{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T15:10:02Z","timestamp":1779117002454,"version":"3.51.4"},"reference-count":35,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>TANGO2-deficiency disorder (TDD) is a rare autosomal recessive condition characterised by neurodevelopmental delay, TANGO2 spells, life-threatening metabolic crises, and cardiac arrhythmias. Genotype\u2013phenotype correlations remain poorly defined and the neurobehavioural profile of affected individuals is largely unexplored. We conducted a retrospective multicentre study of five Italian patients with genetically confirmed TDD, identified between June 2023 and May 2025. Clinical, neurophysiological, neuroimaging, genetic, and neurodevelopmental data were collected. Adaptive functioning, cognitive ability, and behavioural profiles were assessed using standardised instruments. All five patients carried biallelic TANGO2 mutations, including two previously unreported variants. Clinical severity ranged from an asymptomatic individual under preventive therapy to a fatal early-onset metabolic crisis. Marked intrafamilial variability was observed in two siblings sharing the same genotype. Systematic neurodevelopmental assessment revealed a spectrum of cognitive and adaptive outcomes, with attentional difficulties identified as a recurrent feature. No metabolic crises or TANGO2 spells were documented following initiation of B-vitamin and cofactor supplementation in surviving patients. This cohort expands the mutational and phenotypic spectrum of TDD and highlights the diagnostic value of TANGO2 testing in patients with neurodevelopmental delay or paroxysmal neurological episodes, even in the absence of metabolic crises. Early supplementation therapy may contribute to clinical stability, though prospective controlled studies are needed.<\/jats:p>","DOI":"10.3390\/ijms27104389","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T16:27:56Z","timestamp":1778776076000},"page":"4389","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic and Clinical Characterization of TANGO2 Deficiency Disorder: Insights from the Italian Multicentre Cohort"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4896-1164","authenticated-orcid":false,"given":"Emanuela Claudia","family":"Turco","sequence":"first","affiliation":[{"name":"Child Neuropsychiatric Unit, Maternal and Child Health Department, Parma University-Hospital, 43126 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2730-2791","authenticated-orcid":false,"given":"Giulia","family":"Pisan\u00f2","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Department of Pediatrics, Presidio Ospedaliero Santa Maria Nuova, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5183-0246","authenticated-orcid":false,"given":"Laura","family":"Caiazza","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Carestiato","sequence":"additional","affiliation":[{"name":"Department of Neuroscience \u201cRita Levi-Montalcini\u201d, University of Turin, 10124 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2919-7447","authenticated-orcid":false,"given":"Benedetta","family":"Piccolo","sequence":"additional","affiliation":[{"name":"Child Neuropsychiatric Unit, Maternal and Child Health Department, Parma University-Hospital, 43126 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Fecarotta","sequence":"additional","affiliation":[{"name":"Section of Pediatrics, Metabolic Diseases Unit, Department of Translational Medical Science, Federico II University of Naples, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Pochiero","sequence":"additional","affiliation":[{"name":"Metabolic Disease Unit, Neuroscience Department, Meyer Children Hospital, 50139 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2019-612X","authenticated-orcid":false,"given":"Federica","family":"Ricci","sequence":"additional","affiliation":[{"name":"Neuromuscular Center, AOU Citt\u00e0 della Salute e della Scienza, University of Turin, 10126 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8318-7231","authenticated-orcid":false,"given":"Alfredo","family":"Brusco","sequence":"additional","affiliation":[{"name":"Department of Neuroscience \u201cRita Levi-Montalcini\u201d, University of Turin, 10124 Torino, Italy"},{"name":"Medical Genetics Unit, Citt\u00e0 della Salute e della Scienza University Hospital, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni Battista","family":"Ferrero","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4103-2837","authenticated-orcid":false,"given":"Susanna","family":"Esposito","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9321-0952","authenticated-orcid":false,"given":"Carlo","family":"Fusco","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Department of Pediatrics, Presidio Ospedaliero Santa Maria Nuova, AUSL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6777-1721","authenticated-orcid":false,"given":"Maria Carmela","family":"Pera","sequence":"additional","affiliation":[{"name":"Child Neuropsychiatry Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"ref_1","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. 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