Tango2-Related Metabolic Encephalopathy And Arrhythmias
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 (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.
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 variants in TANGO2 (see Table 1).
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 at the most reasonable cost 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 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| TANGO2 | Sequence analysis 3 | ~50% 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | ~50% 4, 5 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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.
Kremer et al [2016], Lalani et al [2016], Dines et al [2019]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include 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 ECG changes and echocardiographic changes can be seen. The most common ECG 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 dilation 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 antiepileptic 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
| Disorder | Gene(s) | MOI | Clinical Features of the Disorder | |
|---|---|---|---|---|
| Overlapping w/TANGO2-Related MEA | Distinguishing from TANGO2-Related MEA | |||
| Mitochondrial disorder (see Mitochondrial Disorders Overview) | Many | AR or maternal inheritance | Lactic acidosis, myopathy, seizures | Not seen: ventricular tachycardia in the setting of acute metabolic crisis |
| Carnitine palmitoyltransferase II deficiency | CPT2 | AR | Muscle weakness during attacks, myoglobinuria, cardiac arrhythmias, seizures, coma after infection or prolonged fasting | Liver failure, hypoketotic hypoglycemia |
| Carnitine acylcarnitine translocase deficiency (OMIM 212138) | SLC25A20 | AR | Ventricular tachycardia, cardiomyopathy, rhabdomyolysis, hyperammonemia, abnormal liver enzymes, ↑ long chain acylcarnitines | Typically, ↑ C16 & C18 (although C14:1 can also be ↑). Not seen: prolongation of QT interval |
| Very long-chain acyl-CoA dehydrogenase deficiency | ACADVL | AR | Arrhythmias, rhabdomyolysis, intermittent hypoglycemia | Hypoketotic hypoglycemia, hepatomegaly |
| Acute recurrent myoglobinuria (OMIM 268200) | LPIN1 | AR | Muscle weakness, acute recurrent rhabdomyolysis, myoglobinuria | Not seen: seizures & cardiac arrhythmias |
| Glycogen storage disease type V & other defects of glucose/glycogen metabolism | PYGM | AR | Recurrent rhabdomyolysis, myoglobinuria | Muscle 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
| Presentation | Evaluation | |
|---|---|---|
| Acute (acute metabolic crisis) | Neurologic | Assessment of ataxic gait, profound lower-extremity weakness |
| Cardiovascular |
| |
| Metabolic | Urine organic acids, acylcarnitine profile, plasma lactate, ammonia, blood glucose, CPK, urine myoglobin, & aldolase | |
| Endocrinologic | TSH, free T4 to evaluate for hypothyroidism | |
| Cortisol levels for adrenal insufficiency, if suspected | ||
| Critical care | Assessment of rhabdomyolysis during metabolic crises, renal failure, & ventricular arrhythmias | |
| Gastrointestinal |
| |
| Non-acute | Development | Neurodevelopmental eval |
| Neurologic | Referral to neurologist for EEG if seizures are suspected & if spasticity is present | |
| Cardiovascular | Referral to cardiac electrophysiologist. Baseline ECG, Holter, echocardiogram w/continuous intermittent monitoring. Consider implantable loop recorder. | |
| Metabolic | CPK | |
| Endocrinologic | TSH, free T4 to evaluate for hypothyroidism | |
| Ophthalmologic | Eval for strabismus, optic atrophy | |
| Audiologic | Eval 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/Concern | Treatment | Consideration/Other | |
|---|---|---|---|
| Rhabdomyolysis | Aggressive IV hydration, often at 1.5x – 2x maintenance rate | To 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 ECG monitoring w/arrhythmia management by an electrophysiologist is recommended. |
| Recurrent VT or TdPs resulting in hemodynamic instability: |
| 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, 5 | Maintain magnesium levels >2 mg/dL. | Potassium (if hypokalemia is present) & IV lidocaine can be added. | |
| |||
| If cardiac function is mild to moderately depressed, isoproterenol can be given but should be used w/caution for extended periods & function followed closely. |
| ||
| 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 support | Backup 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, & glucose | Electrolyte levels should be monitored during acute episodes of metabolic crisis. | |
| Hypothyroidism | Levothyroxine treatment | Thyroid 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 | Treatment | Consideration/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 | Levothyroxine | Consider referral to an endocrinologist. |
| Seizures | Standard treatment w/antiepileptic medication |
|