Clinical characteristics: Individuals with TANGO2-related metabolic encephalopathy and arrhythmias can present in acute metabolic crisis (hypoglycemia, elevated lactate, mild hyperammonemia) or with developmental delay, regression, and/or seizures. The acute presentation varies from profound muscle weakness, ataxia, and/or disorientation to a comatose state. Individuals can present with intermittent acute episodes of rhabdomyolysis. The first episode of myoglobinuria has been known to occur as early as age five months. Acute renal tubular damage due to myoglobinuria can result in acute kidney injury and renal failure. During acute illness, transient electrocardiogram changes can be seen; the most common is QT prolongation. Life-threatening recurrent ventricular tachycardia or torsade de pointes occurs primarily during times of acute illness. Individuals who do not present in metabolic crises may present with gait incoordination, progressively unsteady gait, difficulty with speech, or clumsiness. Intellectual disability of variable severity is observed in almost all individuals. Seizures are observed outside the periods of crises in more than 75% of individuals. Hypothyroidism has been reported in more than one third of individuals.
Diagnosis/testing: The diagnosis of TANGO2-related metabolic encephalopathy and arrhythmias is established in a proband by identification of biallelic pathogenic variants in TANGO2 on molecular genetic testing.
Management: Treatment of manifestations:
Acute presentation: Early management during episodes of metabolic crises with aggressive intravenous hydration and urine alkalinization. Cardiac monitoring should include an early electrocardiogram (ECG), continuous ECG monitoring, and an echocardiogram to determine cardiac function. Arrhythmia management by an electrophysiologist is preferred; monitor electrolytes and treat as necessary to maintain normal levels of potassium, magnesium, and glucose; levothyroxine for hypothyroidism and steroid treatment for adrenal insufficiency, if determined. .
Non-acute presentation: Standard treatment of developmental delay/intellectual disability; levothyroxine is the treatment of choice for hypothyroidism. Antiepileptics have been used for management of seizures.
Prevention of primary manifestations: Avoidance of triggers for acute metabolic crisis (e.g., prolonged fasting, dehydration, ketogenic diet). Infusion of intravenous glucose during significant acute periods of systemic metabolic stress caused by infection or general anesthesia may be required to prevent significant catabolism.
Prevention of secondary complications: Provide hydration and alkalinization of the urine during an attack of rhabdomyolysis and myoglobinuria to prevent renal failure. An "emergency" plan should be in place to initiate steps to suppress acute catabolism and promote hydration in order to minimize the risk of life-threatening rhabdomyolysis and cardiac arrhythmias. Prior to determining the rate and amount of fluid administration, an echocardiogram to assess cardiac function should be considered.
Surveillance: Regular cardiology evaluation for management of cardiac arrhythmias; annual TSH and free T4; neurology follow up to manage epilepsy.
Agents/circumstances to avoid: Fasting; dehydration; ketogenic diet, which can precipitate severe metabolic crises.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing to allow prompt initiation of treatment and preventive measures.
Genetic counseling: TANGO2-related metabolic encephalopathy and arrhythmias is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the TANGO2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
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