Rare Disease Database

Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the recent discovery of the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.

TANGO2-related metabolic encephalopathy and arrhythmias 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 of the symptoms discussed below. Affected individuals can first experience episodes of acute illness called metabolic crisis. Sometimes, affected individuals present with symptoms before a metabolic crisis is apparent. These symptoms can include delays in reaching developmental milestones (developmental delays) and regression, poor coordination, clumsiness, low functioning thyroid gland (hypothyroidism), or seizures.

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 (hyperlactacidemia). A metabolic crisis is often triggered, usually by illness or from not eating 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, some 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 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 repeated during crisis. The most common abnormality during an acute crisis is QT prolongation. Prolongation of the QT interval refers to prolongation of the recovery phase or repolarization of the heart muscle after each heartbeat. Basically, the heart takes longer than normal to recover after each heartbeat. QT prolongation predisposes affected individuals to an increased risk of life-threatening rhythm disturbances, specifically ventricular tachycardia or torsade de pointes. 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 ventricular tachycardia and ventricular fibrillation. While QT prolongation appears to persist until the crisis has resolved, Brugada changes can come and go and thus ECGs and telemetry (which is the monitoring of the electrical activity of the heart over an extended period of time) 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 alterations. In addition to arrhythmias, the heart muscle can develop dysfunction (cardiomyopathy) making it harder to treat the arrhythmias. It is therefore important that all children with TANGO2-related disease be evaluated by an electrophysiologist, who has 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. Researchers do not know whether intellectual disability is an inherent feature of the disorder itself or whether it develops because of neurological damage that occurs during repeated metabolic crises. Many affected individuals experience developmental delays, or they experience the loss of developmental milestones that they have already reached (regression). In addition, muscle weakness can result in sporadic head tilting and difficulty opening the eyelids and drooling and difficulty swallowing. These episodes are most commonly seen during acute crisis and 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 influences 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 can include fatigue, dry skin, constipation, increased sensitivity to cold, unintended weight gain, muscle weakness, and hoarseness.

Additional symptoms that have been reported include exaggerated or heightened reflexes (hyperreflexia), and temporary misalignment of the eyes where one or both eyes are turn 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.