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A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy

A Comment to this article was published on 04 October 2023


Pathogenic variants impacting upon assembly of mitochondrial respiratory chain Complex IV (Cytochrome c Oxidase or COX) predominantly result in early onset mitochondrial disorders often leading to CNS, skeletal and cardiac muscle manifestations. The aim of this study is to describe a molecular defect in the COX assembly factor gene COX18 as the likely cause of a neonatal form of mitochondrial encephalo-cardio-myopathy and axonal sensory neuropathy. The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive developing in the first months of life. Serum lactate was consistently increased. Whole exome sequencing allowed the prioritization of the unreported homozygous substitution NM_001297732.2:c.667 G > C p.(Asp223His) in COX18. Patient’s muscle biopsy revealed severe and diffuse COX deficiency and striking mitochondrial abnormalities. Biochemical and enzymatic studies in patient’s myoblasts and in HEK293 cells after COX18 silencing showed a severe impairment of both COX activity and assembly. The biochemical defect was partially rescued by delivery of wild-type COX18 cDNA into patient’s myoblasts. Our study identifies a novel defect of COX assembly and expands the number of nuclear genes involved in a mitochondrial disorder due to isolated COX deficiency.

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Fig. 1: Instrumental findings and sequence analysis in the Patient.
Fig. 2: Muscle histology and biochemical studies in myoblasts of the COX18-mutated patient.
Fig. 3: Biochemical effects of COX18 downregulation and overexpression.

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Data availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Supplementary Table 1 (genes associated with clinical presentations featuring isolated Complex IV deficiency) and Supplementary Table 2 (predictors and in silico tools used in this study) are included as Supplementary Information.


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We thank the patient and her family for their kind cooperation. This work was promoted within the European Reference Network (ERN) for Rare Neuromuscular Diseases. We thank the Associazione Centro Dino Ferrari for its support.


This study was (partially) funded by Italian Ministry of Health—Current research IRCCS Ca’ Granda Ospedale Maggiore Policlinico and by SEQMD project (IRCCS Cà Granda Ospedale Maggiore Policlinico, PI: Giacomo Comi). The case was part of the RARE (Rapid Analysis for Rapid carE) project using the exome analysis in an urgent setting in neonatal intensive care.

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DR and GPC contributed to the conception and design of the study. DR, MG, FMa, FMe, MM, MFB, RD, VC, IP, FFu, VP, SS, LP, FFo, MB, DP, MR, SZ, LN, PC, MS, MI, GM, FMo contributed to the acquisition and analysis of data. DR, RD, SC, MI and GPC contributed to drafting the text and preparing the figures.

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Correspondence to Giacomo Pietro Comi.

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The studies involving human participants were reviewed and approved by the Comitato Etico Milano Area 2 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milan, Italy).

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Ronchi, D., Garbellini, M., Magri, F. et al. A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy. Eur J Hum Genet 31, 1414–1420 (2023).

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