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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
Purchase on Springer Link
Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Burgis NE. A disease spectrum for ITPA variation: advances in biochemical and clinical research. J Biomed Sci. 2016;23:73.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s10038-020-0765-3
This article is cited by
-
An ITPA Enzyme with Improved Substrate Selectivity
The Protein Journal (2024)
-
Long-read whole-genome sequencing identified a partial MBD5 deletion in an exome-negative patient with neurodevelopmental disorder
Journal of Human Genetics (2021)
-
Cerebrovascular diseases in two patients with entire NSD1 deletion
Human Genome Variation (2021)