TANGO2 Deficiency Disorder

Disease Overview

TANGO2 deficiency disorder is a rare genetic condition caused by disease-causing changes in the TANGO2 gene.  

Affected individuals experience episodes of acute illness called metabolic crises. A metabolic crisis is a sudden, serious episode where the body cannot properly use energy.  These episodes are often triggered by infections, poor intake of food or fluids, or fasting for an extended period of time. During these episodes, individuals may develop irregular heart rhythms (arrhythmias), breakdown of muscle tissue (rhabdomyolysis), and other serious complications.  

Encephalopathy is a general term used to describe problems with brain function, which often occurs during a metabolic crisis. Neurological problems, including intellectual disability and delays in reaching developmental milestones, can occur or worsen after metabolic crises. Additional signs and symptoms can occur both within and outside of metabolic crisis.  

TANGO2 deficiency can affect people very differently. There is no cure for the disorder, but research is underway to better understand and treat this disease. Current treatment focuses on managing the specific symptoms present in each individual. Daily supplementation with B-complex vitamins or multivitamins has shown promise in preventing metabolic crises. 

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Synonyms

• TANGO2-related metabolic encephalopathy (a general term for brain dysfunction) and arrhythmias (irregularities in the rhythm of the heart)
• Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis (rapid breakdown of muscle tissue), cardiac arrhythmias, and neurodegeneration
• MECRCN
• Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
• TANGO2-related metabolic encephalopathy-arrhythmia syndrome
• TANGO2-related disease
• TANGO2 Deficiency Disorder

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Signs & Symptoms

Although researchers have identified a set of characteristic, or “core,” symptoms associated with TANGO2 deficiency, much is still unknown about why these symptoms occur and why they vary between individuals. Parents and caregivers should talk with their child’s physician and medical team about their specific symptoms, medical needs, and overall outlook (prognosis). 

TANGO2 deficiency is a variable disorder, meaning the symptoms and severity can differ widely from one person to another. Therefore, it is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals can first experience episodes of acute illness called metabolic crisis (a sudden, serious episode where the body cannot properly use energy). Some individuals experience early symptoms before ever having a metabolic crisis (a sudden, serious episode in which the body cannot properly use energy). These symptoms can include: 

• Delays in reaching developmental milestones (developmental delays)  

• Regression (loss of skills that were previously learned) 

• Poor gait (walking) coordination 

• Clumsiness 

• Low functioning thyroid gland (hypothyroidism)  

• Seizures 

Many individuals experience episodic symptoms, sometimes called “TANGO2 spells.” These episodes may include sudden head or body tilting, difficulty walking, loss of coordination, significant leg tightness, and extreme fatigue. 

During a metabolic crisis, individuals may develop low blood sugar (hypoglycemia), elevated liver enzymes (transaminitis), and elevated levels of creatinine kinase (an enzyme released into the blood when muscle tissue breaks down) and troponin (a protein released into the blood when the heart muscle is injured). Toxic substances may also build up in the blood, including ammonia (hyperammonemia, high levels of ammonia in the blood, which can be toxic to the brain) and lactic acid (lactic acidosis). Metabolic crises are often triggered by illness, poor intake of food or fluids, or fasting for extended periods of time. Stress or dehydration can also trigger an episode. A metabolic crisis may develop rapidly (acutely) and can cause profound muscle weakness, loss of coordination (ataxia), confusion or disorientation and, in severe instances, unconsciousness (coma or comatose state). 

During a metabolic crisis, individuals develop a condition called rhabdomyolysis, a condition in which muscle tissue breaks down. This can cause muscle pain (myalgia), muscle weakness, and fatigue. When muscle breaks down, it produces substances that are released into the body including creatinine kinase (CK) and a protein called myoglobin. Myoglobin can build up in the urine (myoglobinuria), causing it to appear dark brown. Myoglobinuria can potentially damage of the kidneys by blocking small filtering structures called tubules. Kidney damage can cause decreased kidney function and eventually kidney failure. 

During an acute illness, affected individuals may develop irregular heart rhythms (arrhythmias), changes on the electrocardiogram (ECG, a test that records the heart’s electrical activity), and reduced ability of the heart to pump effectively (cardiac dysfunction). All children should have a baseline ECG and echocardiogram (an ultrasound of the heart to create moving pictures of the chambers, valves and blood vessels) which should be followed and repeated during crisis.  

The most common ECG abnormality during an acute crisis is QT prolongation. This means there is a delay in the heart’s electrical recovery between beats. QT prolongation increases the risk of dangerous heart rhythms, including ventricular tachycardia (a fast, life-threatening heart rhythm starting in the lower chambers of the heart) and torsade de pointes ( a specific, dangerous rhythm that can cause fainting or cardiac arrest).  

In addition to the QT prolongation, some affected individuals also develop Brugada type I changes in their ECG, which is a specific pattern in the ECG that also predisposes the individuals to life-threatening heart rhythm problems (ventricular tachycardia and ventricular fibrillation, which is a chaotic heart rhythm where the heart cannot pump blood effectively). While QT prolongation persists until the crisis has resolved, Brugada changes can come and go and thus ECGs and telemetry (which is active bedside monitoring of the electrical activity of the heart during hospitalization) should be monitored throughout the crisis. These arrhythmias (irregular heart rhythms) can lead to sudden loss of consciousness (syncope), cardiac arrest, and potentially cause sudden cardiac death. 

Arrhythmias that occur during metabolic crisis develop rapidly and can be extremely difficult to manage. Arrhythmias are the leading cause of death among children affected by TANGO2 gene alterations. In addition to arrhythmias, the heart muscle can develop dysfunction (cardiomyopathy). This means the heart can develop heart failure, meaning the heart cannot pump well. It is therefore important that all children in crisis be followed by specialists, who have expertise in heart arrhythmia and cardiomyopathy disorders. 

In addition to symptoms that occur during metabolic crises, many affected individuals have ongoing neurodevelopmental (related to brain development) challenges, including: 

• Intellectual disability that can range in severity from mild to moderate to severe 

• Seizures that usually improve with medication (in rare cases the seizures can be hard to control) 

• Problems coordinating voluntary movements (ataxia) causing clumsiness and an unsteady way of walking (unsteady gait)  

• Difficulty with speech (dysarthria).  

• Developmental delay or loss of developmental milestones that they have already reached (regression)  

Muscle weakness can result in sporadic head or body tilting and difficulty opening the eyelids and drooling and difficulty swallowing (these can be episodic). 

Other signs and symptoms may include: 

• Increased muscle tone in the legs, which can cause muscles to be tight even at rest and can lead to spasticity (abnormally tight or stiff muscles) 

• • Some children are noted to walk on their toes  

• Low function of the thyroid (hypothyroidism), the butterfly-shaped gland located at the base of the neck  

• • The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body’s activities such as the heart rate, body temperature and blood pressure  

• • Symptoms of hypothyroidism in children can include fatigue, constipation, low muscle tone and growth delay 

• Exaggerated or heightened reflexes (hyperreflexia)  

• Temporary misalignment of the eyes where one or both eyes are turned outward away from the nose (exotropia) 

• Sensorineural hearing loss, which  occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain (rare) 

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Causes

TANGO2 deficiency is caused by disease-causing changes (variants) in the TANGO2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When alteration of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.  

Researchers are not yet sure what the protein produced (encoded) by the TANGO2 gene does. Current evidence suggests it may play a role in preparing proteins inside cells so they can function properly (a process called secretory protein loading) within the endoplasmic reticulum, a structure inside cells that helps make and process proteins. Studies also indicate that it may play a role in synthesis of lipids, which is important for normal cell function. 

The penetrance (the likelihood that someone with the gene will develop symptoms) of the TANGO2 gene variants is believed to be 100%. That means everyone who has variants in both copies of the TANGO2 gene will eventually develop some type of associated sign or symptom of the disorder. Variations in this gene also have variable expressivity, which means the signs and symptoms can differ among affected individuals. Consequently, the severity of the disorder may vary among affected individuals. 

Genetic diseases are determined by the genes a person inherits from both parents. Each person receives one copy of most genes from their mother and one copy from their father.  

TANGO2 deficiency is inherited in an autosomal recessive pattern. This means a child must inherit two non-working copies of the TANGO2 gene – one from each parent – to be affected. If a person inherits one non-working copy and one working copy of a gene, they are called a carrier and usually do not have symptoms. When both parents are carriers, there is a:  

• 25% chance with each pregnancy that their child will have TANGO2 deficiency.  

• 50% chance with each pregnancy that a child will be a carrier like the parents. 

• 25% chance with each pregnancy that a child will inherit two working copies of the gene and not be affected.  

The chances are the same for males and females. 

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Affected populations

TANGO2 deficiency is a rare disorder that was first reported in medical literature in 2016. According to the TANGO2 Research Foundation, as of December 2025, the estimated global carrier frequency (the proportion of people who carry one copy of a recessive gene variant but don’t show symptoms)  is 1 in 566 people, and the estimated disease prevalence is about 1 in 1,282,795 individuals worldwide. Based on these estimates, it is likely that more than 6,000 individuals globally are affected by TANGO2 deficiency. However, rare diseases are often undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. 

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of TANGO2-deficiency. Comparisons may be useful for a differential diagnosis. 

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare genetic disorder that affects how the body breaks down certain fats for energy. It is inherited in an autosomal recessive patter, meaning a child must inherit two non-working copies of a gene – one from each parent – to have the condition.  

VLCADD occurs when an enzyme needed to break down certain very long-chain fatty acids is missing or not working properly. It is one of several conditions known as fatty acid oxidation (FAOD) diseases. Three forms of VLCADD have been described:  

• an early-onset, severe form that can cause serious heart muscle weakness (cardiomyopathy) and may be life threatening if not recognized early,  

• a later-onset, milder form characterized by repeated bouts of low blood sugar (hypoglycemia), and 

• a later-onset, milder form characterized by breakdown of muscle tissue (e.g., rhabdomyolysis).  

Since the advent of expanded newborn screening programs using tandem mass spectrometry technology, most VLCADD infants in the United States are being detected in the neonatal period. 

Mitochondrial diseases are a group of rare genetic disorders that affect the mitochondria, which are structures inside cells that produce most of the body’s energy. Because mitochondria play a critical role in energy production, mitochondrial diseases can affect many different organs and systems.  

Mitochondria generate energy through a series of proteins called the respiratory chain (complexes I-V), which convert energy from sugars and fats into ATP, the main energy source for cells. Genetic changes that disrupt this process – often involving mitochondrial DNA (mtDNA) – can lead to mitochondrial disease. energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body.  

Other rare metabolic disorders that may be considered when evaluating individuals with similar symptoms include carnitine palmitotyltransferase II deficiency, carnitine acylcarnitine translocase deficiency, acute recurrent myoglobinuria, multiple acyl-coenzyme A dehydrogenase deficiency, trifunctional protein deficiency, LCHAD deficiency and various disorders of glycogen/glucose metabolism.  

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Diagnosis

A diagnosis of TANGO2 deficiency is based on a combination of characteristic symptoms, a detailed medical history, a thorough physical exam, and a variety of specialized tests. Formal diagnostic criteria for this disorder have not yet been established, which can sometimes make diagnosis challenging. 

Clinical Testing and Workup 

Most people are diagnosed through molecular genetic testing, which can identify disease-causing changes in the TANGO2 gene. This testing is typically performed at specialized laboratories.  

Advanced imaging, such as MRI (magnetic resonance imaging) of the brain, may also be performed. MRI uses magnetic fields and radio waves to create detailed images of organs and tissues. Physicians use an MRI to obtain a detailed image of a major region of the brain called the cerebrum. Some affected individuals have shown reduced size of the cerebrum, meaning a decrease in brain size within the skull (cerebral volume loss). 

Additional tests may be performed to assess specific symptoms. For example, if seizures are suspected (body shaking or staring spells), an electroencephalogram (EEG), which measures the brain’s electrical activity, may be used to help detect seizure activity. When individuals are well, cardiac tests such as an ECG (electrocardiogram, a test that records the heart’s electrical activity) and echocardiogram (an ultrasound that shows how well the heart pumps) are typically normal. 

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Standard Therapies

Treatment
Treatment of TANGO2 deficiency focuses on managing the specific symptoms present in each individual and often requires care from a coordinated team of specialists. This team may include pediatricians, metabolic specialists and geneticists, pediatric cardiologists and electrophysiologists (heart rhythm specialists), intensive care physicians, pediatric neurologists (experts in the diagnosis and treatment of the brain and central nervous system), pediatric endocrinologists who are experts in hypothyroidism, audiologists (specialists who assess and treat hearing problems), and other healthcare professionals. 

Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. 

Because TANGO2 deficiency is rare, large clinical treatment trials have not yet been conducted. However, data from natural history studies (studies that follow people with a disease over time to learn how the condition progresses) suggest that daily supplementation with vitamin B complex or a multivitamin containing all eight B vitamins at the recommended dietary allowance (RDA) may reduce the risk of metabolic crises in children. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with TANGO2 deficiency.  

In laboratory studies, folate (vitamin B9) has shown antiarrhythmic effects, meaning it helped reduce abnormal heart rhythms. These effects were seen in iPSC-derived cardiomyocyte models (heart cells grown from stem cells and used to study disease in the laboratory).  

Pantothenic acid (vitamin B5) has also shown promise by correcting TANGO2-related defects in research studies using both Drosophila (fruit flies commonly used in genetic research) and human cells. 

Starting supplementation early, between 9 and 16 months of age, may improve neurologic outcomes in addition to reducing crisis frequency. Vitamins can be given orally, via nasogastric tube (a tube passed through the nose into the stomach for feeding or medication), intravenously, or through total parenteral nutrition (nutrition given directly into the bloodstream through an IV). A metabolic crisis is a medical emergency that requires prompt treatment. This can include hydration to treat rhabdomyolysis (rapid breakdown of muscle tissue). 

Emergency and Intensive Care Management During Metabolic Crisis 

The following information describes hospital-based emergency care used during metabolic crises. 

During a metabolic crisis, physicians should monitor electrolyte levels. Electrolytes are certain salts and minerals that may be found in the body. Affected individuals should be monitored for normal levels of potassium, magnesium and glucose. 

During a metabolic crisis, treatment of heart rhythm abnormalities depends on what is seen on the ECG and may include several steps:  

• Avoiding QT-prolonging medications: Most children in crisis develop QT prolongation, which means the heart takes longer than normal to reset between beats. Because this increases the risk of dangerous heart rhythms, medications that prolong the QT interval should be avoided. Clinicians often monitor the corrected QT (QTc), which adjusts the QT measurement for heart rate and helps assess risk during illness. 

• Magnesium support: Magnesium is commonly used to support heart rhythm and is maintained above 2.2 mg/dL. 

• Intensive care monitoring: Heart rhythm changes can worsen quickly. Children with significant QTc prolongation or premature ventricular contractions (PVCs, extra or skipped heartbeats that start in the lower chambers of the heart) should be closely monitored in an intensive care unit.  

• Treatment of serious rhythm problems: Isolated PVCs may be treated with intravenous (IV) magnesium. More serious rhythm disturbances, such as ventricular tachycardia (a fast, life-threatening rhythm starting int eh lower chambers of the heart), often respond best to isoproterenol, a medication that helps stabilize heart rhythm by increasing heart rate. 

• Additional support when needed: In some cases, atrial pacing – using a pacemaker to help regulate the heart’s rhythm – may also be considered.  

• Cardioversion for recurrent arrhythmias: Recurrent ventricular tachycardia or torsade de pointes (a specific, dangerous heart rhythm that can cause fainting or cardiac arrest) may be treated with cardioversion, a procedure that restores normal heart rhythm using electricity or medication). However, these abnormal rhythms often return after cardioversion.  

• Rapid escalation to isoproterenol: As soon as ventricular tachycardia or torsade de pointes is detected, isoproterenol should be considered and administered as quickly as possible, if appropriate. Cardiac dysfunction may limit the use of this medication.  

• Last resort life support: in rare, severe cases where arrhythmias cannot be controlled, extracorporeal membrane oxygenation (ECMO), a form of life support that temporarily takes over heart and lung function, may be used as a last resort during crisis management. 

Although cardioversion can temporarily restore normal heart rhythm, dangerous arrhythmias often recur in individuals with TANGO2 deficiency. While isoproterenol currently appears to be the most effective medication for ventricular tachycardia, deaths have occurred despite its use. Because the underlying cause of arrhythmias in this disorder is not fully understood, the most effective long-term treatment strategies remain uncertain.  

Some individuals who have experienced ventricular arrhythmias receive an implantable cardioverter defibrillator (ICD), a small implanted device that detects and corrects dangerous heart rhythms. The decision to place an ICD should be made jointly by the medical team and the family.  

Because arrhythmias typically occur only during metabolic crises (sudden, serious episodes where the body cannot properly use energy) and because many antiarrhythmic medications can cause low blood sugar (hypoglycemia), daily or prophylactic (preventative) antiarrhythmic medications are not recommended.  

Some individuals have undergone a cardiac sympathectomy, a surgical procedure in which certain nerves going to the heart are cut or clamped to interrupt certain nerve signals to the heart. Whether or not this treatment is effective long-term is unclear. 

Hypothyroidism (low thyroid hormone levels) may be treated with a medication called levothyroxine. This medication replaces or provides more of the thyroid hormone that affected individuals are lacking. Seizures may be treated with anti-seizure medications called anticonvulsants or anti-epileptics. 

Affected children may benefit from occupational, physical and speech therapy. Additional medical, social and/or vocational services including specialized learning programs may be necessary. 

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. 

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: 

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected] 

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/ 

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/ 

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/ 

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References

JOURNAL ARTICLES
Asadi P, Milev MP, Saint-Dic D, Gamberi C, Sacher M. Vitamin B5, a coenzyme A precursor, rescues TANGO2 deficiency disease-associated defects in Drosophila and human cells. J Inherit Metab Dis. 2023;46(2):358-368. doi:10.1002/jimd.12579 

Miyake CY, Lay EJ, Soler-Alfonso C, et al. Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients. Genet Med. 2023;25(4):100352. doi:10.1016/j.gim.2022.11.020 

Sandkuhler SE, Zhang L, Meisner JK, et al. B-complex vitamins for patients with TANGO2-deficiency disorder. J Inherit Metab Dis. 2023;46(2):161-162. doi:10.1002/jimd.12585 

Miyake CY, Lay EJ, Beach CM, et al. Cardiac crises: Cardiac arrhythmias and cardiomyopathy during TANGO2 deficiency related metabolic crises. Heart Rhythm. 2022;19(10):1673-1681. doi:10.1016/j.hrthm.2022.05.009 

Ricci F, Scalco R, Mongini T, et al. Multi-system disorder and severe recurrent rhabdomyolysis due to TANGO2 mutations in a 3 year-old child. Neuromuscular Disorders. 2017;27:S207. https://www.nmd-journal.com/article/S0960-8966(17)30982-3/abstract 

Lalani SR, Liu P, Rosenfeld JA, et al. Recurrent muscle weakness with rhabdomyolysis, metabolic crises, and cardiac arrhythmia due to bi-allelic TANGO2 mutations. Am J Hum Genet. 2016;98:347-357. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746334/ 

Kremer LS, Distelmaier F, Alhaddad B, et al. Bi-allelic truncating mutations in TANGO2 cause infancy-onset recurrent metabolic crises with encephalocardiomyopathy. Am J Hum Genet. 2016;98:358-362. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746337/ 

Elsayed EF, Reilly RF. Rhabdomyolysis: a review, with emphasis on the pediatric population. Pediatr Nephrol. 2010;25:7-18. https://www.ncbi.nlm.nih.gov/pubmed/19529963 

INTERNET
Miyake CY, Burrage L, Glinton K, et al. TANGO2 Deficiency. 2018 Jan 25 [Updated 2023 Mar 9]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK476443/ Accessed December 12, 2025. 

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:616878; Last Update: 02/03/2023. Available at: https://www.omim.org/entry/616878 Accessed December 12, 2025. 

TANGO2 Research Foundation. About TANGO2. 2024. Available at: https://tango2research.org/about-tango2/tango2-tango2-related-disorder/ Accessed December 12, 2025.. 

Cardioversion. American Heart Association. Oct 29, 2024. Available at https://www.heart.org/en/health-topics/arrhythmia/prevention–treatment-of-arrhythmia/cardioversion Accessed December 12, 2025. 

Xu W, Cao Y, Stephens SB, et al. Folate as a potential treatment for lethal ventricular arrhythmias in TANGO2-deficiency disorder. JCI Insight. 2024;9(11):e171005. Published 2024 Jun 10. doi:10.1172/jci.insight.171005 

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