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Background: Because the mitochondrial respiratory chain (RC) is ubiquitous, its deficiency can theoretically give rise to any symptom in any organ or tissue at any age with any mode of inheritance, owing to the twofold genetic origin of respiratory enzyme machinery, that is, nuclear and mitochondrial. Not all respiratory enzyme deficiencies are primary and secondary or artefactual deficiency is frequently observed, leading to a number of misleading conclusions and inappropriate investigations in clinical practice. This study is aimed at investigating the potential role of brain MRI in distinguishing primary RC deficiency from phenocopies and other aetiologies., Methods: Starting from a large series of 189 patients (median age: 3.5 years (8 days-56 years), 58% males) showing signs of RC enzyme deficiency, for whom both brain MRIs and disease-causing mutations were available, we retrospectively studied the positive predictive value (PPV) and the positive likelihood ratio (LR+) of brain MRI imaging and its ability to discriminate between two groups: primary deficiency of the mitochondrial RC machinery and phenocopies., Results: Detection of (1) brainstem hyperintensity with basal ganglia involvement (P≤0.001) and (2) lactate peak with either brainstem or basal ganglia hyperintensity was highly suggestive of primary RC deficiency (P≤0.01). Fourteen items had a PPV>95% and LR+ was greater than 9 for seven signs. Biallelic SLC19A3 mutations represented the main differential diagnosis. Non-significant differences between the two groups were found for cortical/subcortical atrophy, leucoencephalopathy and involvement of caudate nuclei, spinothalamic tract and corpus callosum., Conclusion: Based on these results and owing to invasiveness of skeletal muscle biopsies and cost of high-throughput DNA sequencing, we suggest giving consideration to brain MRI imaging as a diagnostic marker and an informative investigation to be performed in patients showing signs of RC enzyme deficiency., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous condition characterized by progressive dystonia with iron accumulation in the basal ganglia. How NBIA-associated mutations trigger iron overload remains poorly understood. After studying fibroblast cell lines from subjects carrying both known and unreported biallelic mutations in CRAT and REPS1, we ascribe iron overload to the abnormal recycling of transferrin receptor (TfR1) and the reduction of TfR1 palmitoylation in NBIA. Moreover, we describe palmitoylation as a hitherto unreported level of post-translational TfR1 regulation. A widely used antimalarial agent, artesunate, rescued abnormal TfR1 palmitoylation in cultured fibroblasts of NBIA subjects. These observations suggest therapeutic strategies aimed at targeting impaired TfR1 recycling and palmitoylation in NBIA., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)