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We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive\n                    <jats:italic>TANGO2<\/jats:italic>\n                    mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited\n                    <jats:italic>in trans<\/jats:italic>\n                    . The other subjects carried three novel homozygous (c.262C&gt;T\/p.Arg88*; c.220A&gt;C\/p.Thr74Pro; c.380+1G&gt;A), and two further novel heterozygous (c.6_9del\/p.Phe6del); c.11\u201013delTCT\/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged\u2010red\/cytochrome c oxidase\u2010negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q\n                    <jats:sub>10<\/jats:sub>\n                    (CoQ\n                    <jats:sub>10<\/jats:sub>\n                    ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum\u2010Golgi network and secretory pathways. Clinical presentation of\n                    <jats:italic>TANGO2<\/jats:italic>\n                    mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ\n                    <jats:sub>10<\/jats:sub>\n                    with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.\n                  <\/jats:p>","DOI":"10.1002\/jimd.12156","type":"journal-article","created":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T11:11:55Z","timestamp":1563966715000},"page":"297-308","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Clinical presentation and proteomic signature of patients with\n                    <i>TANGO2<\/i>\n                    mutations"],"prefix":"10.1002","volume":"43","author":[{"given":"Nadja","family":"Mingirulli","sequence":"first","affiliation":[{"name":"Department of Neuropediatrics and Muscle Disorders Medical Center \u2013 University of Freiburg, Faculty of Medicine  Breisgau Germany"},{"name":"Department of General Pediatrics Adolescent Medicine and Neonatology, Medical Center \u2013 University of Freiburg, Faculty of Medicine  Breisgau Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Pyle","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research Institute of Genetic Medicine, Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denisa","family":"Hathazi","sequence":"additional","affiliation":[{"name":"Biomedical Research Department Leibniz\u2010Institut f\u00fcr Analytische Wissenschaften \u2013 ISAS \u2013 e.V  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte L.","family":"Alston","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research Institute of Neuroscience, Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolai","family":"Kohlschmidt","sequence":"additional","affiliation":[{"name":"Institute of Clinical Genetics and Tumor Genetics  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina","family":"O'Grady","sequence":"additional","affiliation":[{"name":"Kid's Neuroscience Centre, Children's Hospital at Westmead  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh","family":"Waddell","sequence":"additional","affiliation":[{"name":"Kid's Neuroscience Centre, Children's Hospital at Westmead  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Evesson","sequence":"additional","affiliation":[{"name":"Kid's Neuroscience Centre, Children's Hospital at Westmead  Sydney New South Wales Australia"},{"name":"Discipline of Child and Adolescent Health The University of Sydney  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra B. 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