TANGO2 Deficiency

Clinical characteristics: TANGO2 deficiency is characterized by developmental delay, intellectual disability, gait incoordination, speech difficulties, seizures, and hypothyroidism. Most individuals have TANGO2 spells, non-life-threatening paroxysmal worsening of baseline symptoms, including sudden onset of hypotonia, ataxia with loss of balance, head and body tilt, increased dysarthria, drooling, lethargy, and disorientation. In addition, life-threatening acute metabolic crises can occur, including rhabdomyolysis with elevated creatine phosphokinase and liver transaminases, hypoglycemia, prolonged QTc on EKG, ventricular arrhythmias, and/or cardiomyopathy.

Diagnosis/testing: The diagnosis of TANGO2 deficiency is established in a proband with biallelic pathogenic variants in TANGO2 identified by molecular genetic testing.

Management: Targeted therapy: Daily supplementation with a multivitamin including all eight B vitamins or a B-complex vitamin at the minimum recommended daily allowance for age.

Supportive care: Treatment of acute metabolic crises: admission to ICU for individuals who are ill appearing with elevated CK, hypoglycemia, or have prolonged QTc; intravenous (IV) hydration with glucose-containing fluids for hypoglycemia; echocardiogram to assess cardiac function with adjustment of IV fluids to prevent pulmonary edema; potassium supplements as needed; supplemental magnesium to maintain magnesium >2.2 mg/dL to minimize arrhythmias; nutrition support with vitamin supplementation including all eight B vitamins; monitor creatine phosphokinase; EKG to monitor QTc and for development of type 1 Brugada pattern; continuous rhythm monitoring for arrhythmias including premature ventricular contractions, ventricular tachycardia, and torsade de pointes; extracorporeal membrane oxygenation only as needed; levothyroxine as needed for hypothyroidism. Due to the recalcitrant nature of ventricular arrhythmias, management by an electrophysiologist is recommended.

Treatment of non-acute presentation: developmental and educational support; anti-seizure medication for seizures; levothyroxine for hypothyroidism; feeding therapy and/or gastrostomy tube feeding as needed; standard treatments for constipation.

Surveillance: Developmental assessment at each visit; assess vitamin B complex intake at each visit; measure vitamin B₆ serum level as needed to prevent toxicity; EKG, Holter, and echocardiogram with frequency based on history of metabolic and cardiac crises; neurologic follow up to monitor those with seizures; annual TSH and free T4 for hypothyroidism; ophthalmologic follow up as recommended by ophthalmologist; gastrointestinal and nutrition assessments as needed; assessment of hearing loss as needed; assess family and social work needs at each visit.

Agents/circumstances to avoid: Triggers for TANGO2 spells and acute metabolic crises including fasting, dehydration, overexertion, exposure to excessive heat, ketogenic diet, and infections.

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 B-complex vitamins, supportive treatment, and avoidance of triggers for TANGO2 spells and acute metabolic crises.

Genetic counseling: TANGO2 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TANGO2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the TANGO2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.