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TANGO2-Related Metabolic Encephalopathy and Arrhythmias

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

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Initial Posting: .

Summary

Clinical characteristics.

Individuals with TANGO2-related metabolic encephalopathy and arrhythmias can present in acute metabolic crisis (hypoglycemia, hyperlactacidemia, 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. The majority of individuals 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, 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, urine alkalinization, and hemodialysis if indicated; continuous ECG monitoring with arrhythmia management by an electrophysiologist; monitor electrolytes and treat as necessary to maintain normal levels of potassium, magnesium, and glucose; levothyroxine for hypothyroidism.
  • Non-acute presentation: Standard treatment of global developmental delay/intellectual disability; ventricular arrhythmias have been treated with automated implantable cardioverter defibrillator and sympathectomy; levothyroxine is the treatment of choice for hypothyroidism; ketogenic diet and antiepileptics have been used for seizures.

Prevention of primary manifestations: Avoidance of triggers for acute metabolic crisis (e.g., prolonged fasting, dehydration). 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 tachyarrhythmias.

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.

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, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis 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, laboratory, and radiographic features:

  • Recurrent episodes of acute metabolic crises (hypoglycemia, hyperlactacidemia, mild hyperammonemia)
  • Profound muscle weakness
  • Recurrent rhabdomyolysis
  • Elevated creatine phosphokinase, aldolase, transaminases
  • Ataxia
  • Disorientation
  • Coma
  • Cardiac arrhythmias
  • 22q11.2 deletion syndrome and recurrent acute metabolic crises and rhabdomyolysis

Other important clinical features contributing to diagnosis:

  • Developmental delay
  • Intellectual disability
  • Regression of motor and cognitive skills
  • Poor coordination and unsteady gait
  • Dysarthria
  • Myopathic facies
  • Seizures
  • Brain MRI examination may show cerebral volume loss
  • Hypothyroidism

Establishing the Diagnosis

The diagnosis of TANGO2-related metabolic encephalopathy and arrhythmias is established in a proband with 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, hyperlactacidemia, 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:

A multigene panel that includesTANGO2 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 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 1Test MethodProportion of Pathogenic Variants 2 Detectable by This Method
TANGO2Sequence analysis 3~60% 4, 5
Gene-targeted deletion/duplication analysis 6~40% 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. 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 that may be used 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. The majority of individuals 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, hyperlactacidemia, 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 arrhythmias. During acute illness, transient electrocardiogram (ECG) changes can be seen, most commonly QT prolongation 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. Hypertrophic cardiomyopathy was reported in one individual.

Motor development. Baseline gait incoordination, progressively unsteady gait, or clumsiness is frequently reported in ambulatory individuals, even prior to the first episode of acute myoglobinuria.

Increased tone in the extremities, hyperreflexia, and clonus have been reported. Dysarthria, myopathic facies, 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. Generalized myoclonic and atonic seizures have been described. Seizures are generally responsive to antiepileptic medications in individuals with TANGO2-related metabolic encephalopathy and arrhythmias.

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.

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 reported, consistent with primary hypothyroidism. The affected individuals are typically diagnosed with hypothyroidism during acute crises with evaluation for muscle weakness or altered mental status.

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.

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 descent. Consanguineous families from Turkey and of Middle Eastern origin have been described 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 This 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 absence of severe recurrent rhabdomyolysis
Carnitine palmitoyltransferase II deficiencyCPT2ARMuscle weakness during attacks, myoglobinuria, cardiac arrhythmias, seizures, coma after infection or prolonged fastingLiver failure, hypoketotic hypoglycemia
Carnitine acylcarnitine translocase deficiency (OMIM 212138)SLC25A20ARVentricular tachycardia, cardiomyopathy, rhabdomyolysis, hyperammonemia, abnormal liver enzymes, elevated long chain acylcarnitinesTypically, elevated C16 & C18 (although C14:1 can also be elevated). Not seen: prolongation of QT interval
Very long-chain acyl-CoA dehydrogenase deficiencyACADVLARArrhythmias, rhabdomyolysis, intermittent hypoglycemiaHypoketotic hypoglycemia, hepatomegaly
Acute recurrent myoglobinuria (OMIM 268200)LPIN1ARMuscle weakness, acute recurrent rhabdomyolysis, myoglobinuriaNot seen: seizures & cardiac arrhythmias
Glycogen storage disease type V (and other defects of glucose/glycogen metabolism)PYGMARRecurrent rhabdomyolysis, myoglobinuriaMuscle cramps
Not seen: seizures & cardiac arrhythmias

MEA = metabolic encephalopathy and arrhythmias

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 following evaluations are recommended if they have not already been completed.

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
CardiovascularBaseline ECG, echocardiogram. Obtain serial ECGs & continuous monitoring for life-threatening arrhythmias incl ventricular tachycardia; ensure access to an ICU w/extracorporeal membrane oxygenation (ECMO) capability.
MetabolicUrine organic acids, acylcarnitine profile, plasma lactate, ammonia, blood glucose, CPK, urine myoglobin, and aldolase
EndocrinologicTSH, free T4 to evaluate for hypothyroidism
Critical careAssessment of rhabdomyolysis during metabolic crises, renal failure, and ventricular arrhythmias
Non-acuteDevelopmentNeurodevelopmental evaluation
NeurologicReferral to neurology for EEG if seizures are suspected and if spasticity is present
CardiovascularReferral to cardiac electrophysiologist. Baseline ECG, Holter, echocardiogram w/continuous intermittent monitoring. Consider implantable loop recorder.
MetabolicCPK
EndocrinologicTSH, free T4 to evaluate for hypothyroidism
OphthalmologicEvaluate for strabismus, optic atrophy
AudiologicEvaluate for hearing loss

CPK = creatine phosphokinase

ICU = intensive care unit

Treatment of Manifestations

Acute Presentation (Acute Metabolic Crisis)

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

Rhabdomyolysis

  • Aggressive intravenous hydration, often at one and a half to twice maintenance rate, to prevent acute kidney injury
  • Urine alkalinization to pH of 7.0 or greater using sodium bicarbonate-containing fluid, and forced diuresis using mannitol may be considered as adjunct therapies.
  • Hemodialysis may be indicated for severe fluid overload and electrolyte derangements.
    Note: Hemodialysis does not effectively remove circulating myoglobin and therefore is not indicated for the removal of excess serum myoglobin.

Cardiac arrhythmias. Cardiac rhythmic disturbances that occur in individuals with TANGO2-related metabolic encephalopathy and arrhythmias are predominantly ventricular tachyarrhythmias. The mechanism for arrhythmia developments are still being defined and thus acute treatment and long-term management remains unclear. Continuous ECG monitoring with arrhythmia management by an electrophysiologist is recommended. Antiarrhythmic treatment choice should be tailored toward arrhythmia presentation.

  • Recurrent ventricular tachycardia or torsade de pointes resulting in hemodynamic instability requires acute treatment. Direct current cardioversion is acutely effective but ventricular tachycardia / ventricular fibrillation (VT/VF) is often recurrent and recalcitrant, requiring treatment with multiple intravenous (IV) antiarrhythmic medications.
  • If Brugada changes are noted, avoid sodium channel blocking agents (e.g., procainamide, amiodarone).
  • If the QT interval is normal, IV sotalol, procainamide, or amiodarone can be considered.
  • In the setting of QT prolongation, treatment can begin with IV magnesium and an antiadrenergic beta-blocker such as IV esmolol. In addition, potassium (if hypokalemia is present) and IV lidocaine can be added. Persistent ventricular arrhythmias despite this approach are common. Alternatives that have been attempted include quinidine, isoproterenol, and continuous atrial or ventricular pacing. Death due to refractory arrhythmias has occurred despite treatment and thus extracorporeal membrane oxygenation (ECMO) should be considered for support through metabolic crisis.
  • Avoid medications that prolong the QT interval. However, for uncontrollable, hemodynamically unstable VT, one may consider additional antiarrhythmics such as sotalol and amiodarone, although back-up support (e.g., ECMO) needs to be available as these drugs may potentiate or worsen arrhythmias.

Other

  • Monitor electrolytes and treat as necessary to maintain normal levels of potassium, magnesium, and glucose.
  • Thyroid function should be evaluated. Levothyroxine is the treatment of choice for hypothyroidism.

Non-Acute Presentation

Neurodevelopment. Individuals with TANGO2-related metabolic encephalopathy and arrhythmias may benefit from physical therapy, occupational therapy, and speech therapy

Cardiac arrhythmias. Once acute crisis has resolved, individuals with documented ventricular arrhythmias have undergone placement of automated implantable cardioverter defibrillator (ICD), and sympathectomy. However, questions regarding definitive treatment remain; due to concerns for hypoglycemia, the appropriateness of long-term outpatient use of beta antiadrenergic blockade is unclear .

Hypothyroidism. Levothyroxine is the treatment of choice for hypothyroidism.

Seizures. Although seizures are generally responsive to antiepileptic medications in the affected individuals, ketogenic diet has been instituted in a few individuals with refractory seizures.

Prevention of Primary Manifestations

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

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.

Surveillance

Regular cardiology evaluation is appropriate for management of cardiac arrhythmias.

Monitoring TSH and free T4 annually is recommended.

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

Agents/Circumstances to Avoid

Avoid fasting and dehydration.

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 for access to 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, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face 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 (Heterozygote) 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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the TANGO2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis 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 decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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
TANGO222q11​.21Transport and Golgi organization protein 2 homologTANGO2TANGO2

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, DROSOPHILA, HOMOLOG OF; TANGO2
616878METABOLIC ENCEPHALOMYOPATHIC 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 non-coding 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 4). 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 4.

TANGO2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.4delTp.Cys2AlafsTer35NM_152906​.6
NP_690870​.3
c.418C>Tp.Arg140Ter
c.460G>Ap.Gly154Arg
c.605+1G>A--
Exons 3–9 (34 kb) del--
Exons 4–6 (9 kb) del--

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

Note on nomenclature: 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.

References

Literature Cited

  • Elsayed EF, Reilly RF. Rhabdomyolysis: a review, with emphasis on the pediatric population. Pediatr Nephrol. 2010;25:7–18. [PubMed: 19529963]
  • Kremer LS, Distelmaier F, Alhaddad B, Hempel M, Iuso A, Kupper C, Muhlhausen C, Kovacs-Nagy R, Satanovskij R, Graf E, Berutti R, Eckstein G, Durbin R, Sauer S, Hoffmann GF, Strom TM, Santer R, Meitinger T, Klopstock T, Prokisch H, Haack TB. Bi-allelic truncating mutations in tango2 cause infancy-onset recurrent metabolic crises with encephalocardiomyopathy. Am J Hum Genet. 2016;98:358–62. [PMC free article: PMC4746337] [PubMed: 26805782]
  • 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]

Chapter Notes

Revision History

  • 25 January 2018 (sw) Review posted live
  • 23 September 2017 (srl) Original submission
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