Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome

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Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
Other namesTANGO2 Deficiency Disorder, TANGO2-Related Metabolic Encephalopathy and Arrhythmias, MECRCN, Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration.
Autosomal recessive - en.svg
This disorder is inherited in Autosomal recessive fashion.
Specialty Medical genetics, Neurology, Cardiology
Usual onsetInfancy
CausesMutations in a gene TANGO2
Frequency1/1 000 000 births

Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome (sometimes referred to as TANGO2 Deficiency) is a rare metabolic and genetic disorder which is caused by mutation in a gene TANGO2. [1] [2] Main signs of this disorder are: Intellectual disability, ataxia, underactive thyroid, and life-threatening episodes of metabolic and cardiac crises, rhabdomyolysis. [3] [4]

Contents

The syndrome affects about 1/1 000 000 births, with about 110 cases having been reported worldwide (at the time of articles publication as February 28, 2025). [5] [6]

Symptoms

Symptoms of this disorder might include: [7]

Very frequent:

Frequent:

Occasional:

Very rare:

Also, most of the patients experience so called "TANGO2 spells", which include episodes of difficulty in maintaining the position of the head, salivation, exhaustion, and decreased alertness and it can be triggered by fasting, dehydration, exposure to excessive heat, infections, and ketogenic diet. [8] [2]

Cause

This disorder is caused by a mutation in a gene, TANGO2, which codes for protein Transport and golgi organization 2 homolog, and its located on chromosome 22. [9] According to one study, exons 3-9 are frequently deleted in people of European origin and Hispanic ethnicity, although in Hispanic ethnicity c.460G>A (which is expressed as p.Gly154Arg, which means that on position 154, glycine is changed to arginine) is also frequent. [10] [4]

Also, people with 22q11.2DS (DiGeorge syndrome) are at risk of developing this disorder because of hemizygosity (which means that they express only one copy of that gene, consequently chances of getting this disorder is higher). [11] [12]

Pathophysiology

TANGO2 plays role in mitochondrial β-oxidation, consequently in that disease, β-oxidation and ATP levels are reduceed (especially under stress). [13] Interestingly TANGO2 also might participate in retrograde ER-Golgi trafficking, consequently this process is slowed down in this disease, and the supplementation of TANGO2 has restored that process. [14] [15] [16]

According to one study, TANGO2 also might participate in autophagy process, which might be responsible for rhabdomyolysis in this disease. [17]

Diagnosis

This disorder can be suspected by symptoms, although diagnosis can be confirmed by a genetic testing. Also, diagnosis is usually made after first episode of life-threatening symptoms (such as arrhythmia). [18]

Treatment

This disease doesn't have a cure. [19] Although symptom management is available, and this might include: [2]

  1. Supplementation of all B vitamins, such as B5 and B9, because they might alleviate some of the symptoms (such as arrhythmia). [20] [21] [22]
  2. Levothyroxine for Hypothyroidism
  3. Supportive treatment for developmental delays
  4. Antiseizure medication

Prognosis

Life expectancy is limited because the risk of fatal arrhythmia is unpredictable and according to one study median age of death was 6.5 years old. [23] [3]

History

Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome was first identified in 2016. [4] [24]

References

  1. ↑ "METABOLIC CRISES, RECURRENT, WITH RHABDOMYOLYSIS, CARDIAC ARRHYTHMIAS, AND NEURODEGENERATION; MECRCN". omin.org.
  2. 1 2 3 Miyake, Christina Y.; Burrage, Lindsay; Glinton, Kevin; Houck, Kimberly; Hoyos-Martinez, Alfonso; Graham, Brett; Yang, Yaping; Rawls-Castillo, Brandy; Scaglia, Fernando (1993), Adam, Margaret P.; Feldman, Jerry; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "TANGO2 Deficiency", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   29369572 , retrieved 2025-04-17
  3. 1 2 Miyake, Christina Y.; Lay, Erica J.; Soler-Alfonso, Claudia; Glinton, Kevin E.; Houck, Kimberly M.; Tosur, Mustafa; Moran, Nancy E.; Stephens, Sara B.; Scaglia, Fernando; Howard, Taylor S.; Kim, Jeffrey J.; Pham, Tam Dam; Valdes, Santiago O.; Li, Na; Murali, Chaya N. (2023-04-01). "Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients". Genetics in Medicine. 25 (4): 100352. doi:10.1016/j.gim.2022.11.020. ISSN   1098-3600. PMC   10306319 . PMID   36473599.
  4. 1 2 3 Lalani, Seema R.; Liu, Pengfei; Rosenfeld, Jill A.; Watkin, Levi B.; Chiang, Theodore; Leduc, Magalie S.; Zhu, Wenmiao; Ding, Yan; Pan, Shujuan; Vetrini, Francesco; Miyake, Christina Y.; Shinawi, Marwan; Gambin, Tomasz; Eldomery, Mohammad K.; Akdemir, Zeynep Hande Coban (2016-02-04). "Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations". The American Journal of Human Genetics. 98 (2): 347–357. doi:10.1016/j.ajhg.2015.12.008. ISSN   0002-9297. PMC   4746334 . PMID   26805781.
  5. ↑ "Orphanet: Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome". www.orpha.net. Retrieved 2025-04-17.
  6. ↑ "New study on TANGO2 illuminates the path of a rare disease". El·lipse. 2025-02-28. Retrieved 2025-04-17.
  7. ↑ "Orphanet: Clinical signs and symptoms". www.orpha.net. Retrieved 2025-04-17.
  8. ↑ Owlett, Laura D.; Zapanta, Bianca; Sandkuhler, Sarah E.; Ames, Elizabeth G.; Hickey, Scott E.; Mackenzie, Samuel J.; Meisner, Joshua K. (2024). "Multicenter appraisal of comorbid TANGO2 deficiency disorder in patients with 22q11.2 deletion syndrome". American Journal of Medical Genetics Part A. 194 (10): e63778. doi:10.1002/ajmg.a.63778. ISSN   1552-4833. PMC  11502271. PMID   38829177.
  9. ↑ "UniProt". UniProt. Retrieved 2025-04-17.
  10. ↑ Dines, Jennifer N.; Golden-Grant, Katie; LaCroix, Amy; Muir, Alison M.; Cintrón, Dianne Laboy; McWalter, Kirsty; Cho, Megan T.; Sun, Angela; Merritt, J. Lawrence; Thies, Jenny; Niyazov, Dmitriy; Burton, Barbara; Kim, Katherine; Fleming, Leah; Westman, Rachel (2019-03-01). "TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants". Genetics in Medicine. 21 (3): 601–607. doi:10.1038/s41436-018-0137-y. ISSN   1098-3600. PMC   6752277 . PMID   30245509.
  11. ↑ Meisner, Joshua; Ames, Elizabeth (2022-03-01). "eP027: Screening for co-incident TANGO2 related metabolic encephalopathy and arrhythmia syndrome in 22q11 deletion syndrome". Genetics in Medicine. 2022 ACMG Annual Clinical Genetics Meeting. 24 (3, Supplement): S18. doi:10.1016/j.gim.2022.01.065. ISSN   1098-3600.
  12. ↑ "Definition of hemizygous - NCI Dictionary of Genetics Terms". www.cancer.gov. 2012-07-20. Retrieved 2025-04-17.
  13. ↑ Heiman, Paige; Mohsen, Al-Walid; Karunanidhi, Anuradha; St Croix, Claudette; Watkins, Simon; Koppes, Erik; Haas, Richard; Vockley, Jerry; Ghaloul-Gonzalez, Lina (2022-02-23). "Mitochondrial dysfunction associated with TANGO2 deficiency". Scientific Reports. 12 (1): 3045. Bibcode:2022NatSR..12.3045H. doi:10.1038/s41598-022-07076-9. ISSN   2045-2322. PMC   8866466 . PMID   35197517.
  14. ↑ Milev, Miroslav P.; Saint-Dic, Djenann; Zardoui, Khashayar; Klopstock, Thomas; Law, Christopher; Distelmaier, Felix; Sacher, Michael (2021). "The phenotype associated with variants in may be explained by a dual role of the protein in ER-to-Golgi transport and at the mitochondria" . Journal of Inherited Metabolic Disease. 44 (2): 426–437. doi:10.1002/jimd.12312. ISSN   1573-2665. PMID   32909282.
  15. ↑ Bard, Frederic; Casano, Laetitia; Mallabiabarrena, Arrate; Wallace, Erin; Saito, Kota; Kitayama, Hitoshi; Guizzunti, Gianni; Hu, Yue; Wendler, Franz; DasGupta, Ramanuj; Perrimon, Norbert; Malhotra, Vivek (2006-02-02). "Functional genomics reveals genes involved in protein secretion and Golgi organization" . Nature. 439 (7076): 604–607. Bibcode:2006Natur.439..604B. doi:10.1038/nature04377. ISSN   1476-4687. PMID   16452979.
  16. ↑ Mingirulli, Nadja; Pyle, Angela; Hathazi, Denisa; Alston, Charlotte L.; Kohlschmidt, Nicolai; O'Grady, Gina; Waddell, Leigh; Evesson, Frances; Cooper, Sandra B. T.; Turner, Christian; Duff, Jennifer; Topf, Ana; Yubero, Delia; Jou, Cristina; Nascimento, Andrés (2020). "Clinical presentation and proteomic signature of patients with TANGO2 mutations". Journal of Inherited Metabolic Disease. 43 (2): 297–308. doi:10.1002/jimd.12156. ISSN   1573-2665. PMC   7078914 . PMID   31339582.
  17. ↑ de Calbiac, Hortense; Montealegre, Sebastian; Straube, Marjolène; Renault, Solène; Debruge, Hugo; Chentout, Loïc; Ciura, Sorana; Imbard, Apolline; Le Guillou, Edouard; Marian, Anca; Goudin, Nicolas; Caccavelli, Laure; Fabrega, Sylvie; Hubas, Arnaud; van Endert, Peter (2024-12-31). "TANGO2-related rhabdomyolysis symptoms are associated with abnormal autophagy functioning". Autophagy Reports. 3 (1): 2306766. doi:10.1080/27694127.2024.2306766. PMC   7617261 . PMID   39722856.
  18. ↑ Powell, Allison R.; Ames, Elizabeth G.; Knierbein, Erin Neil; Hannibal, Mark C.; Mackenzie, Samuel J. (2021-06-01). "Symptom Prevalence and Genotype-Phenotype Correlations in Patients With TANGO2-Related Metabolic Encephalopathy and Arrhythmias (TRMEA)" . Pediatric Neurology. 119: 34–39. doi:10.1016/j.pediatrneurol.2021.02.011. ISSN   0887-8994. PMID   33845444.
  19. ↑ "TANGO2: A Rare but Important Mutation". www.innovationsincrm.com. Retrieved 2025-04-17.
  20. ↑ Asadi, Paria; Milev, Miroslav P.; Saint-Dic, Djenann; Gamberi, Chiara; Sacher, Michael (2023). "Vitamin B5, a coenzyme A precursor, rescues TANGO2 deficiency disease-associated defects in Drosophila and human cells". Journal of Inherited Metabolic Disease. 46 (2): 358–368. doi:10.1002/jimd.12579. ISSN   1573-2665. PMC   10464931 . PMID   36502486.
  21. ↑ Sandkuhler, Sarah E.; Zhang, Lilei; Meisner, Joshua K.; Ghaloul-Gonzalez, Lina; Beach, Cheyenne M.; Harris, David; de Lonlay, Pascale; Lalani, Seema R.; Miyake, Christina Y.; Mackenzie, Samuel J. (2023). "B-complex vitamins for patients with TANGO2-deficiency disorder". Journal of Inherited Metabolic Disease. 46 (2): 161–162. doi:10.1002/jimd.12585. ISSN   1573-2665. PMC   10204720 . PMID   36550018.
  22. ↑ Xu, Weiyi; Cao, Yingqiong; Stephens, Sara B.; Arredondo, Maria Jose; Chen, Yifan; Perez, William; Sun, Liang; Yu, Andy C.; Kim, Jean J.; Lalani, Seema R.; Li, Na; Horrigan, Frank T.; Altamirano, Francisco; Wehrens, Xander H. T.; Miyake, Christina Y. (2024-06-10). "Folate as a potential treatment for lethal ventricular arrhythmias in TANGO2-deficiency disorder". JCI Insight. 9 (11). doi:10.1172/jci.insight.171005. ISSN   0021-9738. PMC   11382877 . PMID   38855866.
  23. ↑ Alghamdi, Fouad; Alharbi, Alanoud; Mohamed, Fatema; Alghamdi, Alaa; Bashir, Shahid (2023-08-01). "Clinical phenotype associated with variants in TANGO2: A case study" . Archives de Pédiatrie. 30 (6): 438–440. doi:10.1016/j.arcped.2023.04.008. ISSN   0929-693X. PMID   37394363.
  24. ↑ Kremer, Laura S.; Distelmaier, Felix; Alhaddad, Bader; Hempel, Maja; Iuso, Arcangela; Küpper, Clemens; Mühlhausen, Chris; Kovacs-Nagy, Reka; Satanovskij, Robin; Graf, Elisabeth; Berutti, Riccardo; Eckstein, Gertrud; Durbin, Richard; Sauer, Sascha; Hoffmann, Georg F. (2016-02-04). "Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy". The American Journal of Human Genetics. 98 (2): 358–362. doi:10.1016/j.ajhg.2015.12.009. ISSN   0002-9297. PMC   4746337 . PMID   26805782.
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