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Review
. 2023 Apr;25(4):100352.
doi: 10.1016/j.gim.2022.11.020. Epub 2022 Dec 5.

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

Christina Y Miyake  1 , Erica J Lay  2 , Claudia Soler-Alfonso  2 , Kevin E Glinton  2 , Kimberly M Houck  3 , Mustafa Tosur  4 , Nancy E Moran  5 , Sara B Stephens  6 , Fernando Scaglia  7 , Taylor S Howard  6 , Jeffrey J Kim  6 , Tam Dam Pham  6 , Santiago O Valdes  6 , Na Li  8 , Chaya N Murali  2 , Lilei Zhang  9 , Maina Kava  10 , Deane Yim  11 , Cheyenne Beach  12 , Gregory Webster  13 , Leonardo Liberman  14 , Christopher M Janson  15 , Prince J Kannankeril  16 , Samantha Baxter  17 , Moriel Singer-Berk  17 , Jordan Wood  17 , Samuel J Mackenzie  18 , Michael Sacher  19 , Lina Ghaloul-Gonzalez  20 , Claudia Pedroza  21 , Shaine A Morris  6 , Saad A Ehsan  22 , Mahshid S Azamian  2 , Seema R Lalani  2
Affiliations
Review

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

Christina Y Miyake et al. Genet Med. 2023 Apr.

Abstract

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.

Keywords: Metabolic crises; Natural history study; TANGO2; Treatment; Vitamins.

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Conflict of interest statement

Conflict of Interest The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from clinical laboratory testing conducted at Baylor Genetics. S.A.M. serves as Scientific Advisor and consultant for Aytu BioPharma, Inc for the AR101 Enzastaurin Clinical Trial. All other authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Developmental Milestones TANGO Deficient Patients compared to Average.
Major developmental milestones in early development demonstrates a progressive delay in the age at which TANGO2-deficient children meet milestones when compared to national averages. Diamonds represent age range for average expected normal development.
Figure 2.
Figure 2.. Metabolic Crisis and Vitamin Supplementation.
A) Kaplan Meier curve freedom from metabolic crisis. The time to first metabolic crisis is shown. In this cohort, 50% of patients had suffered a crisis by age 5.6 years. B) Supplemental use of multivitamin or B-complex significantly decreases metabolic crisis. Blue bars indicate incident rate of crisis when patients were not taking supplement and green bars indicate incident rate of events when taking the supplement. The incident rate ratio (IRR) is the rate of metabolic crises events per ten patient-years when patients were not taking B- complex vitamin or multivitamin compared to the rate of metabolic crises events per patient-years when patients were taking each vitamin. There was a significant decrease in rate of events by 12-fold when taking multivitamins. This difference was not seen with supplemental carnitine or CoQ10. There were no events when patients were taking B-complex and thus IRR was not calculable.
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