Association between CACNA1A and ATP1A2 Variants are Responsible for Severe Neurodevelopmental Disorder

Abstract

ATP1A2 and CACNA1A genes encode proteins forming transmembrane channels, Na⁺/K⁺/ATPase transporter, and voltage-gated calcium channels, respectively. Pathogenic variants in these genes are associated with hemiplegic migraines, movement disorders, and developmental and epileptic encephalopathy.

We report a child presenting epileptic encephalopathy with cognitive and behavioral troubles. He carries a likely pathogenic variant in the ATP1A2 gene, inherited from his mother who presents hemiplegic migraines, and a variant of uncertain significance in the CACNA1A gene, inherited from his asymptomatic father and also found in his brother, who presents a milder neurodevelopmental disorder (NDD). No other significant copy number or single nucleotide variations were identified after an in-depth genetic study including whole exome sequencing, array comparative genomic hybridization, and screening for Fragile X and Prader–Willi/Angelman syndromes.

We illustrate the synergetic impact of ATP1A2 and CACNA1A genes in NDDs.

Keywords

CACNA1A - ATP1A2 - neurodevelopmental disorders - epileptic encephalopathy

Patient Consent

Parents of patients have given their consent for the use of the photograph of their children for the purpose of this scientific work.

Publication History

Received: 10 September 2024

Accepted: 10 December 2024

Accepted Manuscript online:
12 December 2024

Article published online:
27 December 2024

• References

• 1 Kordasiewicz HB, Thompson RM, Clark HB, Gomez CM. C-termini of P/Q-type Ca2+ channel α1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Hum Mol Genet 2006; 15 (10) 1587-1599 . Accessed June 18, 2024 at: https://pubmed.ncbi.nlm.nih.gov/16595610/
• 2 Shull MM, Lingrel JB. Multiple genes encode the human Na+, K+-ATPase catalytic subunit. Proc Natl Acad Sci U S A 1987; 84 (12) 4039-4043 . Accessed June 18, 2024 at: https://pubmed.ncbi.nlm.nih.gov/3035563/
• 3 Bando Y, Ishibashi M, Yamagishi S, Fukuda A, Sato K. Orchestration of ion channels and transporters in neocortical development and neurological disorders. Front Neurosci 2022; 16: 827284
• 4 Indelicato E, Boesch S. From genotype to phenotype: expanding the clinical spectrum of CACNA1A variants in the era of next generation sequencing. Front Neurol 2021; 12: 639994
• 5 Sweadner KJ, Arystarkhova E, Penniston JT, Swoboda KJ, Brashear A, Ozelius LJ. Genotype-structure-phenotype relationships diverge in paralogs ATP1A1, ATP1A2, and ATP1A3 . Neurol Genet 2019; 5 (01) e303
• 6 Moya-Mendez ME, Mueller DM, Pratt M. et al. Early onset severe ATP1A2 epileptic encephalopathy: clinical characteristics and underlying mutations. Epilepsy Behav 2021; 116: 107732
• 7 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424 . Accessed March 19, 2021 at: https://pubmed.ncbi.nlm.nih.gov/25741868/
• 8 Durkie M, Cassidy E-J, Berry I. et al. ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2024. Devon Univ Healthcare NHS Found Trust Exet Div Genet Epidemiol 2024; 12: 15-17
• 9 Chen S, Francioli LC, Goodrich JK. et al; Genome Aggregation Database Consortium. A genomic mutational constraint map using variation in 76,156 human genomes. Nature 2024; 625 (7993) 92-100
• 10 Weigand KM, Swarts HGP, Russel FGM, Koenderink JB. Biochemical characterization of sporadic/familial hemiplegic migraine mutations. Biochim Biophys Acta 2014; 1838 (07) 1693-1700 . Accessed June 18, 2024 at: https://pubmed.ncbi.nlm.nih.gov/24704353/
• 11 Tavraz NN, Friedrich T, Dürr KL. et al. Diverse functional consequences of mutations in the Na+/K+-ATPase α2-subunit causing familial hemiplegic migraine type 2. J Biol Chem 2008; 283 (45) 31097-31106 . Accessed June 18, 2024 at: https://pubmed.ncbi.nlm.nih.gov/18728015/
• 12 Schack VR, Holm R, Vilsen B. Inhibition of phosphorylation of na+,k+-ATPase by mutations causing familial hemiplegic migraine. J Biol Chem 2012; 287 (03) 2191-2202 . Accessed June 18, 2024 at: https://pubmed.ncbi.nlm.nih.gov/22117059/
• 13 Riant F, De Fusco M, Aridon P. et al. ATP1A2 mutations in 11 families with familial hemiplegic migraine. Hum Mutat 2005; 26 (03) 281 . Accessed June 18, 2024 at: https://pubmed.ncbi.nlm.nih.gov/16088919/
• 14 Lipman AR, Fan X, Shen Y, Chung WK. Clinical and genetic characterization of CACNA1A-related disease. Clin Genet 2022; 102 (04) 288-295 . Accessed October 27, 2024 at: https://pubmed.ncbi.nlm.nih.gov/35722745/
• 15 Angelini C, Van Gils J, Bigourdan A. et al. Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant. Eur J Med Genet 2019; 62 (06) 103530 . Accessed June 18, 2024 at: https://pubmed.ncbi.nlm.nih.gov/30142438/