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Natural History of TANGO2 Deficiency Disorder: Baseline Assessment of 73 Patients

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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    ,
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    2 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston TX USA
    Christina Y. Miyake
    Correspondence
    Address for correspondence:Christina Miyake, MD MS, Texas Children’s Hospital, 6651 Main Street, Houston, TX 77030, Phone: 832-826-5650
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    2 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston TX USA
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
    Erica J. Lay
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
    Claudia Soler-Alfonso
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
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  • Kevin E. Glinton
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    4 Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    Kim Houck
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    4 Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
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    5 Department of Pediatrics, Division of Diabetes and Endocrinology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    Mustafa Tosur
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    5 Department of Pediatrics, Division of Diabetes and Endocrinology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
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    6 USDAARS Children’s Nutrition Research Center, Department of Pediatrics, Division of Nutrition, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    Nancy E. Moran
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    6 USDAARS Children’s Nutrition Research Center, Department of Pediatrics, Division of Nutrition, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    Sara B. Stephens
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
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    7 BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Hong Kong
    Fernando Scaglia
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
    7 BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Hong Kong
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    Taylor S. Howard
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    Jeffrey J. Kim
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    Tam Dam Pham
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    Santiago O. Valdes
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
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    2 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston TX USA
    Na Li
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    2 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston TX USA
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
    Chaya Murali
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
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    2 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston TX USA
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
    Lilei Zhang
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    2 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston TX USA
    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
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    8 Department of Neurology and Metabolic Medicine, Perth Children’s Hospital, Perth, Western Australia
    Maina Kava
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    8 Department of Neurology and Metabolic Medicine, Perth Children’s Hospital, Perth, Western Australia
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    9 Department of Cardiology, Perth Children’s Hospital, Perth, Western Australia
    Deane Yim
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    9 Department of Cardiology, Perth Children’s Hospital, Perth, Western Australia
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    10 Yale University School of Medicine, New Haven, CT USA
    Cheyenne Beach
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    10 Yale University School of Medicine, New Haven, CT USA
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    11 Lurie Children’s Hospital, Chicago, IL USA
    Gregory Webster
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    11 Lurie Children’s Hospital, Chicago, IL USA
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    12 New York Presbyterian, Morgan Stanley Children’s Hospital, New York, NY USA
    Leonardo Liberman
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    12 New York Presbyterian, Morgan Stanley Children’s Hospital, New York, NY USA
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    13 Children’s Hospital Philadelphia, Philadelphia, PA USA
    Christopher Janson
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    13 Children’s Hospital Philadelphia, Philadelphia, PA USA
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    14 Center for Pediatric Precision Medicine, Department of Pediatrics, Vanderbilt University Medical Center and the Monroe Carell Jr. Children’s Hospital at Vanderbuilt, Nashville, TN USA
    Prince J. Kannankeril
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    14 Center for Pediatric Precision Medicine, Department of Pediatrics, Vanderbilt University Medical Center and the Monroe Carell Jr. Children’s Hospital at Vanderbuilt, Nashville, TN USA
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    15 Broad Institute of MIT and Harvard, Cambridge, MA, USA
    Samantha Baxter
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    15 Broad Institute of MIT and Harvard, Cambridge, MA, USA
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    15 Broad Institute of MIT and Harvard, Cambridge, MA, USA
    Moriel Singer-Berk
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    15 Broad Institute of MIT and Harvard, Cambridge, MA, USA
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    15 Broad Institute of MIT and Harvard, Cambridge, MA, USA
    Jordan Wood
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    15 Broad Institute of MIT and Harvard, Cambridge, MA, USA
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    16 Department of Neurology, University of Rochester Medical Center, Rochester, NY USA
    Samuel Mackenzie
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    16 Department of Neurology, University of Rochester Medical Center, Rochester, NY USA
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    17 Concordia University Department of Biology and McGill University Department of Anatomy and Cell Biology, Montreal, Quebec, Canada
    Michael Sacher
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    17 Concordia University Department of Biology and McGill University Department of Anatomy and Cell Biology, Montreal, Quebec, Canada
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    18 Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA USA
    Lina Gonzalez
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    18 Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA USA
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    19 Department of Pediatrics, McGovern Medical School, University of Texas Health Center at Houston, Houston, TX USA
    Claudia Pedroza
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    19 Department of Pediatrics, McGovern Medical School, University of Texas Health Center at Houston, Houston, TX USA
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    Shaine A. Morris
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    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
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    20 Baylor College School of Medicine, Houston, TX
    Saad A. Ehsan
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    20 Baylor College School of Medicine, Houston, TX
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
    Mahshid Azamian
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
    Seema R. Lalani
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    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
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  • Author Footnotes
    1 Department of Pediatrics, Division of Pediatric Cardiology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    2 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston TX USA
    3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
    4 Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    5 Department of Pediatrics, Division of Diabetes and Endocrinology, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    6 USDAARS Children’s Nutrition Research Center, Department of Pediatrics, Division of Nutrition, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX USA
    7 BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Hong Kong
    8 Department of Neurology and Metabolic Medicine, Perth Children’s Hospital, Perth, Western Australia
    9 Department of Cardiology, Perth Children’s Hospital, Perth, Western Australia
    10 Yale University School of Medicine, New Haven, CT USA
    11 Lurie Children’s Hospital, Chicago, IL USA
    12 New York Presbyterian, Morgan Stanley Children’s Hospital, New York, NY USA
    13 Children’s Hospital Philadelphia, Philadelphia, PA USA
    14 Center for Pediatric Precision Medicine, Department of Pediatrics, Vanderbilt University Medical Center and the Monroe Carell Jr. Children’s Hospital at Vanderbuilt, Nashville, TN USA
    15 Broad Institute of MIT and Harvard, Cambridge, MA, USA
    16 Department of Neurology, University of Rochester Medical Center, Rochester, NY USA
    17 Concordia University Department of Biology and McGill University Department of Anatomy and Cell Biology, Montreal, Quebec, Canada
    18 Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA USA
    19 Department of Pediatrics, McGovern Medical School, University of Texas Health Center at Houston, Houston, TX USA
    20 Baylor College School of Medicine, Houston, TX
Published:December 02, 2022DOI:https://doi.org/10.1016/j.gim.2022.11.020
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      ABSTRACT:

      PURPOSE

      TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delays, 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 TDD patients enrolled between February 2019 – May 2022. Data were obtained through phone-based parent interviews and medical record review.

      RESULTS

      Data were collected from 73 patients (56% male) from 57 unrelated families in 17 different countries. The median age of participants at time of data collection was 9.0 years (IQR 5.3-15.9 years, range fetal – 31 years). A total of 24 different TANGO2 alleles were observed. Patients demonstrated normal development in early infancy with progressive delays in developmental milestones thereafter. Symptoms including ataxia, dystonia and speech difficulties typically starting between the ages of 1-3 years. A total of 48 (66%) patients suffered metabolic crises and, of these, 29/48 (73%) developed cardiac crises. Metabolic crises were significantly decreased after initiation of B-complex or multivitamins.

      CONCLUSIONS

      We provide the most comprehensive review of natural history of TDD and provide important observational data suggesting B-complex or multivitamins may prevent metabolic crises.

      Key words

      ABBREVIATIONS:

      ACP (acyl carnitine profile), ALT (alanine aminotransferase), AST (aspartate aminotransferase), CK (creatinine kinase), ECG (electrocardiogram), ECHO (echocardiogram), ECMO (extra corporeal membrane oxygenation), PAA (plasma amino acids), QTc (Corrected QT interval), TdP (torsade de pointes), TANGO2 (Transport and Golgi Organization Homolog 2), TDD (TANGO2 deficiency disorder), UOA (urine organic acids), VT (ventricular tachycardia)
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