The Leigh phenotype resulting from C12orf65 variants

Abstract

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

Cytochrome c oxidase biogenesis – from translation to early assembly of the core subunit COX1

“…Hence, the interruption of translation termination of COX1 induces the mtRQC system involving C12ORF65. This also underlines the central importance of the mtRQC system, since a growing number of patients with mutated C12orf65 have been described, developing Leigh syndrome [32–34]. However, as these patients with usually undetectable levels of C12ORF65 display a general translation defect, mtRQC mediated by C12ORF65 seems to be generally involved in ribosome rescue and not selectively responsible for the release of stalled COX1‐translating ribosomes.…”

Fabrication Techniques for Curved Electronics on Arbitrary Surfaces

“…As for stretchable/flexible electronics, recent developments in materials and mechanics create a number of other approaches to expand the well‐conformal situations. [ 52 ] Significant works have been developed in the area of new structure design (e.g., buckled, [ 53 ] serpentine, [ 54,55 ] fractal structures, [ 56,57 ] corrugated structures, [ 58 ] multistage corrugated structures, [ 59–61 ] and island bridges [ 13,62,63 ] ) and highly stretchable material development (e.g., elastic conductors [ 64,65 ] and liquid metal [ 66–68 ] ).…”