TANGO2 deficiency disorder is a genetic condition caused by genetic changes to the TANGO2 gene. It is characterised by TANGO2 spells, which are sudden episodes of extreme tiredness and muscle weakness, as well as episodes of metabolic crisis.^1-4 Metabolic crisis is a life-threatening medical emergency that occurs when the body cannot properly use stored energy. This often occurs during periods of fasting, dehydration, illness, exertion, and other times of high energy demand. Complications of metabolic crisis in people with TANGO2 deficiency disorder include the breakdown of muscles which release toxic substances into the blood (rhabdomyolysis) and abnormal heart rhythms (cardiac arrhythmias), which can be life threatening if not treated promptly.

Other symptoms typically seen in individuals with TANGO2 deficiency disorder include developmental delay, speech difficulties, progressive (worsening over time) intellectual disability, poor coordination and unusual gait (walking pattern).

Synonyms: Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome; TANGO2 disease; TANGO2-related disorder; TANGO2-related deficiency disorder; TANGO2-Related Metabolic Encephalopathy and Arrhythmia; metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN); transport and golgi organisation protein 2 (TANGO2) deficiency; transport and golgi organization 2 homolog-related metabolic encephalopathy, arrhythmia syndrome.^1-4

Universal rare disease classifications provide a common language for recording, reporting and monitoring diseases. Please visit the Rare Disease Classifications page for more information about these internationally recognised classifications.

ORPHA:480864 Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome

There is currently no known ICD-11 classification.

The symptoms and severity of TANGO2 deficiency disorder varies widely between individuals. People with this condition may have different combinations of the symptoms, and the order in which the symptoms appear may differ.^1,2,5

Common symptoms of TANGO2 deficiency include:

• Delays in movement (motor) and speech development
• Speech difficulties such as slurred or nasal speech
• Poor coordination
• Mild to moderate intellectual disability that slowly worsens over time

Many people with TANGO2 deficiency disorder experience sudden (paroxysmal) episodes called ‘TANGO2 spells’. These can last anywhere from a few minutes to several days and usually improve with rest. Symptoms of a TANGO2 spell include:^1,2

• Loss of muscle control and coordination (ataxia), leading to wobbly movements, loss of balance, muscle spasms (dystonia), drooping eyelids, drooling, and slurred speech
• Extreme tiredness (fatigue)
• Confusion and disorientation
• Seizures

Individuals with TANGO2 deficiency disorder are also at risk of metabolic crisis, which is a medical emergency. Symptoms vary widely and may include low blood sugar (hypoglycaemia), muscle weakness (ataxia) and pain, confusion, and abnormal heart rhythms (arrhythmias). This can lead to coma or early death. Triggers of TANGO2 spells and metabolic crisis in people with TANGO2 deficiency disorder include: fasting, dehydration, overexertion, exposure to excessive heat, ketogenic diet, and infection.^1,2

Some individuals also experience seizures, hypothyroidism, deviation of one or both eyes to the side (exotropia), and constipation, although these are less common.

Please speak to your medical team to learn more about the symptoms and complications of TANGO2 deficiency.

Rare diseases are often serious and progressive, exhibiting a high degree of symptom complexity, leading to significant disability. Majority of the estimated two million Australians living with a rare disease meet the Australian Government’s definition for disability (in accordance to the Australian Public Service Commission and Australian Bureau of Statistics), and many experience severe and permanent disability impacts. If you or someone you care for is experiencing disability-related impacts from a rare condition, please speak with a health or disability professional for advice. Information about relevant disability support can be found at the RARE Portal’s Disability Support Information page.

TANGO2 deficiency disorder is a genetic condition.¹ TANGO2 deficiency disorder is caused by disease-causing changes (variants) in the TANGO2 gene. All individuals have two copies (alleles) of the TANGO2 gene – one on each chromosome that is inherited from each parent. TANGO2 deficiency disorder is an autosomal recessive condition, which means both copies of the TANGO2 gene must have the disease-causing genetic variants for the condition to occur.

Individuals with a genetic variant in only one copy of TANGO2 are unaffected but will be a carrier and may pass on that variant to their children. If both parents are carriers (each have a copy of the disease-causing TANGO2 variant), there is a 25% chance the child will inherit both disease-causing variants and have TANGO2 deficiency disorder. More information on autosomal recessive inheritance pattern can be found at Centre for Genetics Education: Autosomal recessive inheritance.

If you would like to learn more about the inheritance and impact of this condition, please ask your doctor for a referral to a genetic counsellor. Genetic counsellors are qualified allied health professionals who can provide information and support regarding genetic conditions and testing. More information about genetic counselling can be found at:

• Information on Genetic Services
• The National and State Services pages underneath the ‘Genetic Counselling’ sections listed

There are no published consensus clinical diagnostic criteria for TANGO2 deficiency disorder.^{1, 2}

Diagnosis of TANGO2 deficiency disorder may be made based on observation of the characteristic symptoms, a clinical exam, and specialised tests that measure heart function. A genetic test can then confirm the diagnosis by identifying the variant in the TANGO2 gene.^1,2

As part of the diagnosis process, doctors may also do tests to rule out other conditions that have similar symptoms (differential diagnosis).^1,2 These conditions are likely to include metabolic disorders such as Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, Carnitine palmitoyltransferase II (CPT II) deficiency, Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) / trifunctional protein deficiency (TFP), Carnitine-acylcarnitine translocase (CACT) deficiency, LPIN1-related acute recurrent myoglobinuria, Glycogen storage disease type V (GSDV, McArdle disease), and other defects of glucose/glycogen metabolism.

Please speak to your medical team to learn more about the available pathways for diagnosis of TANGO2 deficiency disorder.

There is currently no curative treatment for TANGO2 deficiency disorder.^1,2,6 Treatment is targeted at managing symptoms and preventing TANGO2 spells and metabolic crisis. This often involves a multidisciplinary care team.

People with TANGO2 deficiency disorder are generally advised to avoid the main triggers of TANGO2 spells and metabolic crisis by eating regularly to avoid fasting, staying well hydrated, and avoiding overexertion, excessive heat, ketogenic diets, and infections where possible. As illness can trigger a metabolic crisis, infections should be assessed and treated promptly.^1,2

Doctors may also prescribe medication to control hyperthyroidism and seizures, if these symptoms are present.¹

Please speak to your medical team to learn more about the possible treatment or management options for your condition. Treatment will depend on an individual’s specific condition and symptoms. It is also important to stay connected to your medical team so that you can be made aware of any upcoming clinical trial opportunities.

Healthcare professionals involved in the care of individuals with TANGO2 deficiency disorder may include general practitioners (GP), paediatricians, metabolic specialists, clinical geneticists, genetic counsellors, cardiologists and electrophysiologists (heart rhythm specialists), neurologists, endocrinologists, intensive care professionals and occupational therapists. The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here.

Clinical care for rare diseases often involves a multidisciplinary team of medical, care and support professionals. Please note that the information provided here is as a guide and that RVA does not necessarily monitor or endorse specific clinics or health experts.

For many rare diseases, palliative care services may be relevant and useful. Palliative care services are available for people (adults, children and their families) living with a life-limiting illness and is not only for end-of-life care. It can also help at any stage of illness from diagnosis onwards, and will look different for different people. Palliative care services provide assistance, support, resources and tools to help people manage their illness and the symptoms, ease pain, and improve comfort and quality of life. If this is relevant to you and you wish to find out more information about palliative care and how it can help you, please visit:

• Australian Institute of Health and Welfare: Palliative care Overview
• Australian Government Department of Health, Disability and Ageing: Palliative care
• Palliative Care Australia

We are not aware of any clinical care guidelines for TANGO2 deficiency disorder in Australia. If you know of any relevant care guidelines, please let us know via the Contribute page.

Individuals living with rare diseases may have complex medical issues and disabilities, which are not always visible. It is often useful to refer to their medical history as well as personal information such as a medical card, doctor’s letter, or if available, a rare disease passport, for relevant information.

In addition, individuals, their parents, families and carers often develop extensive expertise on their specific rare disease. It is important to recognise that they can contribute valuable knowledge about their rare condition. Rare diseases often impact individuals differently, so it’s important to consider a person’s lived experience.

It may be important to consider the following when managing individuals living with TANGO2 deficiency syndrome at emergency departments/services:

• Individuals with TANGO2 deficiency syndrome are at risk of metabolic crisis and arrhythmias

There are specific considerations around participating in rare disease research, including clinical trials. It is important to be mindful of issues such as data privacy, research ethics, consent and differences in research regulations between Australia and other countries. For more information, please visit the RARE Portal’s Considerations for Participating in Health and Medical Research page.

If you are interested in finding clinical trials for your condition, please visit the following websites; however, there may not be any clinical trials available:

• Australian Clinical Trials
• ClinicalTrials.gov

It is best to discuss your interest in research, including clinical trials,  with your medical team to determine suitability and eligibility.

Australian Organisation:
TANGO2 Australia
Website: https://tango2australia.org.au

International Organisation:
TANGO2 Research Foundation (United States of America)
Website: https://tango2research.org/

Please note that RVA does not monitor or endorse each group/organisation’s operational governance and activities. When engaging with a group, please consider the information on the RARE Portal’s Finding Helpful Peer and Community Supports page.

TANGO2 deficiency disorder varies between individuals, and each person’s experience is unique.

If you would like to share your personal story with RVA, please visit the Rare Voices Australia: Share Your Story page. RVA will consider your story for publishing on our website and inclusion on the RARE Portal.

For information on available government and social services that provide support for individuals with a rare disease, please visit the National and State Services pages.

People living with a rare disease often face unique challenges such as diagnostic delays, misdiagnoses, limited treatment options, and limited access to rare disease specialists and support. These challenges may impact people’s emotional wellbeing and quality of life. Many find it helpful to seek mental health and wellbeing support to cope with ongoing stress and uncertainty. Connecting with people who have shared experiences through a support group may also be helpful. Information about relevant mental health and wellbeing support can be found at:

• Mental Health and Wellbeing Support for Australians Living with a Rare Disease
• The National and State Services pages underneath the ‘Mental Health’ sections listed

Further information on TANGO2 deficiency disorder can be found at:

• Genetic and Rare Diseases (GARD) Information Center: Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
• National Organization for Rare Disorders (NORD): TANGO2 Deficiency Disorder

GeneReviews®: TANGO2 Deficiency

Online Mendelian Inheritance in Man, OMIM^®:# 616878; metabolic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration; MECRN

Orphanet: Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome

Human Phenotype Ontology (HPO): Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome

Inborn Errors of Metabolism Knowledgebase (IEMbase): #IEM0640: TANGO2-related Recurrent metabolic encephalomyopathic crises associated with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration

This page has been developed by Rare Voices Australia (RVA)’s RARE Portal team.

If you are aware of any additional information that may benefit stakeholders with an interest in this page, or if you notice any broken links or inaccurate information, please let us know via the Contribute page.