected. Sporadic occurrence of the variant is rather unlikely given the homozygous state.

Missing in the report is if lactate was measured in the cerebro-spinal fluid (CSF) or not. Neither did the patient undergo magnetic resonance spectroscopy (MRS), nor was a spinal tap carried out. Since cerebral lactic acidosis strongly determines the phenotype it is crucial to know if lactate was elevated in the CSF respectively the parenchyma or not.

Since some patients with LS may develop stroke-like episodes (SLEs) (Morin et al., 1999Morin C, Dubé J, Robinson BH, Lacroix J, Michaud J, De Braekeleer M, Geoffroy G, Lortie A, Blanchette C, Lambert MA et al. (1999) Stroke-like episodes in autosomal recessive cytochrome oxidase deficiency. Ann Neurol 45:389-392.), we should know if the patient ever developed features of a SLE and if any of the cerebral MRIs ever showed a characteristic stroke-like lesion (SLL), the morphological equivalent of a SLE.

Since LS may go along with epilepsy and since epileptiform discharges were recorded on electroencephalography (EEG) (Perrone et al., 2020Perrone E, Cavole TR, Oliveira MG, Virmond LDA, Silva MFB, Soares MFF, Iglesias SBO, Falconi A, Silva JS, Nakano V et al. (2020) Leigh syndrome in apatient with a novel C12orf65 pathogenic variant: Case report and literature review. Genet Mol Biol 43:e20180271.), we should know if the patient ever developed seizures or not and if treatment with anti-epileptic drugs (AEDs) was ever necessary or not.

Since cerebral MRI at age 2y and 9 months revealed bilaterally symmetric T2-hyperintense lesions in the substantia nigra, we should know if the patient ever developed Parkinsonism or a Parkinson-related disorder. Did the patient ever require anti-Parkinson drugs?

Overall, this interesting case has a number of shortcomings, which should be solved before the case is revaluated and final conclusions are drawn. Patients with LS are not only heterogeneous with regards to the genetic background but also with regard to the phenotype.

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