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Childhood-related neural genotype–phenotype in ATP1A3 mutations: comprehensive analysis

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Abstract

Background

ATP1A3 is a gene that encodes the ATPase Na + /K + transporting subunit alpha-3 isoenzyme that is widely expressed in GABAergic neurons. It maintains metabolic balance and neurotransmitter movement. These pathways are essential for the proper functioning of the nervous system. A mutation in the ATP1A3 gene demonstrates remarkable genotype–phenotype heterogeneity.

Objectives

To provide insight into patients with ATP1A3 mutation.

Material and methods

These cases were identified using next generation sequencing. The patients' clinical and genetic data were retrieved. Detailed revision of the literature was conducted to illustrate and compare findings. The clinical, genetical, neuroimaging, and electrophysiological data of all pediatric patients were extracted.

Results

The study included 14 females and 12 males in addition to two novel females cases. Their mean current age is 6.3 ± 4.24 years. There were 11.54% preterm pregnancies with 5 cases reporting pregnancy complications. Mean age of seizure onset was 1.07 ± 1.06 years. Seizure semiology included generalized tonic–clonic, staring spells, tonic–clonic, and others. Levetiracetam was the most frequently used Anti-seizure medication. The three most frequently reported classical symptoms included alternating hemiplegia of childhood (50%), cerebellar ataxia (50%), and optic atrophy (23.08%). Non-classical symptoms included dystonia (73.08%), paroxysmal dyskinesias (34.62%), and encephalopathy (26.92%). Developmental delay was reported among 84.62% in cognitive, 92.31% in sensorimotor, 80.77% in speech, and 76.92% in socioemotional. EEG and MRI were non-specific.

Conclusion

Our study demonstrated high heterogeneity among patients with pathogenic variants in the ATP1A3 gene. Such variation is multifactorial and can be a predisposition of wide genetic and clinical variables. Many patients shared few similarities in their genetic map including repeatedly reported de novo, heterozygous, mutations in the gene. Clinically, higher females prevalence of atypical presentation was noted. These findings are validated with prior evidence and the comprehensive analysis in this study.

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Data availability

The datasets used and/or analyzed during the current study are available from the firts author on reasonable request.

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Acknowledgement

The authors extend their appreciation to the King Salman center For Disability Research for funding this work through Research Group no KSRG-2023-024.

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Authors and Affiliations

  1. Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia

    Osama Y. Muthaffar

  2. Department of Neurology, Neuroscience Centre, King Faisal Specialist Hospital & Research Centre, 21313, Jeddah, Saudi Arabia

    Asma Alqarni

  3. Faculty of Medicine, King Abdulaziz University, 23446, Jeddah, Saudi Arabia

    Jumana A. Shafei, Sarah Y. Bahowarth & Anas S. Alyazidi

  4. Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, 21589, Jeddah, Saudi Arabia

    Muhammad Imran Naseer

  5. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, 21589, Jeddah, Saudi Arabia

    Muhammad Imran Naseer

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  1. Osama Y. Muthaffar
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Correspondence to Muhammad Imran Naseer.

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Muthaffar, O.Y., Alqarni, A., Shafei, J.A. et al. Childhood-related neural genotype–phenotype in ATP1A3 mutations: comprehensive analysis. Genes Genom 46, 475–487 (2024). https://doi.org/10.1007/s13258-023-01481-8

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