Genetic defects in the nuclear encoded subunits and assembly factors of cytochrome c oxidase (mitochondrial complex IV) are very rare and are associated with a wide variety of phenotypes. Biallelic pathogenic variants in the COX11 protein were previously identified in two unrelated children with infantile-onset mitochondrial encephalopathies. Through comprehensive clinical, genetic and functional analyses, here we report on a new patient harboring novel heterozygous variants in COX11, presenting with Leigh-like features, and provide additional experimental evidence for a direct correlation between COX11 protein expression and sensitivity to oxidative stress. To sort out the contribution of the single mutations to the phenotype, we employed a multi-faceted approach using Saccharomyces cerevisiae as a genetically manipulable system, and in silico structure-based analysis of human COX11. Our results reveal differential effects of the two novel COX11 mutations on yeast growth, respiration, and cellular redox status, as well as their potential impact on human protein stability and function. Strikingly, the functional deficits observed in patient fibroblasts are recapitulated in yeast models, validating the conservation of COX11’s role in mitochondrial integrity across evolutionarily distant organisms. This study not only expands the mutational landscape of COX11-associated mitochondrial disorders but also underscores the continued translational relevance of yeast models in dissecting complex molecular pathways.

Background: BRAT1-related disorders constitute a continuous neurodevelopmental spectrum ranging from rigidity and multifocal seizure syndrome, lethal neonatal form (RMFSL) to milder phenotypes characterized by cerebellar involvement and variable developmental impairment. Genotype–phenotype correlations remain incompletely defined, particularly for missense variants that may retain residual function. Objectives: To characterize clinical and molecular findings in a patient with a mild BRAT1-related phenotype. Methods: An 18-year-old boy underwent clinical, neuroradiological, neurophysiological, and genetic evaluations. Exome sequencing with in silico filtering on an ataxia gene panel and parental segregation analysis was performed. BRAT1 protein expression was assessed by Western blot analysis in patient-derived fibroblasts. Results: We report an 18-year-old male carrying compound heterozygous BRAT1 variants, including a recurrent truncating variant (c.294dup) and a novel missense variant (c.1784A>T; p.(Glu595Val)). The patient presented with early-onset global developmental delay, cerebellar ataxia, dysarthria, action tremor, and oculomotor abnormalities without epilepsy. Brain MRI showed marked hypoplasia of the inferior cerebellar vermis associated with a mega cisterna magna, without involvement of the cerebellar hemispheres. Follow-up over more than fifteen years showed relatively preserved functional autonomy in late adolescence (SARA 8.5/40; FARS-ADL 11/36). Western blot analysis of patient-derived fibroblasts revealed low but detectable BRAT1 protein levels (approximately 15–20% of mean control expression), indicating reduced but retained BRAT1 protein expression, compatible with, but not proof of, a residual-function effect. Conclusions: These findings are compatible with a contribution of residual BRAT1 protein expression to phenotypic attenuation in this patient and further expand the mild end of the BRAT1-related disease spectrum. Functional assays performed on readily accessible patient material may improve the interpretation of rare variants in neurodevelopmental disorders.