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

Jennions, Elizabeth ; Hedberg-Oldfors, Carola ; Berglund, Anna Karin ; Kollberg, Gittan ; Törnhage, Carl Johan ; Eklund, Erik A. LU ; Oldfors, Anders ; Verloo, Patrick ; Vanlander, Arnaud V. and De Meirleir, Linda , et al. (2019) In Journal of Inherited Metabolic Disease 42(5). p.898-908
Abstract

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... (More)

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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keywords
copy-number variation, developmental delay, FAD, rare disease, succinate dehydrogenase
in
Journal of Inherited Metabolic Disease
volume
42
issue
5
pages
898 - 908
publisher
Springer
external identifiers
  • pmid:31276219
  • scopus:85069934561
ISSN
0141-8955
DOI
10.1002/jimd.12149
language
English
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yes
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c99d2b1f-66f9-4520-815a-fce24855e210
date added to LUP
2019-08-27 12:24:33
date last changed
2020-01-13 02:18:07
@article{c99d2b1f-66f9-4520-815a-fce24855e210,
  abstract     = {<p>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.</p>},
  author       = {Jennions, Elizabeth and Hedberg-Oldfors, Carola and Berglund, Anna Karin and Kollberg, Gittan and Törnhage, Carl Johan and Eklund, Erik A. and Oldfors, Anders and Verloo, Patrick and Vanlander, Arnaud V. and De Meirleir, Linda and Seneca, Sara and Sterky, Fredrik H. and Darin, Niklas},
  issn         = {0141-8955},
  language     = {eng},
  number       = {5},
  pages        = {898--908},
  publisher    = {Springer},
  series       = {Journal of Inherited Metabolic Disease},
  title        = {TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism},
  url          = {http://dx.doi.org/10.1002/jimd.12149},
  doi          = {10.1002/jimd.12149},
  volume       = {42},
  year         = {2019},
}