A Novel Homozygous ATP8A2 Variant in a Patient With Phenotypic Features of Dysequilibrium Syndrome

  • Amene Saghazadeh Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. AND MetaCognition Interest Group (MCIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
  • Seyed Hassan Tonekaboni Pediatric Neurology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
  • Hossein Najmabadi Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Evin, Tehran, Iran. AND Kariminejad-Najmabaadi Pathology and Genetics Laboratory, Tehran, Iran.
  • Nima Rezaei Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. AND Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AND Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
Keywords: Dysequilibrium syndrome type 4, Case report, Whole exome sequencing, ATP8A2 gene, Iran

Abstract

The ATP8A2 protein is mainly located in the brain and takes part in the lipid flipping process. Mutations in the ATP8A2 gene and chromosomal translocations that interfere with the ATP8A2 gene product have been reported in association with global developmental delay and hypotonia. Here, we will report a three-year-old male presented with major phenotypic features of dysequilibrium syndrome (DES), including severe hypotonia, global developmental delay, speech problem, and strabismus. Whole exome sequencing revealed a homozygous in-frame deletion in the ATP8A2 gene (c.1286_1288delAGA, p.Lys429del). This ATP8A2 variant has not been reported yet and seems to be linked to the phenotypic features of dysequilibrium syndrome.

References

Folmer DE, Elferink RPJO, Paulusma CC. P4 ATPases-lipid flippases and their role in disease. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2009;1791(7):628-35.

Sun XL, Li D, Fang JIN, Noyes I, Casto B, Theil K, et al. Changes in levels of normal ML-1 gene transcripts associated with the conversion of human nontumorigenic to tumorigenic phenotypes. Gene Expression. 1999;8(2):129-39.

Onat OE, Gulsuner S, Bilguvar K, Nazli Basak A, Topaloglu H, Tan M, et al. Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion. European Journal of Human Genetics. 2013;21(3): 281-5.

Cacciagli P, Haddad M-R, Mignon-Ravix C, El-Waly B, Moncla A, Missirian C, et al. Disruption of the ATP8A2 gene in a patient with at (10; 13) de novo balanced translocation and a severe neurological phenotype. European Journal of Human Genetics. 2010;18(12):1360-3.

Boycott KM, Bonnemann C, Herz J, Neuert S, Beaulieu C, Scott JN, et al. Mutations in VLDLR as a cause for autosomal recessive cerebellar ataxia with mental retardation (dysequilibrium syndrome). Journal of Child Neurology. 2009;24(10):1310-5.

Tan U. A new syndrome with quadrupedal gait, primitive speech, and severe mental retardation as a live model for human evolution. International Journal of Neuroscience. 2006;116(3):361-9.

Türkmen S, Demirhan O, Hoffmann K, Diers A, Zimmer C, Sperling K, et al. Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p. Journal of Medical Genetics. 2006;43(5):461-4.

Gulsuner S, Tekinay AB, Doerschner K, Boyaci H, Bilguvar K, Unal H, et al. Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred. Genome Research. 2011;21(12):1995-2003.

Garcias GDL, Roth MDGM. A Brazilian family with quadrupedal gait, severe mental retardation, coarse facial characteristics, and hirsutism. International Journal of Neuroscience. 2007;117(7):927-33.

Moheb LA, Tzschach A, Garshasbi M, Kahrizi K, Darvish H, Heshmati Y, et al. Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome. European Journal of Human Genetics. 2008;16(2):270-3.

Komara M, John A, Suleiman J, Ali BR, Al‐Gazali L. Clinical and molecular delineation of dysequilibrium syndrome type 2 and profound sensorineural hearing loss in an inbred Arab family. American Journal of Medical Genetics Part A. 2016;170(2):540-3.

Ozcelik T, Akarsu N, Uz E, Caglayan S, Gulsuner S, Onat OE, et al. Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(11): 4232-6.

Published
2019-01-13
How to Cite
1.
Saghazadeh A, Tonekaboni SH, Najmabadi H, Rezaei N. A Novel Homozygous ATP8A2 Variant in a Patient With Phenotypic Features of Dysequilibrium Syndrome. Acta Med Iran. 56(10):677.
Section
Case Report(s)