recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome

Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, often called TANGO2 deficiency disorder, is an autosomal recessive condition that disrupts energy production in many tissues, particularly the brain, muscles, and heart. Pathogenic variants in the TANGO2 gene impair a protein involved in cellular transport and metabolism, setting the stage for episodic metabolic crises and progressive neurological challenges. Symptoms usually begin in early childhood, though age at first crisis can vary. Fewer than one in a million people worldwide are thought to be affected, so most clinicians will never encounter a case. Severity and symptoms vary widely between individuals, making early recognition and coordinated care essential.

The hallmark of TANGO2 deficiency is recurrent metabolic crises that can be triggered by infections, fasting, or other stressors. During a crisis, children may develop profound muscle weakness, ataxia, seizures, and life-threatening cardiac arrhythmias. Laboratory findings often reveal metabolic acidosis, lactic acidosis, hypoglycemia, elevated creatine kinase, and myoglobinuria consistent with rhabdomyolysis. Outside of acute episodes, developmental and intellectual disabilities are universal; many children have global developmental delay in infancy, followed by progressive neurological decline that can include loss of expressive language, dysarthria, brisk reflexes, spasticity, and ataxia. Cognitive and motor skills may plateau or regress after each crisis, reflecting ongoing neurological injury. Less consistently, hyperammonemia and elevated medium-chain acylcarnitines are reported. Not all individuals experience all features, and the frequency and severity of crises differ considerably, so each child’s clinical course is unique.

TANGO2 deficiency results from inheriting two non-working copies of the TANGO2 gene, one from each parent, in an autosomal recessive pattern. Parents who each carry a single variant are usually healthy but have a 25 percent chance with each pregnancy of having a child who is affected. The condition is more common when parents share a common ancestor because they are more likely to carry the same rare variant. Genetic counseling can clarify carrier status for extended family members and support informed family planning.

Currently, management focuses on supportive care and symptom control because no disease-specific therapies are yet available. During acute crises, rapid treatment of hypoglycemia, metabolic acidosis, and rhabdomyolysis in an intensive care setting can be life-saving. Long-term management includes regular monitoring of cardiac rhythm, liver function, and muscle enzyme levels, as well as prompt treatment of infections that could precipitate a crisis. Physical, occupational, and speech therapies help children reach their developmental potential, and antiseizure medications are prescribed when needed. Because multiple organ systems are at risk, multidisciplinary care coordinated by a metabolic specialist, neurologist, and cardiologist is recommended. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious.

Outcomes depend on the frequency and severity of metabolic crises, the timeliness of emergency care, and access to specialists familiar with the disorder. Some children experience only a few crises and maintain stable neurologic function, while others have repeated episodes that lead to progressive impairments in movement, speech, and cognition. Serious cardiac arrhythmias or severe rhabdomyolysis can be life-threatening, but early recognition and aggressive treatment have improved survival for many individuals. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with metabolic specialists and patient support organizations to stay informed about emerging management strategies and research opportunities.

Clinical trials are underway exploring new treatment approaches for TANGO2 deficiency. Individuals interested in participating can search ClinicalTrials.gov or consult their care team about eligibility.