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A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction

Abstract

Inborn errors of metabolism can cause epileptic encephalopathies. Biallelic loss-of-function variants in the ITPA gene, encoding inosine triphosphate pyrophosphatase (ITPase), have been reported in epileptic encephalopathies with lack of myelination of the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices (MIM:616647). ITPase plays an important role in purine metabolism. In this study, we identified two novel homozygous ITPA variants, c.264-1 G > A and c.489-1 G > A, in two unrelated consanguineous families. The probands had epilepsy, microcephaly with characteristic magnetic resonance imaging findings (T2 hyperintensity signals in the pyramidal tracts of the internal capsule, delayed myelination, and thin corpus callosum), hypotonia, and developmental delay; both died in early infancy. Our report expands the knowledge of clinical consequences of biallelic ITPA variants.

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References

  1. Burgis NE. A disease spectrum for ITPA variation: advances in biochemical and clinical research. J Biomed Sci. 2016;23:73.

    Article  Google Scholar 

  2. Stenmark P, Kursula P, Flodin S, Graslund S, Landry R, Nordlund P, et al. Crystal structure of human inosine triphosphatase. Substrate binding and implication of the inosine triphosphatase deficiency mutation P32T. J Biol Chem. 2007;282:3182–7.

    Article  CAS  Google Scholar 

  3. Pang B, McFaline JL, Burgis NE, Dong M, Taghizadeh K, Sullivan MR, et al. Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA. Proc Natl Acad Sci USA. 2012;109:2319–24.

    Article  CAS  Google Scholar 

  4. Behmanesh M, Sakumi K, Abolhassani N, Toyokuni S, Oka S, Ohnishi YN, et al. ITPase-deficient mice show growth retardation and die before weaning. Cell Death Differ. 2009;16:1315–22.

    Article  CAS  Google Scholar 

  5. Kevelam SH, Bierau J, Salvarinova R, Agrawal S, Honzik T, Visser D, et al. Recessive ITPA mutations cause an early infantile encephalopathy. Ann Neurol. 2015;78:649–58.

    Article  CAS  Google Scholar 

  6. Kaur P, Neethukrishna K, Kumble A, Girisha KM, Shukla A. Identification of a novel homozygous variant confirms ITPA as a developmental and epileptic encephalopathy gene. Am J Med Genet A. 2019;179:857–61.

    CAS  PubMed  Google Scholar 

  7. Handley MT, Reddy K, Wills J, Rosser E, Kamath A, Halachev M, et al. ITPase deficiency causes a Martsolf-like syndrome with a lethal infantile dilated cardiomyopathy. PLoS Genet. 2019;15:e1007605.

    Article  CAS  Google Scholar 

  8. Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, et al. Biallelic TBCD Mutations cause early-onset neurodegenerative encephalopathy. Am J Hum Genet. 2016;99:950–61.

    Article  CAS  Google Scholar 

  9. Chen YJ, Nabavizadeh SA, Vossough A, Kumar S, Loevner LA, Mohan S. Wallerian degeneration beyond the corticospinal tracts: conventional and advanced MRI findings. J Neuroimaging. 2017;27:272–80.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the affected individuals and their families for participating in this study. This work was supported by AMED under the grant numbers JP19ek0109280, JP19dm0107090, JP19ek0109301, JP19ek0109348, and JP18kk020501 (to NM); JSPS KAKENHI under the grant numbers JP17H01539 (to NM) and JP19H03621 (to NM); grants from the Ministry of Health, Labour, and Welfare (to NM); and the Takeda Science Foundation (to NM and NM). We thank Louise Adam, ELS(D), from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

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Correspondence to Noriko Miyake or Naomichi Matsumoto.

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Sakamoto, M., Kouhei, D., Haniffa, M. et al. A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction. J Hum Genet 65, 751–757 (2020). https://doi.org/10.1038/s10038-020-0765-3

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