Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients

Authors: MIYAKE, CHRISTINE - Texas Children'S Hospital; LAY, ERICA - Baylor College Of Medicine; SOLER-ALFONSO, CLAUDIA - Baylor College Of Medicine; GLINTON, KEVIN - Baylor College Of Medicine; HOUCK, KIMBERLY - Texas Children'S Hospital; TOSUR, MUSTAFA - Children'S Nutrition Research Center (CNRC); MORAN, NANCY - Children'S Nutrition Research Center (CNRC); STEPHENS, SARA - Texas Children'S Hospital; SCAGLIA, FERNANDO - Baylor College Of Medicine; HOWARD, TAYLOR - Texas Children'S Hospital; KIM, JEFFREY - Texas Children'S Hospital; PHAM, TAM DAM - Texas Children'S Hospital; VALDRES, SANTIAGO - Texas Children'S Hospital; LI, NA - Baylor College Of Medicine; MURALI, CHAYA - Baylor College Of Medicine; ZHANG, LILEI - Baylor College Of Medicine; KAVA, MAINA - The University Of Western Australia; YIM, DEAN - The University Of Western Australia; BEACH, CHEYENNE - Yale School Of Medicine; WEBSTER, GREGORY - Northwestern University; LIBERMAN, LEONARDO - Northwestern University; JANSON, CHRISTOPHER - The Children'S Hospital Of Philadelphia; KANNANKERIL, PRINCE - Vanderbilt University Medical Center; BAXTER, SAMANTHA - Broad Institute Of Mit/harvard; SINGER-BERK, MORIEL - Broad Institute Of Mit/harvard; WOOD, JORDAN - Broad Institute Of Mit/harvard; MACKENZIE, SAMUEL - University Of Rochester; SACHER, MICHAEL - Concordia University; GHALOUL-GONZALEZ, LINA - University Of Pittsburgh School Of Medicine; PEDROZA, CLAUDIA - University Of Texas Health Science Center; MORRIS, SHAINE - Texas Children'S Hospital; EHSAN, SAAD - Baylor College Of Medicine; AZAMIAN, MAHSHID - Baylor College Of Medicine; LALANI, SEEMA - Baylor College Of Medicine

Submitted to: Genetics in Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/30/2022
Publication Date: 12/3/2022
Citation: Miyake, C.Y., Lay, E.J., Soler-Alfonso, C., Glinton, K.E., Houck, K.M., Tosur, M., Moran, N.E., Stephens, S.B., Scaglia, F., Howard, T.S., Kim, J.J., Pham, T., Valdres, S.O., Li, N., Murali, C.N., Zhang, L., Kava, M., Yim, D., Beach, C., Webster, G., Liberman, L., Janson, C.M., Kannankeril, P.J., Baxter, S., Singer-Berk, M., Wood, J., Mackenzie, S.J., Sacher, M., Ghaloul-Gonzalez, L., Pedroza, C., Morris, S.A., Ehsan, S.A., Azamian, M.S., Lalani, S.R. 2022. Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients. Genetics in Medicine. 25(4). Article 100352. https://doi.org/10.1016/j.gim.2022.11.020.
DOI: https://doi.org/10.1016/j.gim.2022.11.020

Interpretive Summary: TANGO2 deficiency disorder (TDD) is a life-threatening genetic condition that is seen in children that causes severe medical symptoms like neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. This condition was recently characterized and may have linkages with very special nutritional needs for these individuals with TDD. In order to learn more about the disease, data were collected from 73 individuals with TDD from around the world. Many of the children experienced severe metabolic and heart problems. The metabolic problems appeared to be reduced after multivitamin or B-complex vitamin supplementation. These observations provide a foundation upon which to study the role of nutritional/dietary supplementation interventions to reduce the symptom severity of TDD.

Technical Abstract: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD. Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review. Results: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation. We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.