TANGO2

TANGO2 (transport and Golgi organization 2 homolog)

• was first identified in 2016 and encodes a protein that is postulated to be involved in redistributing the Golgi membranes into the endoplasmic reticulum (ER) (1,2)
• TANGO2 itself is a protein-coding gene on chromosome 22 (22q11.21)
  • the function of the TANGO2 gene is still not clear (2)
    • data suggest multiple potential functions of the TANGO2 protein, including a role in the fusion of the Golgi apparatus with the endoplasmic reticulum, and mitochondrial structure and function
      
      
• TANGO2 deficiency is hypothesised to induce dysfunction in lipid biosynthesis that is exacerbated under conditions that stress the body
  
  
• is a rare, genetic, metabolic disorder characterized by (2):
  • developmental delay
  • gait incoordination
  • hypothyroidism
  • recurrent crises with associated metabolic derangements, myositis, rhabdomyolysis, and severe cardiac tachyarrhythmias

Presentation is often with a metabolic crisis precipitated by an infection or other catabolic state (1,2):

• patients with TANGO2 deficiency generally have a history or current symptoms of psychomotor impairment characterized by ambulatory dysfunction and hypotonia as well as signs of neurodevelopmental decline
• features of metabolic crises may consist of findings of rhabdomyolysis, seizures, ECG abnormalities including prolonged QT intervals and/or type I Brugada pattern, and severe arrhythmias including potentially life-threatening recalcitrant ventricular tachycardia
• the diagnosis of TANGO2 deficiency should be considered in patients presenting in an acute metabolic crisis with life-threatening recalcitrant ventricular arrhythmias (2)
• study evidence suggests (3):
  • development of hypothyroidism in 48% by age 4y
  • epilepsy occurs in 42% of individuals and is often drug-resistant
  • constipation occurs in 54%
  • speech delay/dysarthria 97%
  • development delay in the Majority of affected individuals 94% 
  • TANGO2 spells occur in 94% - generally consisting of ataxia/ head lag/ drooling/ strabismus

Management:

• there is currently no cure
• requires urgent involvement of metabolic team to support
• research has shown huge benefits to B vitamins and it thought to be protective from over Crisis and improve access to energy due to its role in Coenzyme A production

Reference:

1. Dines J et al. TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants. Genet Med. 2019 Mar;21(3):601-607.
2. Walters B, McConkey N, Imundo JR. TANGO2: A Rare but Important Mutation. J Innov Card Rhythm Manag. 2024 May 15;15(5):5871-5875.
3. Miyake CY et al. Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients. Genetics in Medicine (2023) 25, 100352