Clinical Description
Individuals with TANGO2-related metabolic encephalopathy and arrhythmias can present in acute metabolic crisis or with developmental delay, regression, and/or seizures.
Acute metabolic crises. The acute presentation varies from profound muscle weakness, ataxia, and/or disorientation to a comatose state, frequently precipitated by an acute illness or fasting. Individuals can present with intermittent acute episodes of rhabdomyolysis. Dark urine due to myoglobinuria and profound lower-extremity weakness can develop. The first episode of myoglobinuria has been known to occur as early as age five months. Creatine phosphokinase (CPK) can be significantly elevated in some individuals (>200,000 U/l). Elevated aldolase and transaminases are also reported, indicative of muscle injury. During an acute crisis, hypoglycemia, elevated lactate, and mild hyperammonemia can also be seen. Urine organic acids can show marked ketoacidosis and lactic acidosis. Acylcarnitine profiles during acute episodes may show elevated C14:1 in some individuals and elevated C10 species in others. Metabolic abnormalities typically normalize after the metabolic crisis, although some individuals continue to have mildly elevated CPK levels.
Renal complications. Acute renal tubular damage due to myoglobinuria can result in acute kidney injury and renal failure [Elsayed & Reilly 2010].
Cardiac dysfunction and ventricular arrhythmias. During acute illness, transient EKG changes and echocardiographic changes can be seen. The most common EKG finding, seen almost universally among affected individuals in crisis, is marked QT prolongation (often >500 msec) and, rarely, Brugada type I pattern. Life-threatening recurrent ventricular tachycardia (VT) or torsade de pointes occurs primarily during times of acute illness and metabolic crises and can result in hemodynamic instability. Recalcitrant VT unresponsive to antiarrhythmic treatment leading to in-hospital death as well as out-of-hospital unexplained sudden death has been reported. Affected individuals can also demonstrate ventricular dilatation and episodic systolic dysfunction during crisis. Hypertrophic cardiomyopathy has been reported in one individual [Dines et al 2019].
Motor development. Baseline gait incoordination, progressively unsteady gait, difficulty with speech, or clumsiness is frequently reported in ambulatory individuals, even prior to the first episode of acute myoglobinuria.
Spasticity of lower extremities, hyperreflexia, and clonus have been reported. Dysarthria, myopathic facies, intermittent head tilt, and drooling can be observed in individuals between acute metabolic crises.
Intellectual disability of variable severity is observed in almost all individuals with TANGO2-related metabolic encephalopathy and arrhythmias. It is unclear whether this is an inherent feature of the disorder or a sequela of multiple metabolic crises experienced over time.
Seizures are observed outside the periods of crises in more than 75% of individuals. A variety of seizure types have been reported, including generalized myoclonic and atonic seizures. Seizures are generally responsive to anti-seizure medications in individuals with TANGO2-related metabolic encephalopathy and arrhythmias, although refractory epilepsy has been reported [Dines et al 2019].
Brain imaging abnormalities. Prominent lateral ventricles, with progressive brain atrophy on MRI examination, have been reported in several affected individuals. While some older individuals have normal brain imaging studies, generalized cerebral atrophy has been described in young infants with early disease presentation.
Endocrinopathy. Hypothyroidism has been reported in more than one third of individuals with TANGO2-related metabolic encephalopathy and arrhythmias. Elevated serum thyroid stimulating hormone (TSH) and low free T4 are seen, consistent with primary hypothyroidism. The affected individuals are typically diagnosed with hypothyroidism during acute crises with evaluation for muscle weakness or altered mental status. Adrenal insufficiency may also occur.
Ophthalmology. Intermittent exotropia has been observed in affected individuals. Rare individuals have been diagnosed with optic atrophy.
Hearing loss. Sensorineural hearing loss has been described in rare instances.
Gastrointestinal concerns. Dysphagia and episodic worsening of swallow function has been observed, increasing the risk of aspiration due to inability to manage secretions and liquids. Delayed gastric emptying with gastrointestinal dysmotility are additional concerns. Some affected individuals have required gastrostomy tube feedings [Dines et al 2019]. Acute pancreatitis in the setting of prolonged hospitalization has been seen in one individual.