TANGO2: A Rare but Important Mutation 2024 Walters et al

Andy · May 30, 2024

Abstract

We report the case of a 7-year-old boy who presented with post-viral myositis, rhabdomyolysis, and hepatitis, who was later readmitted due to a seizure-like activity and ultimately found to have episodes of recalcitrant polymorphic ventricular tachycardia secondary to simultaneous QT prolongation and severe hypothyroidism.

Temporary transvenous atrial pacing was successful at controlling the ventricular arrhythmias in the intensive care unit. With levothyroxine therapy and cessation of QT-prolonging medications, the corrected QT (QTc) normalized. A comprehensive arrhythmia panel identified a pathogenic mutation in KCNQ1, consistent with long QT syndrome (LQTS) type 1.

After the patient experienced progressive neurodegeneration and seizures, he was referred to a genetics clinic to rule out genetic epilepsy. On the epilepsy panel of genetic testing, he was found to have two pathogenic variants in TANGO2. TANGO2 deficiency explains the initial presentation of myositis, rhabdomyolysis, hypothyroidism, and life-threatening arrhythmias surrounding a viral illness more so than the initial diagnosis of mere LQTS. However, the TANGO2 gene is not included in most comprehensive arrhythmia and cardiomyopathy panels.

TANGO2 deficiency is a rare condition that often presents with arrhythmias but may be unfamiliar to many cardiologists and electrophysiologists. This case describes management strategies and caveats, which could aid in the successful diagnosis and treatment of TANGO2 deficiency at the time of presentation.

PubMed abstract only available at time of posting, https://pubmed.ncbi.nlm.nih.gov/38808169/

Hutan · May 30, 2024

More information on Tango2 deficiency here: https://rarediseases.org/rare-diseases/tango2-related-metabolic-encephalopathy-and-arrhythmias/

metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration
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TANGO2 deficiency disorder is a rare genetic disorder caused by disease causing changes in the TANGO2gene. 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.
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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.
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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).
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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.
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Very interesting @Andy, thanks for posting. The metabolic crisis has aspects similar to PEM. I get dark brown urine.

Hutan · May 30, 2024

More from the rare diseases link

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.
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Disorders with similar symptoms

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare genetic disorder of fatty acid metabolism that is inherited in an autosomal recessive pattern. It occurs when an enzyme needed to break down certain very long-chain fatty acids is missing or not working properly. VLCADD is one of the metabolic diseases known as fatty acid oxidation (FOD) diseases. The breakdown of fatty acids takes place in the mitochondria found in each cell. ...Classically, three forms of VLCADD have been described: an early-onset, severe form which, if unrecognized and undiagnosed, may lead to extreme weakness of the heart muscles (cardiomyopathy) and may be life-threatening, a later-onset, milder form that is characterized by repeated bouts of low blood sugar (hypoglycemia), and a later-onset, milder form that is characterized by breakdown of muscle tissue (e.g., rhabdomyolysis). Patients may present with a combination of symptoms and the disorder is best thought of as being a continuum.
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Mitochondrial diseases are a group of rare genetic disorders.
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Additional disorders that can be mistaken for TANGO2 deficiency include carnitine palmitotyltransferase II deficiency, carnitine acylcarnitine translocase deficiency, acute recurrent myoglobinuria, LPIN1 deficiency, multiple acyl-coenzyme A dehydrogenase deficiency, trifunctional protein deficiency, LCHAD deficiency and various disorders of glycogen/glucose metabolism. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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TANGO2: A Rare but Important Mutation 2024 Walters et al

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