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Advanced Neurology

CASE REPORT
Cognitive and autonomic dysfunction associated

with a novel RYR2 variant: A case report

1†
1†
1†
Leilani Miranda * , Liam Power , Justin Ho , Charly Edmiston ,
1†
1,2
Okeanis Vaou , and Anna Hohler 1,2
1 Tufts University School of Medicine, Boston, Massachusetts, United States of America
2 Department of Neurology, St. Elizabeth’s Medical Center, Brighton, Massachusetts,
United States of America

Abstract

Variants in the ryanodine receptor 2 (RYR2) gene are primarily associated with
catecholaminergic polymorphic ventricular tachycardia. However, recent studies
have also identified potential links to neurological pathologies, including Alzheimer’s
disease, benign epilepsy of childhood, and neurodevelopmental disorders. Despite
these findings, there is limited data on the association between RYR2 variants and
additional neurological symptoms, such as autonomic dysfunction. This case report
describes the clinical progression of a father-son pair, who carry a novel pAsn2517Ser
† These authors contributed equally variant in the RYR2 gene, identified through genetic studies. The report highlights
to this work. distinct neurological manifestations in both individuals: the father exhibited
*Corresponding author: Alzheimer’s-like cognitive dysfunction, while the son presented with an autonomic
Leilani Miranda disorder. This case aims to provide additional information on the role of RyR2 in
(leilani.miranda@tufts.edu) the brain and the symptomatology associated with pathological variants. Given
Citation: Miranda L, Power L, that both father and son share the same RYR2 mutation, the observed neurological
Ho J, Edmiston C, Vaou O, manifestations are likely attributable to this genetic alteration. These cases offer novel
Hohler A. Cognitive and autonomic
dysfunction associated with a novel clinical insights into the role of cytoplasmic calcium regulators and their impact on
RYR2 variant: A case report. Adv the neurological system.
Neuro. 2025;4(3):117-121.
doi: 10.36922/an.4509
Received: August 13, 2024 Keywords: Ryanodine receptors; RyR2; Autonomic dysfunction; Alzheimer’s disease
Revised: October 21, 2024
Accepted: November 13, 2024
Published online: December 4, 1. Background
2024 Ryanodine receptors (RyRs) are calcium ion channels located on the sarcoplasmic
1
Copyright: © 2024 Author(s). reticulum in cardiac and skeletal muscle cells. Intracellular calcium release, triggered by
This is an Open-Access article depolarization through L-type calcium channels, is mediated by RyRs, which facilitate
distributed under the terms of the 2+ 2,3
Creative Commons Attribution the rapid release of Ca from the sarcoplasmic reticulum into the cytosol. These
License, permitting distribution, homotetrameric protein ion channels exist in three isoforms: RyR1, predominantly
and reproduction in any medium, expressed in skeletal muscle; RyR2, primarily found in cardiac muscle and also Purkinje
4
provided the original work is
properly cited. cells of the cerebellum, hippocampus, and cerebral cortex; and RyR3, expressed in
hippocampal neurons, the thalamus, Purkinje cells, and the corpus striatum. 5
Publisher’s Note: AccScience
Publishing remains neutral with Mutations in both RyR1 and RyR2 have been associated with severe pathological
regard to jurisdictional claims in
published maps and institutional conditions. RyR1 mutations are associated with central core disease, exertional
affiliations. rhabdomyolysis, and malignant hyperthermia. RyR2 mutations, meanwhile, are

Volume 4 Issue 3 (2025) 117 doi: 10.36922/an.4509