Última actualización:
8/15/2023
Años publicados: 2018, 2023
NORD gratefully acknowledges Seema Lalani, MD, Professor, Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children’s Hospital; Christina Miyake, MD, MS, Associate Professor, Pediatrics (TCH), Associate Professor, Molecular Physiology and Biophysics (BCM), Baylor College of Medicine, Texas Children’s Hospital; Lindsay Burrage, MD, PhD, Associate Professor, Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children’s Hospital, and the TANGO2 Research Foundation, for assistance in the preparation of this report.
TANGO2 deficiency disorder is a rare genetic disorder caused by disease causing changes in the TANGO2 gene. Affected individuals experience episodes of acute illness called metabolic crises. These episodes can be triggered, often by a preceding infection or from decreased oral intake or fasting for an extended period of time. Irregularities in the rhythm of the heart (arrhythmias), the breakdown of muscle tissue (rhabdomyolysis) and other complications can occur during an episode. The term encephalopathy is a general term for brain disease. Neurological problems including intellectual disability and delays in reaching developmental milestones can occur. 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 is aimed at the specific symptoms present in each individual.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the basis of these symptoms remains unclear. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
TANGO2 deficiency is a variable disorder. This means that how the disorder affects people can vary greatly from one affected individual 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. Affected individuals often present with symptoms before a metabolic crisis is apparent. These symptoms can include delays in reaching developmental milestones (developmental delays) and regression, poor gait coordination, clumsiness, low functioning thyroid gland (hypothyroidism) or seizures. Episodic symptoms termed as TANGO2 spells can be seen in many individuals characterized by sudden onset of head tilt, body tilt, inability to walk properly, loss of coordination, significant leg tightness and extreme fatigue.
During a metabolic crisis there can be low blood sugar (hypoglycemia, elevated liver enzymes (transaminitis), elevated creatinine kinase and troponin (enzymes found in skeletal and heart muscle) and a buildup of toxic substances including ammonia (hyperammonemia) and lactic acid in the blood (lactic acidosis). A metabolic crisis is often triggered, usually by illness or from eating poorly or fasting for an extended period 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), disorientation and, in severe instances, unconsciousness (comatose state).
During a metabolic crisis, individuals develop a condition called rhabdomyolysis, in which muscle tissue breaks down. Muscle pain (myalgia), muscle weakness and fatigue can develop. When muscle tissue breaks down, it produces substances that are released into the body including creatinine kinase (CK) and a protein called myoglobulin. Myoglobin can build up in the urine (myoglobinuria). This can cause the urine to appear dark brown. Myoglobinuria can potentially lead to damage of the kidneys. The kidneys have several functions in the body including filtering waste products from the blood. Myoglobulins can cause obstruction of tiny structures in the kidneys called tubules, which damages the kidney. Kidney damage can cause decreased kidney function and eventually kidney failure.
During an acute illness, affected individuals may develop irregular heart rhythms (arrhythmias), abnormalities in the resting electrocardiogram (ECG), and decreased ability for the heart to pump (cardiac dysfunction). All children should have a baseline ECG and echocardiogram which should be followed and repeated during crisis. The most common abnormality during an acute crisis is QT prolongation. Prolongation of the QT interval refers to a change seen on the ECG. QT prolongation predisposes affected individuals to an increased risk of life-threatening rhythm disturbances, specifically ventricular tachycardia or torsade de pointes. These abnormal rhythms originate from the bottom pumping chamber of the heart. 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). 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 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.
Affected individuals will also have neurodevelopmental problems including intellectual disability, seizures and problems coordinating voluntary movements (ataxia) causing clumsiness and an unsteady way of walking (unsteady gait) and difficulty with speech (dysarthria). Intellectual disability can range in severity from mild to moderate to severe.. Many affected individuals experience developmental delay, or they experience the loss of developmental milestones that they have already reached (regression). About half of the affected individuals have seizures that usually respond to medications. In a subset of children, these can be difficult to control. In addition, muscle weakness can result in sporadic head or body tilting and difficulty opening the eyelids and drooling and difficulty swallowing. These episodes can come and go within hours.
Some individuals have increased muscle tone in their legs, which can cause muscles to be tight even at rest. Some children are noted to walk on their toes. Some children may have a reduced ability to stretch. Increased muscle tone can lead to spasticity.
Some individuals have low function of the thyroid (hypothyroidism). The thyroid is a 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. Hormones are secreted directly into the bloodstream where they travel to various areas of the body. Symptoms of hypothyroidism in children can include fatigue, constipation, low muscle tone and growth delay.
Additional symptoms that have been reported include exaggerated or heightened reflexes (hyperreflexia) and temporary misalignment of the eyes where one or both eyes are turned outward away from the nose (exotropia). In rare instances, affected children have developed sensorineural hearing loss. Sensorineural hearing loss occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain.
TANGO2 deficiency is caused by variations in the TANGO) 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 sure what the protein produced (encoded) by the TANGO2 gene does. It may have a role in secretory protein loading within the endoplasmic reticulum, which is an extensive membrane network found within certain cells where proteins are processed. Studies also indicate that it may play a role in synthesis of lipids, important for cell functions.
The penetrance of disease-causing variations in the TANGO2 gene is believed to be 100%. That means everyone who has disease causing changes 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 combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
TANGO2 deficiency is a rare disorder that was first reported in the medical literature in 2016. According to the TANGO2 Research Foundation, as of January 2023, over 100 individuals have been identified with the disorder worldwide. Based on the known carrier frequency of TANGO2 changes in different populations, it is likely that over 8,000 individuals are affected with TANGO2 deficiency in the world. Rare diseases often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
A diagnosis of TANGO2 deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Diagnostic criteria for this disorder have not yet been established.
Clinical Testing and Workup
Most individuals are diagnosed through molecular genetic testing. Molecular genetic testing can detect a variation in the TANGO2 gene known to cause TANGO2 deficiency but is available only as a diagnostic service at specialized laboratories.
Advanced imaging techniques such as magnetic resonance imaging (MRI) of the brain may also be performed. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues, including the brain. 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 within the skull (cerebral volume loss).
Other tests may be performed to assess specific symptoms. For example, if seizure activity is seen or suspected – body shaking or staring spells, physicians may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain and may show changes in brain function and help to detect seizures. During health the cardiac ECG and echocardiogram are typically normal.
Treatment
The treatment of TANGO2 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of metabolic disease in children (pediatric metabolic physicians and geneticists), heart arrhythmias in children (pediatric cardiologists and electrophysiologists), intensive care physicians who specialize in taking care of children in intensive care units, physicians who are experts in the diagnosis and treatment of the brain and central nervous system in children (pediatric neurologists), physicians who specialize in the diagnosis and treatment of hypothyroidism (pediatric endocrinologists), specialists who asses and treat hearing problems (audiologists) and other healthcare professionals may need to systematically and comprehensively plan treatment.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. However, natural history study data shows that vitamin B complex or multivitamins including all 8 vitamin Bs 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.
A metabolic crisis is a medical emergency that requires prompt treatment. This can include hydration to treat rhabdomyolysis.
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 can differ depending on the specific type of ECG abnormality that is present. Because nearly all children in crisis have QT prolongation, all drugs that prolong the QT interval should be avoided during crises. Magnesium should be used to maintain levels above 2.2 mg/dl. However, arrhythmias develop rapidly and any child with marked QTc prolongation or premature ventricular contractions (PVCs) should be immediately transferred to an intensive care unit. Single PVCs can be treated with IV magnesium, but any higher-grade arrhythmias or ventricular tachycardia appears to respond best to isoproterenol. Atrial pacing can also be used.
Recurrent ventricular tachycardia or torsade de pointes can be treated by cardioversion but will typically recur. As soon as ventricular tachycardia or torsade de pointes is seen, isoproterenol should be considered and quickly administered if possible. Cardiac dysfunction may limit the use of this drug. Cardioversion is a method of restoring heart rhythm to normal, either through electrical shock or with specific medications. Direct current cardioversion is a procedure in which a small electrical charge is delivered to the heart to “shock” it back to normal rhythm. Although currently isoproterenol appears to be the most effective drug choice for ventricular tachycardia, death has occurred despite its use. Because researchers do not completely understand the underlying reason that arrhythmias occur in this disorder, the ideal treatments for heart rhythm problems are not known. Extracorporeal membrane oxygenation (ECMO) is a life support system that can be used as a last resort for arrhythmia management during crises.
Some but not all individuals who have had ventricular arrhythmias receive an implantable cardioverter defibrillator (ICD) and its use should be decided by the team and family. Because arrhythmias appear to only occur during metabolic crisis and because these medications can cause hypoglycemia, prophylactic or daily 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. Whether or not this is a long-term effective treatment is unclear.
Hypothyroidism 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.
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/
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 August 14, 2023.
Genetic and Rare Disease Information Center. TANGO2-related metabolic encephalopathy and arrhythmias. March 19, 2018. Available at: https://rarediseases.info.nih.gov/diseases/13423/tango2-related-metabolic-encephalopathy-and-arrhythmias Accessed August 14, 2023.
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 August 14, 2023.
TANGO2 Research Foundation. About TANGO2. Available at: https://tango2research.org/about-tango2/tango2-tango2-related-disorder/ Accessed August 14, 2023.
Cardioversion. American Heart Association. Nov 17, 2022. Available at https://www.heart.org/en/health-topics/arrhythmia/prevention–treatment-of-arrhythmia/cardioversion Accessed August 14, 2023.
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Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View reportGeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.
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