Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy

Kremer, Laura S.; Distelmaier, Felix; Alhaddad, Bader; Hempel, Maja; Iuso, Arcangela; Küpper, Clemens; Mühlhausen, Chris; Kovács-Nagy, Réka; Satanovskij, Robin; Graf, Elisabeth; Berutti, Riccardo; Eckstein, Gertrud; Durbin, Richard; Sauer, Sascha; Hoffmann, Georg F.; Strom, Tim M.; Santer, René; Meitinger, Thomas; Klopstock, Thomas; Prokisch, Holger; Haack, Tobias B.

doi:10.1016/j.ajhg.2015.12.009

Cited by 90 publications

(147 citation statements)

References 11 publications

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“…The variants were absent or extremely rare (<0.002%) in the gnomAD database, and homozygous carriers were lacking. In three European families without known consanguineous descent (families 1, 5, and 7), five patients were homozygous for the previously described approximately 34‐kb deletion encompassing exons 3 to 9, likely reflecting an ancestral variant in Europeans . Population‐based studies have shown that heterozygous loss of this region is found in white Europeans with an allele frequency of between 0.062% and 0.11%, with homozygous deletions being absent in large control datasets.…”

Section: Discussionmentioning

confidence: 54%

“…Not fully compatible with this notion, a subsequent study found mouse Tango2 (also known as T10) to carry a conserved N‐terminal leader sequence that directs it to the mitochondrial compartment . Clinical resemblance between TANGO2 ‐related disease and fatty acid oxidation disorders such as carnitine palmitoyltransferase II (CPT2) deficiency, led to the speculation that TANGO2 may play a direct role in mitochondrial beta‐oxidation . In light of this we revisited the subcellular distribution of TANGO2.…”

Section: Resultsmentioning

confidence: 90%

“…The pattern of biochemical abnormalities found during crises with hypoglycaemia, hyperlacticacidaemia (and hyperammonaemia in one patient) followed by rhabdomyolysis is similar to previously described patients . It is unclear at present why some patients do not present with the metabolic derangements above and instead have rhabdomyolysis only.…”

Section: Discussionmentioning

confidence: 99%

“…We found that five out of six patients in our cohort had mildly reduced mitochondrial complex II activity. This is in contrast with previous reports that described essentially normal mitochondrial function . Although we lack longitudinal data with repeated investigations of mitochondrial function from the same patients, we note a temporal association between crises and the complex II impairment, with the subjects hospitalized for crisis management having the most pronounced biochemical defects.…”

Section: Discussionmentioning

confidence: 99%

“…Urine organic acids and acylcarnitine profiles have shown varying abnormalities with no consistent metabolic signature. Seizures have been found in 75% of patients and primary hypothyroidism in 40% …”

Section: Introductionmentioning

confidence: 99%

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TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism

Jennions

Hedberg‐Oldfors

Berglund

et al. 2019

J of Inher Metab Disea

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Exome sequencing has recently identified mutations in the gene TANGO2 (transport and Golgi organization 2) as a cause of developmental delay associated with recurrent crises involving rhabdomyolysis, cardiac arrhythmias, and metabolic derangements. The disease is not well understood, in part as the cellular function and subcellular localization of the TANGO2 protein remain unknown. Furthermore, the clinical syndrome with its heterogeneity of symptoms, signs, and laboratory findings is still being defined. Here, we describe 11 new cases of TANGO2‐related disease, confirming and further expanding the previously described clinical phenotype. Patients were homozygous or compound heterozygous for previously described exonic deletions or new frameshift, splice site, and missense mutations. All patients showed developmental delay with ataxia, dysarthria, intellectual disability, or signs of spastic diplegia. Of importance, we identify two subjects (aged 12 and 17 years) who have never experienced any overt episode of the catabolism‐induced metabolic crises typical for the disease. Mitochondrial complex II activity was mildly reduced in patients investigated in association with crises but normal in other patients. In one deceased patient, post‐mortem autopsy revealed heterotopic neurons in the cerebral white matter, indicating a possible role for TANGO2 in neuronal migration. Furthermore, we have addressed the subcellular localization of several alternative isoforms of TANGO2, none of which were mitochondrial but instead appeared to have a primarily cytoplasmic localization. Previously described aberrations in Golgi morphology were not observed in cultured skin fibroblasts.

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Section: Discussionmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism

Jennions

Hedberg‐Oldfors

Berglund

et al. 2019

J of Inher Metab Disea

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Molecular genetics of 22q11.2 deletion syndrome

Morrow

McDonald‐McGinn

Emanuel

et al. 2018

American J of Med Genetics Pt A

115

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The 22q11.2 deletion syndrome (22q11.2DS) is a congenital malformation and neuropsychiatric disorder caused by meiotic chromosome rearrangements. One of the goals of this review is to summarize the current state of basic research studies of 22q11.2DS. It highlights efforts to understand the mechanisms responsible for the 22q11.2 deletion that occurs in meiosis. This mechanism involves the four sets of low copy repeats (LCR22) that are dispersed in the 22q11.2 region and the deletion is mediated by non-allelic homologous recombination events. This review also highlights selected genes mapping to the 22q11.2 region that may contribute to the typical clinical findings associated with the disorder and explain that mutations in genes on the remaining allele can uncover rare recessive conditions. Another important aspect of 22q11.2DS is the existence of phenotypic heterogeneity. While some patients are mildly affected, others have severe medical, cognitive and/or psychiatric challenges. Variability may be due in part to the presence of genetic modifiers. This review discusses current genome-wide efforts to identify such modifiers that could shed light on molecular pathways required for normal human development, cognition or behavior.

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Variable clinical severity in TANGO2 deficiency: Case series and literature review

Schymick

Leahy

Cowan

et al. 2021

American J of Med Genetics Pt A

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Biallelic pathogenic variants in the TANGO2 (transport and Golgi organization 2 homolog) gene have been identified as causing a rare metabolic disorder characterized by susceptibility to recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life-threatening tachyarrhythmias. Recently published reports suggest variable clinical severity and phenotypes. This study details five new patients from two families with biallelic pathogenic variants in the TANGO2 gene identified by whole exome sequencing and includes the largest number of affected individuals from a single family reported to date. We document significant intrafamilial variability and highlight that milder phenotypes may be underrecognized. We present biochemical and clinical data to help highlight the features that aid in consideration of this condition in the differential with disorders of fatty acid oxidation. We also present a comprehensive literature review summarizing the molecular, clinical, and biochemical findings for 92 individuals across 13 publications. Of the 27 pathogenic variants reported to date, the recurrent exons 3-9 deletion represents the most common variant seen in 42% of individuals with TANGO2 deficiency. Common clinical features seen in >70% of all individuals include acute metabolic crisis, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability. Findings such as elevated creatine kinase, hypothyroidism, ketotic hypoglycemia, QT prolongation, or abnormalities of long-chain acylcarnitines and urine dicarboxylic acids should raise clinical suspicion for this life-threatening condition.

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Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy

Cited by 90 publications

References 11 publications

TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism

TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism

Molecular genetics of 22q11.2 deletion syndrome

Variable clinical severity in TANGO2 deficiency: Case series and literature review

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