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TANGO2-Related Metabolic Encephalopathy and Arrhythmias

, MD, , MD, PhD, , MD, PhD, , MD, , MD, , MD, , MD, MS, and , PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: December 20, 2018.

Estimated reading time: 18 minutes

Summary

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 (EKG), continuous EKG 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. Anti-seizure medications 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.

Diagnosis

The diagnostic criteria for TANGO2-related metabolic encephalopathy and arrhythmias have not yet been established.

Suggestive Findings

TANGO2-related metabolic encephalopathy and arrhythmias should be suspected in a proband with the following clinical, supportive laboratory, and radiographic findings.

Clinical findings

  • Recurrent acute metabolic crises (See Supportive laboratory findings.)
  • Profound episodic muscle weakness
  • Ataxia
  • Disorientation
  • Coma
  • Intermittent dysphagia
  • Cardiac arrhythmias
  • Developmental delay
  • Intellectual disability
  • Regression of motor and cognitive skills
  • Poor coordination and unsteady gait
  • Dysarthria
  • Myopathic facies
  • Seizures

Supportive laboratory findings

  • Recurrent episodes of acute metabolic crises (hypoglycemia, elevated lactate, mild hyperammonemia)
  • Elevated creatine phosphokinase, aldolase, and transaminases
  • Recurrent rhabdomyolysis
  • Hypothyroidism
  • 22q11.2 deletion syndrome and recurrent acute metabolic crises and rhabdomyolysis

Brain MRI findings. Cerebral volume loss

Establishing the Diagnosis

The diagnosis of TANGO2-related metabolic encephalopathy and arrhythmias is established in a proband by the identification of biallelic pathogenic (or likely pathogenic) variants in TANGO2 (see Table 1).

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and comprehensive genomic testing (genomic sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of TANGO2-related metabolic encephalopathy and arrhythmias is broad, individuals with the distinctive findings of rhabdomyolysis and cardiac arrhythmias in the setting of metabolic derangements such as hypoglycemia, elevated lactate, and mild hyperammonemia are likely to be diagnosed using single-gene testing or a multigene panel (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders associated with developmental delay and/or intellectual disability are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing includes sequence analysis and gene-targeted deletion/duplication analysis of TANGO2.

Targeted analysis for pathogenic variants can be performed first in selected populations:

  • In individuals of Hispanic ancestry, targeted analysis for pathogenic variant p.Gly154Arg
  • In individuals of European ancestry, targeted deletion analysis for the ~34-kb deletion encompassing exons 3-9

A multigene panel that includes TANGO2 and other genes of interest (see Differential Diagnosis) may also be considered; however, given how recently TANGO2-related metabolic encephalopathy and arrhythmias were identified, many panels may not include this gene.

Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

A multigene panel for disorders associated with developmental delay and/or intellectual disability that includes TANGO2 and other genes of interest (see Differential Diagnosis) may be also considered; however, given how recently TANGO2-related metabolic encephalopathy and arrhythmias were identified, many panels may not include this gene.

Table 1.

Molecular Genetic Testing Used in TANGO2-Related Metabolic Encephalopathy and Arrhythmias

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
TANGO2 Sequence analysis 3~50% 4, 5
Gene-targeted deletion/duplication analysis 6~50% 4, 5
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Detection rate varies with the ethnicity of the individual being tested.

5.
6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

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.

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations exist.

Penetrance

To date, penetrance in those with TANGO2 pathogenic variants is 100%. There is known variable expressivity with this disorder.

Nomenclature

TANGO2-related metabolic encephalopathy and arrhythmias is referred to as "metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration" (MECRCN) in OMIM.

Prevalence

The minor allele frequency (MAF) of the c.460G>A (p.Gly154Arg) variant in the Hispanic/Latino population is estimated at 0.26%. The ~34-kb deletion encompassing exons 3-9 is observed with an approximate allele frequency of 0.11% in white Europeans. The majority of the reported individuals to date are of Hispanic or European ancestry. Consanguineous families from Turkey and of Middle Eastern origin with private pathogenic variants (both intragenic deletions and sequence variants) have been described.

Differential Diagnosis

Table 2.

Disorders to Consider in the Differential Diagnosis of TANGO2-Related Metabolic Encephalopathy and Arrhythmias

DisorderGene(s)MOIClinical Features of the Disorder
Overlapping w/TANGO2-Related MEADistinguishing from TANGO2-Related MEA
Mitochondrial disorder (see Mitochondrial Disorders Overview)ManyAR or maternal inheritanceLactic acidosis, myopathy, seizuresNot seen: ventricular tachycardia in the setting of acute metabolic crisis

Carnitine palmitoyltransferase II deficiency

CPT2 ARMuscle weakness during attacks, myoglobinuria, cardiac arrhythmias, seizures, coma after infection or prolonged fastingLiver failure, hypoketotic hypoglycemia
Carnitine-acylcarnitine translocase deficiency SLC25A20 ARVentricular tachycardia, cardiomyopathy, rhabdomyolysis, hyperammonemia, abnormal liver enzymes, ↑ long chain acylcarnitinesTypically, ↑ C16 & C18 (although C14:1 can also be ↑). Not seen: prolongation of QT interval

Very long-chain acyl-CoA dehydrogenase deficiency

ACADVL ARArrhythmias, rhabdomyolysis, intermittent hypoglycemiaHypoketotic hypoglycemia, hepatomegaly
Acute recurrent myoglobinuria (OMIM 268200) LPIN1 ARMuscle weakness, acute recurrent rhabdomyolysis, myoglobinuriaNot seen: seizures & cardiac arrhythmias
Glycogen storage disease type V & other defects of glucose/glycogen metabolism PYGM ARRecurrent rhabdomyolysis, myoglobinuriaMuscle cramps
Not seen: seizures & cardiac arrhythmias

↑ = elevated; AR = autosomal recessive; MEA = metabolic encephalopathy and arrhythmias; MOI = mode of inheritance

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TANGO2-related metabolic encephalopathy and arrhythmias, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluation of Individuals with TANGO2-Related Metabolic Encephalopathy and Arrhythmias

PresentationEvaluation
Acute
(acute metabolic crisis) 		NeurologicAssessment of ataxic gait, profound lower-extremity weakness
Cardiovascular
  • Baseline EKG. Serial EKGs & continuous monitoring for life-threatening ventricular arrhythmias is recommended.
  • Baseline echocardiogram to identify ventricular dysfunction
  • Ensure access to an ICU &, in case of recalcitrant arrhythmia, ECMO capability should be available.
MetabolicUrine organic acids, acylcarnitine profile, plasma lactate, ammonia, blood glucose, CPK, urine myoglobin, & aldolase
EndocrinologicTSH, free T4 to evaluate for hypothyroidism
Cortisol levels for adrenal insufficiency, if suspected
Critical careAssessment of rhabdomyolysis during metabolic crises, renal failure, & ventricular arrhythmias
Gastrointestinal
  • Monitor dysphagia & be aware of episodic worsening, which can ↑ risk of aspiration due to inability to manage secretions & liquids.
  • Lipase for pancreatitis, if suspected
Non-acute DevelopmentNeurodevelopmental eval
NeurologicReferral to neurologist for EEG if seizures are suspected & if spasticity is present
CardiovascularReferral to cardiac electrophysiologist. Baseline EKG, Holter, echocardiogram w/continuous intermittent monitoring. Consider implantable loop recorder.
MetabolicCPK
EndocrinologicTSH, free T4 to evaluate for hypothyroidism
OphthalmologicEval for strabismus, optic atrophy
AudiologicEval for hearing loss

CPK = creatine phosphokinase; ECMO = extracorporeal membrane oxygenation; ICU = intensive care unit

Treatment of Manifestations

Early management during episodes of metabolic crises is paramount; provide appropriate intravenous fluids with glucose to maintain normoglycemia and promote anabolism (see Table 4).

Table 4.

Acute Treatment (Acute Metabolic Crisis) in Individuals with TANGO2-Related Metabolic Encephalopathy and Arrhythmias

Manifestation/ConcernTreatmentConsideration/Other
Rhabdomyolysis Aggressive IV hydration, often at 1.5x – 2x maintenance rateTo prevent acute kidney injury
Urine alkalinization to pH of ≥7.0 using sodium bicarbonate-containing fluid, & forced diuresis using mannitol may be considered as adjunct therapies.Hemodialysis may be indicated for severe fluid overload & electrolyte derangements. 1
Cardiac arrhythmias 2, 3 General Antiarrhythmic treatment choice should be tailored to arrhythmia presentation.Continuous EKG monitoring w/arrhythmia management by an electrophysiologist is recommended.
Recurrent VT or TdPs resulting in hemodynamic instability:
  • Rhythm should be monitored closely.
  • Single PVCs are harbingers for VT. Those w/PVCs should be treated in ICU setting.
  • Direct current cardioversion is acutely effective but VT/VF is often recurrent & recalcitrant.
Treatment w/multiple IV antiarrhythmic medications, in addition to direct current cardioversion, may be required.
If Brugada changes are noted:Avoid sodium-channel-blocking agents (e.g., procainamide, amiodarone).
If QT interval is normal:IV sotalol, procainamide, or amiodarone can be considered.QTc is almost uniformly prolonged during crisis & thus these drugs may not be options for treatment.
In the setting of QT prolongation, monitor closely for any PVCs: 4, 5Maintain magnesium levels >2 mg/dL.Potassium (if hypokalemia is present) & IV lidocaine can be added.
  • If PVCs are seen but rare, replete w/bolus of magnesium or use an IV drip to consistently maintain magnesium level ≥2.2 mg/dL.
  • If high-grade ectopy incl frequent PVCs, couplets, or TdPs are seen (& cardiac function is normal), give isoproterenol (bolus if TdPs), or as continuous infusion if persistent high-grade ectopy or persistent TdPs.
If cardiac function is mild to moderately depressed, isoproterenol can be given but should be used w/caution for extended periods & function followed closely.
  • An alternative to isoproterenol, esp if there is cardiac dysfunction, can be atrial pacing. 6
  • Atrial pacing is preferred over ventricular pacing.
  • A transesophageal lead can be used in emergency or for short-term pacing until a temporary wire can be placed.
If systolic function is severely depressed, continue magnesium as first-line treatment.Death due to refractory arrhythmias has occurred despite treatment; thus ECMO should be considered for support through metabolic crises.
For uncontrollable, hemodynamically unstable VT:DC cardioversion, pacing, & consideration of ECMO supportBackup support (e.g., ECMO) needs to be available as these drugs may potentiate or worsen arrhythmias.
Electrolyte imbalance Treatment as necessary to maintain normal levels of potassium, magnesium, & glucoseElectrolyte levels should be monitored during acute episodes of metabolic crisis.
Hypothyroidism Levothyroxine treatmentThyroid function should be evaluated.
Adrenal insufficiency Cortisol replacement, typically hydrocortisone

ECMO = extracorporeal membrane oxygenation; ICU = intensive care unit; IV = intravenous; PVC = premature ventricular contraction; TdPs = torsade de pointes; VF = ventricular fibrillation; VT = ventricular tachycardia

1.

Hemodialysis does not effectively remove circulating myoglobin and therefore is not indicated for the removal of excess serum myoglobin.

2.

Cardiac rhythmic disturbances that occur in individuals with TANGO2-related metabolic encephalopathy are predominantly ventricular tachyarrhythmias.

3.

The mechanisms for arrhythmia development are still being defined and thus acute treatment and long-term management remain unclear.

4.

Avoid medications that prolong the QT interval.

5.

Persistent ventricular arrhythmias despite these approaches are common.

6.

This can be done with a temporary pacing wire for longer-term pacing.

Non-Acute Presentation

Table 5.

Routine Treatment in Individuals with TANGO2-Related Metabolic Encephalopathy and Arrhythmias

Manifestation/
Concern		TreatmentConsideration/Other
Cardiac arrhythmias 1 Persons w/documented ventricular arrhythmias typically undergo placement of an automated implantable cardioverter defibrillator.Due to concerns for hypoglycemia, the appropriateness of long-term outpatient use of beta antiadrenergic blockade is unclear.
Hypothyroidism LevothyroxineConsider referral to an endocrinologist.
Seizures Standard treatment w/anti-seizure medication
  • Consider referral to a neurologist.
  • Ketogenic diet has been instituted in a few affected persons w/refractory seizures. Acute metabolic crises after initiation of ketogenic diet have been reported.
Neurodevelopmental delays Supportive therapies (e.g., PT, OT, speech therapy)

OT = occupational therapy; PT = physical therapy

1.

Questions regarding definitive treatment remain.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.

Ages 5-21 years

  • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
  • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.

Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.

In the US:

  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications.
  • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, Botox®, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy – typically from an occupational or speech therapist – is recommended for affected individuals who have difficulty feeding.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties.

Prevention of Primary Manifestations

Avoid triggers for acute metabolic crisis (e.g., prolonged fasting, dehydration, ketogenic diet).

Extreme vigilance for signs and symptoms of dehydration during intercurrent illnesses is indicated. 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

Adequate hydration and alkalinization of the urine during an attack of rhabdomyolysis and myoglobinuria is recommended to prevent renal failure.

An "emergency" plan should be in place for both families and physicians to initiate appropriate steps to suppress acute catabolism and promote hydration in order to minimize the risk of life-threatening rhabdomyolysis and cardiac tachyarrhythmias in this disorder. Prior to determining the rate and amount of fluid administration, an echocardiogram to assess cardiac function should be obtained.

Surveillance

Regular cardiology evaluation is appropriate for management of cardiac arrhythmias.

Annual monitoring of TSH and free T4 is recommended.

Follow up with a neurologist to manage epilepsy may be required.

Agents/Circumstances to Avoid

Avoid fasting, dehydration, and ketogenic diet.

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 of the TANGO2 pathogenic variants in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Due to suspicion of mitochondrial dysfunction prior to diagnosis in several individuals, many have been treated with coenzyme Q10, riboflavin, and levocarnitine. The efficacy of these supplements in preventing metabolic crises remains unclear at present.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

TANGO2-related metabolic encephalopathy and arrhythmias is inherited in an autosomal recessive manner.

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one TANGO2 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with TANGO2-related metabolic encephalopathy and arrhythmias are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a TANGO2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the TANGO2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the TANGO2 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

TANGO2-Related Metabolic Encephalopathy and Arrhythmias: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
TANGO2 22q11​.21 Transport and Golgi organization protein 2 homolog TANGO2 TANGO2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for TANGO2-Related Metabolic Encephalopathy and Arrhythmias (View All in OMIM)

616830TRANSPORT AND GOLGI ORGANIZATION 2 HOMOLOG; TANGO2
616878METABOLIC CRISES, RECURRENT, WITH RHABDOMYOLYSIS, CARDIAC ARRHYTHMIAS, AND NEURODEGENERATION; MECRCN

Gene structure. TANGO2 is approximately 50 kb in size and has multiple different isoforms as a result of alternative splicing. Isoform a (NM_152906.6) consists of one noncoding and eight coding exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The pathogenic variants reported to date include nonsense, missense, and splice junction variants and small and large deletions [Kremer et al 2016, Lalani et al 2016] (see Table 6). Of the recurrent variants, the c.460G>A (p.Gly154Arg) allele is enriched in the Hispanic-Latino population and the exon 3-9 deletion has been identified in individuals of European origin.

Table 6.

TANGO2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.4delTp.Cys2AlafsTer35 NM_152906​.6
NP_690870​.3
c.418C>Tp.Arg140Ter
c.460G>Ap.Gly154Arg
c.605+1G>A-- NM_152906​.6
Exons 3–9 (34 kb) del--
Exons 4–6 (9 kb) del--

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. TANGO2 belongs to the transport and Golgi organization family, whose members are predicted to play roles in secretory protein loading in the endoplasmic reticulum. Depletion of this gene in Drosophila S2 cells causes fusion of the Golgi with the ER. In mouse tissue culture cells, this protein co-localizes with a mitochondrial-targeted mCherry protein and displays very low levels of co-localization with Golgi and peroxisomes (provided by RefSeq; 4/2016).

Abnormal gene product. TANGO2-related metabolic encephalopathy and arrhythmias is inherited in an autosomal recessive manner. Biallelic pathogenic variants resulting in complete or partial loss of protein function is likely the underlying basis of this disorder.

Chapter Notes

Revision History

  • 20 December 2018 (ma) Comprehensive update posted live
  • 25 January 2018 (sw) Review posted live
  • 23 September 2017 (srl) Original submission

References

Literature Cited

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  • Lalani SR, Liu P, Rosenfeld JA, Watkin LB, Chiang T, Leduc MS, Zhu W, Ding Y, Pan S, Vetrini F, Miyake CY, Shinawi M, Gambin T, Eldomery MK, Akdemir ZH, Emrick L, Wilnai Y, Schelley S, Koenig MK, Memon N, Farach LS, Coe BP, Azamian M, Hernandez P, Zapata G, Jhangiani SN, Muzny DM, Lotze T, Clark G, Wilfong A, Northrup H, Adesina A, Bacino CA, Scaglia F, Bonnen PE, Crosson J, Duis J, Maegawa GH, Coman D, Inwood A, McGill J, Boerwinkle E, Graham B, Beaudet A, Eng CM, Hanchard NA, Xia F, Orange JS, Gibbs RA, Lupski JR, Yang Y. Recurrent muscle weakness with rhabdomyolysis, metabolic crises, and cardiac arrhythmia due to bi-allelic tango2 mutations. Am J Hum Genet. 2016;98:347–57. [PMC free article: PMC4746334] [PubMed: 26805781]
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