Medicine: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.
This disorder is inherited in Autosomal recessive fashion.
SpecialtyMedical 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]

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:

  • Abnormal ECG
  • Elevated blood creatine phosphokinase
  • Global developmental delay
  • Intellectual disability
  • Ketone bodies in urine
  • Abnormally increased level of blood lactate

Frequent:

  • Extrapyramidal signs
  • Rhabdomyolysis, acute
  • Ataxia
  • Irregular heart beat
  • Mild hypothyroidism
  • Loss of milestones
  • Delayed speech and language acquisition
  • Delayed walking
  • Abnormal liver enzymes
  • Gastrointestinal dysmotility
  • Generalised brain atrophy
  • High blood ammonia levels
  • Low blood sugar
  • Involuntary muscle contractions
  • Increased lactate in body
  • Prolonged QT interval
  • Seizure

Occasional:

  • Lazy eye
  • Positive Babinski sign
  • Generalised convulsion
  • Cortical visual impairment
  • Involuntary rhythmic muscular contractions and relaxations
  • Swallowing difficulties
  • Dystonic movements
  • Elevated plasma acylcarnitine levels
  • Increased deep tendon reflexes
  • Increased muscle tone
  • Infantile spasms
  • Involuntary, rapid, rhythmic eye movements
  • Optic-nerve degeneration
  • Stroke
  • Supranuclear gaze paralysis

Very rare:

  • Decreased size of head
  • Sensorineural deafness

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 reduced (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.". https://www.omim.org/entry/616830?search=tango2&highlight=tango2. 
  2. ↑ 2.0 2.1 2.2 Miyake, Christina Y.; Burrage, Lindsay; Glinton, Kevin; Houck, Kimberly; Hoyos-Martinez, Alfonso; Graham, Brett; Yang, Yaping; Rawls-Castillo, Brandy et al. (1993), Adam, Margaret P.; Feldman, Jerry; Mirzaa, Ghayda M. et al., eds., "TANGO2 Deficiency", GeneReviews® (Seattle (WA): University of Washington, Seattle), PMID 29369572, https://www.ncbi.nlm.nih.gov/books/NBK476443/, retrieved 2025-04-17 
  3. ↑ 3.0 3.1 Miyake, Christina Y.; Lay, Erica J.; Soler-Alfonso, Claudia; Glinton, Kevin E.; Houck, Kimberly M.; Tosur, Mustafa; Moran, Nancy E.; Stephens, Sara B. et al. (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. PMID 36473599. 
  4. ↑ 4.0 4.1 4.2 Lalani, Seema R.; Liu, Pengfei; Rosenfeld, Jill A.; Watkin, Levi B.; Chiang, Theodore; Leduc, Magalie S.; Zhu, Wenmiao; Ding, Yan et al. (2016-02-04). "Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations" (in English). The American Journal of Human Genetics 98 (2): 347–357. doi:10.1016/j.ajhg.2015.12.008. ISSN 0002-9297. PMID 26805781. 
  5. ↑ "Orphanet: Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome" (in en). https://www.orpha.net/en/disease/detail/480864?search=&mode=name. 
  6. ↑ "New study on TANGO2 illuminates the path of a rare disease" (in en-US). 2025-02-28. https://ellipse.prbb.org/new-study-on-tango2-illuminates-the-path-of-a-rare-disease/. 
  7. ↑ "Orphanet: Clinical signs and symptoms" (in en). https://www.orpha.net/en/disease/sign/480864. 
  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" (in en). American Journal of Medical Genetics Part A 194 (10). doi:10.1002/ajmg.a.63778. ISSN 1552-4833. PMID 38829177. 
  9. ↑ "UniProt" (in en). https://www.uniprot.org/uniprotkb/Q6ICL3/entry. 
  10. ↑ Dines, Jennifer N.; Golden-Grant, Katie; LaCroix, Amy; Muir, Alison M.; Cintrón, Dianne Laboy; McWalter, Kirsty; Cho, Megan T.; Sun, Angela et al. (2019-03-01). "TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants" (in English). Genetics in Medicine 21 (3): 601–607. doi:10.1038/s41436-018-0137-y. ISSN 1098-3600. PMID 30245509. PMC 6752277. https://www.gimjournal.org/article/S1098-3600(21)01041-8/fulltext. 
  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" (in en). 2012-07-20. https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/hemizygous. 
  13. ↑ Heiman, Paige; Mohsen, Al-Walid; Karunanidhi, Anuradha; St Croix, Claudette; Watkins, Simon; Koppes, Erik; Haas, Richard; Vockley, Jerry et al. (2022-02-23). "Mitochondrial dysfunction associated with TANGO2 deficiency" (in en). Scientific Reports 12 (1): 3045. doi:10.1038/s41598-022-07076-9. ISSN 2045-2322. PMID 35197517. Bibcode: 2022NatSR..12.3045H. 
  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" (in en). Journal of Inherited Metabolic Disease 44 (2): 426–437. doi:10.1002/jimd.12312. ISSN 1573-2665. PMID 32909282. https://onlinelibrary.wiley.com/doi/abs/10.1002/jimd.12312. 
  15. ↑ Bard, Frederic; Casano, Laetitia; Mallabiabarrena, Arrate; Wallace, Erin; Saito, Kota; Kitayama, Hitoshi; Guizzunti, Gianni; Hu, Yue et al. (2006-02-02). "Functional genomics reveals genes involved in protein secretion and Golgi organization" (in en). Nature 439 (7076): 604–607. doi:10.1038/nature04377. ISSN 1476-4687. PMID 16452979. Bibcode: 2006Natur.439..604B. https://www.nature.com/articles/nature04377. 
  16. ↑ Mingirulli, Nadja; Pyle, Angela; Hathazi, Denisa; Alston, Charlotte L.; Kohlschmidt, Nicolai; O'Grady, Gina; Waddell, Leigh; Evesson, Frances et al. (2020). "Clinical presentation and proteomic signature of patients with TANGO2 mutations" (in en). Journal of Inherited Metabolic Disease 43 (2): 297–308. doi:10.1002/jimd.12156. ISSN 1573-2665. PMID 31339582. 
  17. ↑ de Calbiac, Hortense; Montealegre, Sebastian; Straube, Marjolène; Renault, Solène; Debruge, Hugo; Chentout, Loïc; Ciura, Sorana; Imbard, Apolline et al. (2024-12-31). "TANGO2-related rhabdomyolysis symptoms are associated with abnormal autophagy functioning". Autophagy Reports 3 (1). doi:10.1080/27694127.2024.2306766. 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)" (in English). Pediatric Neurology 119: 34–39. doi:10.1016/j.pediatrneurol.2021.02.011. ISSN 0887-8994. PMID 33845444. https://www.pedneur.com/article/S0887-8994(21)00031-X/abstract. 
  19. ↑ "TANGO2: A Rare but Important Mutation" (in en-us). https://www.innovationsincrm.com/cardiac-rhythm-management/articles-2024/may/2209-tango2-a-rare-but-important-mutation. 
  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" (in en). Journal of Inherited Metabolic Disease 46 (2): 358–368. doi:10.1002/jimd.12579. ISSN 1573-2665. 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. et al. (2023). "B-complex vitamins for patients with TANGO2-deficiency disorder" (in en). Journal of Inherited Metabolic Disease 46 (2): 161–162. doi:10.1002/jimd.12585. ISSN 1573-2665. PMID 36550018. 
  22. ↑ Xu, Weiyi; Cao, Yingqiong; Stephens, Sara B.; Arredondo, Maria Jose; Chen, Yifan; Perez, William; Sun, Liang; Yu, Andy C. et al. (2024-06-10). "Folate as a potential treatment for lethal ventricular arrhythmias in TANGO2-deficiency disorder" (in en). JCI Insight 9 (11). doi:10.1172/jci.insight.171005. ISSN 0021-9738. 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. https://www.sciencedirect.com/science/article/abs/pii/S0929693X23000970. 
  24. ↑ Kremer, Laura S.; Distelmaier, Felix; Alhaddad, Bader; Hempel, Maja; Iuso, Arcangela; Küpper, Clemens; Mühlhausen, Chris; Kovacs-Nagy, Reka et al. (2016-02-04). "Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy" (in English). The American Journal of Human Genetics 98 (2): 358–362. doi:10.1016/j.ajhg.2015.12.009. ISSN 0002-9297. PMID 26805782. 



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