What is Tango2 deficiency?

TANGO2 Deficiency: A Rare Genetic Disorder with Severe Metabolic and Cardiac Manifestations

TANGO2 deficiency disorder (TDD) is a rare autosomal recessive condition characterized by developmental delay, intermittent metabolic crises, cardiac arrhythmias, rhabdomyolysis, and neurological symptoms that can lead to sudden death.

Clinical Features

• TANGO2 deficiency presents with developmental delay, speech difficulties, intellectual disability, and neurological symptoms including ataxia and dystonia, typically beginning between ages 1-3 years 1
• Patients experience life-threatening metabolic crises characterized by rhabdomyolysis, encephalopathy, and cardiac arrhythmias 2, 1
• Cardiac manifestations include potentially fatal arrhythmias such as Torsades de pointes, ventricular tachycardia, and ventricular fibrillation 2
• Additional features include hypothyroidism, seizures, and progressive spasticity 3, 1
• Early development may appear normal, with progressive developmental delay becoming apparent later in infancy 1

Genetics and Pathophysiology

• TDD is caused by biallelic pathogenic variants in the TANGO2 gene (Transport And Golgi Organization 2) 3, 4
• The TANGO2 gene is located within the 22q11.2 region, making patients with 22q11.2 deletion syndrome at higher risk for comorbid TDD if they have a pathogenic variant on their remaining allele 5, 6
• The exact function of the TANGO2 protein remains incompletely understood, but it appears to have primarily cytoplasmic localization rather than mitochondrial 4
• Despite not being directly localized to mitochondria, TANGO2 deficiency has indirect effects on mitochondrial energy metabolism, with some patients showing mildly reduced mitochondrial complex II activity during metabolic crises 4

Diagnosis

• Diagnosis is based on clinical features and confirmed by genetic testing showing biallelic pathogenic variants in TANGO2 1
• Diagnosis is often delayed until after an acute metabolic crisis, even in patients with pre-existing developmental delay 3
• Patients with 22q11.2 deletion syndrome who exhibit symptoms of rhabdomyolysis, cardiac arrhythmias, or metabolic crises should be evaluated for possible comorbid TDD 5, 6
• Post-mortem findings in one patient revealed heterotopic neurons in cerebral white matter, suggesting TANGO2 may play a role in neuronal migration 4

Management

• B-complex vitamin or multivitamin supplementation has been shown to significantly reduce the frequency of metabolic crises 1, 2
• Acute metabolic crises require aggressive management, including vitamin B-complex administration, which has shown dramatic improvement in mental status, rhabdomyolysis, and cardiac manifestations 2
• Preventive measures include avoiding fasting and catabolic states that may trigger metabolic decompensation 1
• Long-term management involves supportive care for developmental delay, neurological symptoms, and monitoring for cardiac arrhythmias 1

Prognosis

• Mortality rates are significant, with deaths typically occurring during acute metabolic crises 1
• Some patients (approximately 35%) never experience overt metabolic crises, suggesting variable expressivity 4, 1
• Early diagnosis and preventive measures, particularly B-vitamin supplementation, may improve outcomes 1

Special Considerations

• High index of suspicion is needed in patients with developmental delay or neurological symptoms who develop episodic rhabdomyolysis 3
• Patients with 22q11.2 deletion syndrome require screening for possible comorbid TDD, as the TANGO2 gene is located within the commonly deleted region 5, 6
• Infections can trigger metabolic decompensation and should be promptly treated 3