With interest we read the article by Perrone et al. (2020) 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., 2020). 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., 2020). Though presenting with an onset <2y of age in 80% of the cases (Hong et al., 2020), the remaining portion of LS patients has an onset >2y of age (Hong et al., 2020). We also do not agree with the statement that “brain changes are almost identical in all patients” with LS (Perrone et al., 2020). 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, 2008). 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., 1999), 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., 2020), 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.

中文翻译：

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由 C12orf65 变异引起的 Leigh 表型

我们饶有兴趣地阅读了 Perrone 等人的文章。(2020) 关于一名患有 Leigh 综合征 (LS) 的 2 岁女性，由于编码 COXPD7 的 C12orf65 中出现纯合 14bp 移码缺失。得出的结论是，突变的蛋白质结构域 GGQ 负责保守的肽基水解酶功能，并且该结构域中的功能丧失突变对 LS 的发展起着致病作用（Perrone 等，2020）。我们有以下意见和担忧。我们不同意 LS 完全是一种早发性疾病的观点（Perrone 等，2020）。尽管 80% 的病例发病年龄小于 2 岁（Hong 等，2020），但其余部分 LS 患者的发病年龄大于 2 岁（Hong 等，2020）。我们也不同意 LS 的“所有患者的大脑变化几乎相同”的说法（Perrone 等，2020）。虽然大脑病变在分布方面通常是对称的，但可能会影响不同的结构。这些包括尾状核、壳核、苍白球、丘脑、脑干或小脑 (Finsterer, 2008)。尽管影像学上的这些杂项表现不允许建立密切的基因型-表型相关性，但它们在某种程度上代表了该综合征的广泛遗传异质性。我们应该知道呼吸窘迫发作是否归因于延髓脑干病变，影响呼吸肌的周围神经的影响，包括呼吸肌在内的轴性肌病，或乳酸性酸中毒。尽管 C12orf65 缺失以纯合状态存在，并且虽然从亲本中提取了 DNA，但没有提及是否有任何亲本在杂合状态下携带突变，正如预期的那样。考虑到纯合状态，变体的零星出现是不太可能的。报告中遗漏的是是否在脑脊液 (CSF) 中测量了乳酸。患者既没有接受磁共振波谱 (MRS)，也没有进行脊椎穿刺。由于脑乳酸酸中毒强烈地决定了表型，因此了解脑脊液和实质中的乳酸是否升高是至关重要的。由于一些 LS 患者可能会出现中风样发作 (SLE)（Morin 等，1999），我们应该知道患者是否曾出现过 SLE 的特征，以及是否有任何大脑 MRI 显示出特征性的卒中样病变 (SLL)，即 SLE 的形态学等效性。由于 LS 可能伴有癫痫，并且由于在脑电图 (EEG) 上记录了癫痫样放电（Perrone 等人，2020 年），我们应该知道患者是否曾出现癫痫发作以及是否使用抗癫痫药物 (AED) 进行治疗有没有必要。由于 2 岁和 9 个月时的脑 MRI 显示黑质双侧对称的 T2 高信号病变，我们应该知道患者是否曾患过帕金森症或帕金森相关疾病。患者是否曾经需要抗帕金森药物？总的来说，这个有趣的案例有许多缺点，这应该在案件重新评估和得出最终结论之前解决。LS 患者不仅在遗传背景方面存在异质性，而且在表型方面也存在异质性。