Clinical characteristics.

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

Diagnosis/testing.

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

Management.

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

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

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

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

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

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing to allow prompt initiation of B-complex vitamins, supportive treatment, and avoidance of triggers for TANGO2 spells and acute metabolic crises.

Genetic counseling.

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

Suggestive Findings

TANGO2 deficiency should be suspected in a proband with the following clinical, laboratory, EKG, imaging, and family history findings.

Clinical findings

• Developmental delay (including motor and speech delays)
• Spasticity
• Poor coordination and unsteady gait
• Speech difficulties (dysarthria, slurred or nasal speech)
• Intellectual disability
• Paroxysmal neurologic episodes (TANGO2 spells). Sudden onset of clumsy gait, falling, head tilt, body tilt, dystonia, abnormal posturing with hypertonicity, dysarthria, drooling, extreme fatigue, and disorientation
• Acute metabolic crises. Rhabdomyolysis with muscle weakness, pain, or dark urine; ataxia, disorientation or coma, and developmental regression
• Seizures
• Exotropia
• Constipation
• TANGO2 spells or acute metabolic crisis in an individual with 22q11.2 deletion syndrome

Laboratory findings

• During acute metabolic crises, elevated creatine phosphokinase, alanine transaminase, and aspartate transaminase, hypoglycemia, mild lactic acidosis, and mild hyperammonemia
• Hypothyroidism with elevated thyroid-stimulating hormone and low thyroxine

EKG findings. During acute metabolic crisis, QTc prolongation with or without type 1 Brugada pattern. Note: EKG will normalize when crisis resolves.

Imaging findings on brain MRI. Diffuse ventriculomegaly, cerebral volume loss, and diminished white matter have been observed.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of TANGO2 deficiency is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in TANGO2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of biallelic TANGO2 variants of uncertain significance (or of one known TANGO2 pathogenic variant and one TANGO2 variant of uncertain significance) does not establish or rule out the diagnosis.

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

Gene-targeted testing requires that the clinician determine which gene is likely involved, whereas genomic testing does not. Individuals with the distinctive findings of rhabdomyolysis, cardiac arrhythmias, and/or TANGO2 spells in the setting of neurodevelopmental delay are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other neurodevelopmental disorders are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

TANGO2 deficiency is characterized by developmental delay, intellectual disability, TANGO2 spells, acute metabolic crises, and risk of cardiac crisis. Additional features can include seizures, hypothyroidism, exotropia, and constipation. To date, more than 100 individuals have been identified with biallelic pathogenic variants in TANGO2 [Kremer et al 2016, Lalani et al 2016, Dines et al 2019, Powell et al 2021, Schymick et al 2022, Miyake et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Motor delays are generally seen by age one to two years. The median age of walking is about 16 months. Regression of developmental milestones such as walking is common after a metabolic crisis. Some individuals never achieve ambulation after an early metabolic crisis.

Spasticity of lower extremities, hyperreflexia, and clonus are also frequently seen. Poor coordination, progressively unsteady gait, and clumsiness are frequently reported in ambulatory individuals, even prior to the first episode of rhabdomyolysis [Powell et al 2021, Schymick et al 2022, Miyake et al 2023].

Speech delay/difficulties. Speech delay is common. There is variability in expressive language delay, with some individuals able to speak easily and others being nonverbal. Individuals who have had significant developmental regression secondary to metabolic crises can have severe language impairment.

Almost all individuals with TANGO2 deficiency have speech difficulties, including dysarthria and slurred or nasal speech.

Intellectual disability of variable severity is observed in almost all individuals. Most individuals have mild-to-moderate intellectual disability, although some have severe cognitive impairment.

TANGO2 spells (non-life-threatening paroxysmal neurologic episodes) occur in most individuals with TANGO2 deficiency. Onset is typically between ages one and three years. TANGO2 spells can be recognized by the sudden onset of hypotonia with loss of muscle control (e.g., clumsy gait, sudden falling while walking or sitting, inability to upright themselves after falling), head tilt (either to the side or back), body tilt, dystonia, abnormal posturing with hypertonicity, increased dysarthria, drooling, extreme fatigue, and disorientation. The episodes usually last for minutes to hours but can last for days and tend to resolve with rest. Episodes occur most often in the morning upon awakening, after exertion, and with decreased oral intake, illness, and exposure to warmer weather. TANGO2 spells can occur throughout life but are more common in toddlers and may increase during puberty. TANGO2 spells are not associated with metabolic derangements such as elevated creatine phosphokinase (CK), alanine transaminase (ALT), and aspartate transaminase (AST) and/or hypoglycemia; EKG changes do not occur during TANGO2 spells [Miyake et al 2023].

Acute metabolic crises. The acute presentation varies from significant muscle weakness and/or pain, ataxia, and disorientation to a comatose state. Acute metabolic crises are frequently precipitated by reduced oral intake or fasting, dehydration, or febrile illness. Cryptic infections such as a tooth abscess can trigger an acute metabolic crisis. In a natural history study of 73 individuals with TANGO2 deficiency, approximately two thirds of individuals presented in acute metabolic crisis, with the first episode occurring at a median age of three years (range: age five months to 20 years) [Miyake et al 2022].

Individuals present with rhabdomyolysis with elevated CK, ALT, and AST and may have dark urine due to myoglobinuria. Complications from rhabdomyolysis are not common, even though CK levels can be significantly elevated in some individuals (>200,000 U/L). Severe hypoglycemia can be present in addition to mild hyperammonemia, elevated aldolase, elevated troponin, elevated lactate, and evidence of ketoacidosis and lactic acidosis on urine organic acids. Although an acylcarnitine profile during an acute metabolic crisis may show elevated C14:1, C14:2, and C16:1, no consistent acylcarnitine abnormalities have been identified in large studies [Bérat et al 2021, Schymick et al 2022, Miyake et al 2023].

While cardiac workup including EKG is normal at baseline, during an acute metabolic crisis, EKG changes are noted. The most common EKG finding is prolonged QTc that is often markedly prolonged (>500 msec). Transient type 1 Brugada pattern can also be seen in 33% of individuals.

B-complex vitamins or multivitamins may prevent metabolic crises in individuals with TANGO2 deficiency [Miyake et al 2023].

Cardiac crisis is defined by the development of ventricular arrhythmias, cardiomyopathy (heart failure), or cardiac arrest during an acute metabolic crisis. Cardiac crisis only occurs during metabolic crisis, affecting 65% of all individuals with acute metabolic crises in the natural history study [Miyake et al 2023].

During cardiac crisis, life-threatening recalcitrant ventricular tachycardia (VT) or torsade de pointes can occur, leading to hemodynamic instability and cardiac arrest. These events can occur when an individual is acutely ill but also in those who appear stable with improving CK levels. The presence of marked QTc prolongation, type I Brugada pattern, and ventricular ectopy are concerning, as they precede VT (QTc >500 msec is associated with an increased risk of torsade de pointes). VT is difficult to control, often unresponsive to typical anti-arrhythmic therapy, and once VT occurs it may result in cardiac arrest and death. Cardiac arrest has been reported in almost 75% of individuals in cardiac crisis.

Ventricular arrhythmias and unexplained cardiovascular collapse during crises are the leading causes of mortality. Unexplained sudden death during sleep not associated with metabolic crisis has also been reported [Hoebeke et al 2021, Miyake et al 2022].

Affected individuals can also demonstrate echocardiographic changes during metabolic crisis, including ventricular dilatation and heart failure (systolic dysfunction). About 70% of those in cardiac crisis can develop heart failure. Systolic dysfunction can develop rapidly, and systolic function should be monitored closely during crisis. Both arrhythmias and cardiomyopathy are reversible, and full recovery is possible if the crisis resolves [Miyake et al 2022]. Heart failure (systolic dysfunction) has not yet been reported in individuals who are not experiencing a cardiac crisis; however, heart transplantation has been performed in one individual, and long-term cardiac follow up among all affected individuals is lacking [Meisner et al 2020].

Supraventricular tachycardias and heart block have also been rarely reported.

Seizures are observed outside the periods of crisis in approximately 40%-50% of individuals [Schymick et al 2022, Miyake et al 2023]. A variety of seizure types have been reported, including myoclonic and tonic-clonic events. Other seizure types included generalized tonic, atonic, absence, and focal motor seizures. Infantile spasms have been reported in a few individuals. Seizures are generally responsive to anti-seizure medications, although about one third of affected individuals have drug-resistant epilepsy [Dines et al 2019, Miyake et al 2023].

Brain imaging abnormalities. Prominent lateral ventricles and 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 even in young infants with early disease presentation. Microcephaly has been seen in about 20% of affected individuals.

Hypothyroidism. Elevated serum thyroid-stimulating hormone (TSH) with low or low-normal free thyroxine are seen, consistent with primary hypothyroidism. Affected individuals are typically diagnosed with hypothyroidism during acute crises with evaluation for muscle weakness or altered mental status. Hypothyroidism has also been identified in individuals without a history of metabolic crisis.

Ophthalmologic manifestations. Intermittent exotropia has been observed in affected individuals and appears to worsen with fatigue, illness, TANGO2 spells, and metabolic crises. Rarely, optic atrophy has been identified.

Gastrointestinal concerns. Constipation is common and affects approximately 50% of individuals. TANGO2 spell manifestations are more common when constipation is more severe. Dysphagia and episodic worsening of swallow function have been observed during TANGO2 spells and metabolic crises, increasing the risk of aspiration due to inability to manage secretions and liquids. Delayed gastric emptying with gastrointestinal dysmotility have also been reported during crises. Some individuals require gastrostomy tube feeding, particularly if maintaining feedings is difficult during times of illness and even at baseline [Dines et al 2019, Miyake et al 2022].

Hearing loss. Sensorineural hearing loss has been described in rare instances.

Genotype-Phenotype Correlations

To date, no clear genotype-phenotype correlations have been reported.

Nomenclature

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

Prevalence

The worldwide prevalence of TANGO2 deficiency is estimated to be 1:1,000,000, likely affecting more than 8,000 individuals.

TANGO2 pathogenic variants that are reported to be more common include a ~34-kb deletion encompassing exons 3-9; this is the most common allele observed, with an approximate allele frequency of 0.14% in the non-Finnish/European population. The minor allele frequency of another recurrent variant, c.460G>A (p.Gly154Arg), is reported to be 0.07% in the Latino/admixed American population in gnomAD.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TANGO2 deficiency in acute metabolic crisis, the evaluations summarized in Table 4a are recommended.

To establish the extent of disease and needs in all other individuals diagnosed with TANGO2 deficiency, the evaluations summarized in Table 4b (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for TANGO2 deficiency.

Surveillance

Agents/Circumstances to Avoid

Avoid triggers for TANGO2 spells and acute metabolic crisis (e.g., fasting, dehydration, overexertion, exposure to excessive heat, ketogenic diet, infections).

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing for the familial TANGO2 pathogenic variants in order to identify as early as possible those who would benefit from prompt initiation of B-complex vitamin supplementation and recommended surveillance.

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. An international natural history study on TANGO2 deficiency is recruiting (NCT05374616).

Vitamin dosing and which specific vitamins help alleviate manifestations of TANGO2 deficiency are still under investigation.

Mode of Inheritance

TANGO2 deficiency is inherited in an autosomal recessive manner.

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a TANGO2 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a TANGO2 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. (This is frequently observed in TANGO2 deficiency.)
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and to date, are not known to be at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a TANGO2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Significant differences in clinical manifestations have been observed among sibs with the same biallelic TANGO2 pathogenic variants [Schymick et al 2022]. For the most part, younger sibs appear to be less affected; this may be related to earlier recognition of the disease and possibly early initiation of B-complex vitamin supplementation.
• Heterozygotes (carriers) are asymptomatic and to date, are not known to be at risk of developing the disorder.

Offspring of a proband. To date, individuals with TANGO2 deficiency 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 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 carriers or are at risk of being carriers.

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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TANGO2 encodes for transport and Golgi organization protein 2 homolog (TANGO2) protein. The function of TANGO2 is not known. However, emerging studies suggest that TANGO2 deficiency likely causes perturbation in lipid biosynthesis and metabolism [Asadi et al 2023]. TANGO2 deficiency appears to cause intrinsic metabolic defects that are exacerbated under stress conditions. Data also suggest that TANGO2 is required for ER-Golgi trafficking in cells [Milev et al 2021]. In the absence of TANGO2, there is a striking delay in transport of cargo proteins to the Golgi [Milev et al 2021].

Mechanism of disease causation. Loss of function

Author Notes

Author websites:

• Seema R Lalani, MD
• Brett H Graham, MD, PhD
• Lindsay Burrage, MD, PhD
• Fernando Scaglia, MD
• Claudia Soler-Alfonso, MD
• Alfonso Hoyos-Martinez, MD
• Brandy Rawls-Castillo, MS, RD, LD
• Kimberly Houck, MD
• Kevin Glinton, MD, PhD
• Christina Y Miyake, MD, MS

Acknowledgments

We thank the TANGO2 Research Foundation for their continued support.

Author History

Lindsay Burrage, MD, PhD (2018-present)
Kevin Glinton, MD, PhD (2023-present)
Brett Graham, MD, PhD (2018-present)
Kimberly Houck, MD (2023-present)
Alfonso Hoyos-Martinez, MD (2023-present)
Seema R Lalani, MD (2018-present)
Yi-Chen Lai, MD; Baylor College of Medicine (2018-2023)
Christina Y Miyake, MD, MS (2018-present)
Brandy Rawls-Castillo, MS, RD, LD (2023-present)
Fernando Scaglia, MD (2018-present)
Claudia Soler-Alfonso, MD (2018-present)
Yaping Yang, PhD (2018-present)

Revision History

• 9 March 2023 (sw) Comprehensive update posted live
• 20 December 2018 (ma) Comprehensive update posted live
• 25 January 2018 (sw) Review posted live
• 23 September 2017 (srl) Original submission

Literature Cited

• Asadi P, Milev MP, Saint-Dic D, Gamberi C, Sacher M. Vitamin B5, a coenzyme A precursor, rescues TANGO2 deficiency disease-associated defects in Drosophila and human cells. J Inherit Metab Dis. 2023;46:358-68. [PMC free article: PMC10464931] [PubMed: 36502486]
• Bérat CM, Montealegre S, Wiedemann A, Nuzum MLC, Blondel A, Debruge H, Cano A, Chabrol B, Hoebeke C, Polak M, Stoupa A, Feillet F, Torre S, Boddaert N, Bruel H, Barth M, Damaj L, Abi-Wardé MT, Afenjar A, Benoist JF, Madrange M, Caccavelli L, Renard P, Hubas A, Nusbaum P, Pontoizeau C, Gobin S, van Endert P, Ottolenghi C, Maltret A, de Lonlay P. Clinical and biological characterization of 20 patients with TANGO2 deficiency indicates novel triggers of metabolic crises and no primary energetic defect. J Inherit Metab Dis. 2021;44:415-25. [PubMed: 32929747]
• Dines JN, Golden-Grant K, LaCroix A, Muir AM, Cintrón DL, McWalter K, Cho MT, Sun A, Merritt JL, Thies J, Niyazov D, Burton B, Kim K, Fleming L, Westman R, Karachunski P, Dalton J, Basinger A, Ficicioglu C, Helbig I, Pendziwiat M, Muhle H, Helbig KL, Caliebe A, Santer R, Becker K, Suchy S, Douglas G, Millan F, Begtrup A, Monaghan KG, Mefford HC. TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants. Genet Med. 2019;21:601-7. [PMC free article: PMC6752277] [PubMed: 30245509]
• Hoebeke C, Cano A, De Lonlay P, Chabrol B. Clinical phenotype associated with TANGO2 gene mutation. Arch Pediatr. 2021;28:80-6. [PubMed: 33342685]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
• 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]
• Meisner JK, Ames EG, Ahmad A, Si MS, Schumacher KR, Lim HM, Rabah R, Peng DM. Heart transplantation for TANGO2-related metabolic encephalopathy and arrhythmia syndrome-associated cardiomyopathy. Circ Genom Precis Med. 2020;13:e002928. [PubMed: 32527145]
• Milev MP, Saint-Dic D, Zardoui K, Klopstock T, Law C, Distelmaier F, Sacher M. The phenotype associated with variants in TANGO2 may be explained by a dual role of the protein in ER-to-Golgi transport and at the mitochondria. J Inherit Metab Dis. 2021;44:426-37. [PubMed: 32909282]
• Miyake CY, Lay EJ, Beach CM, Ceresnak SR, Delauz CM, Howard TS, Janson CM, Jardine K, Kannankeril PJ, Kava M, Kim JJ, Liberman L, Macicek SL, Pham TD, Robertson T, Valdes SO, Webster G, Stephens SB, Milewicz DM, Azamian M, Ehsan SA, Houck KM, Soler-Alfonso C, Glinton KE, Tosur M, Li N, Xu W, Lalani SR, Zhang L. Cardiac crises: cardiac arrhythmias and cardiomyopathy during TANGO2 deficiency related metabolic crises. Heart Rhythm. 2022;19:1673-81. [PMC free article: PMC10642301] [PubMed: 35568137]
• Miyake CY, Lay EJ, Soler-Alfonso C, Glinton KE, Houck K, Tosur M, Moran NE, Stephens SB, Scaglia F, Howard TS, Kim JJ, Pham TD, Valdes SO, Li N, Murali C, Zhang L, Kava M, Yim D, Beach C, Webster G, Liberman L, Janson C, Kannankeril PJ, Baxter S, Singer-Berk M, Wood J, Mackenzie S, Sacher M, Gonzalez L, Pedroza C, Morris SA, Ehsan SA, Azamian M, Lalani SR. Natural history of TANGO2 deficiency disorder: baseline assessment of 73 patients. Genet Med. 2023;25:100352. [PMC free article: PMC10306319] [PubMed: 36473599]
• Powell AR, Ames EG, Knierbein EN, Hannibal MC, Mackenzie SJ. Symptom prevalence and genotype-phenotype correlations in patients with TANGO2-related metabolic encephalopathy and arrhythmias (TRMEA). Pediatr Neurol. 2021;119:34-9. [PubMed: 33845444]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Sandkuhler SE, Zhang L, Meisner JK, Ghaloul-Gonzalez L, Beach CM, Harris D, de Lonlay P, Lalani SR, Miyake CY, Mackenzie SJ. B-complex vitamins for patients with TANGO2-deficiency disorder. J Inherit Metab Dis. 2023;46:161-2. [PMC free article: PMC10204720] [PubMed: 36550018]
• Schymick J, Leahy P, Cowan T, Ruzhnikov MRZ, Gates R, Fernandez L, Pramanik G; Undiagnosed Diseases Network, Yarlagadda V, Wheeler M, Bernstein JA, Enns GM, Lee C. Variable clinical severity in TANGO2 deficiency: case series and literature review. Am J Med Genet A. 2022;188:473-487. [PubMed: 34668327]