1 Division of Pediatric Cardiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston TX. Electronic address: cymiyake@bcm.edu.
2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
3 Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX.
4 Division of Diabetes and Endocrinology, Department of Pediatrics, USDA/ARS Children's Nutrition Research Center, Texas Children's Hospital and Baylor College of Medicine, Houston, TX.
5 USDA/ARS Children's Nutrition Research Center, Division of Nutrition, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX.
6 Division of Pediatric Cardiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX.
7 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Hong Kong, Special Administrative Region.
8 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston TX; Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX.
9 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
10 Department of Neurology, Perth Children's Hospital, Perth, Western Australia, Australia; Departments of Metabolic Medicine and Rheumatology, Perth Children's Hospital, Perth, Western Australia, Australia; Medical School, University of Western Australia, Perth, Western Australia, Australia.
11 Department of Cardiology, Perth Children's Hospital, Perth, Western Australia, Australia.
12 Division of Cardiology, Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT.
13 Division of Cardiology, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Nortwestern University Feinberg School of Medicine, Chicago, IL.
14 Division of Cardiology, Department of Pediatrics, New York Presbyterian Morgan Stanley Children's Hospital, New York, NY.
15 Division of Cardiology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA.
16 Center for Pediatric Precision Medicine, Department of Pediatrics, Vanderbilt University Medical Center and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, TN.
17 Broad Institute of MIT and Harvard, Cambridge, MA.
18 Department of Neurology, University of Rochester Medical Center, Rochester, NY.
19 Department of Biology, Concordia University, Montreal, Quebec, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
20 Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA.
21 Department of Pediatrics, McGovern Medical School, University of Texas Health Center at Houston, Houston, TX.
22 Baylor College of Medicine, Houston, TX.

Purpose: 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.

Methods: 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.

Conclusion: 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.