Pancreatitis in RYR1-related disorders

TY - JOUR

T1 - Pancreatitis in RYR1-related disorders

AU - Famili, Dennis T.

AU - Mistry, Arti

AU - Gerasimenko, Oleg

AU - Gerasimenko, Julia

AU - Tribe, Rachel M.

AU - Kyrana, Eirini

AU - Dhawan, Anil

AU - Goldberg, Michael F.

AU - Voermans, Nicol

AU - Willis, Tracey

AU - Jungbluth, Heinz

N1 - Funding Information: We like to thank our patients for their participation in this study, and the RYR-1 Foundation, Pittsburgh, PA, United States (www.ryr1.org) for their support of this work. NV is a member of the European Reference Network for rare neuromuscular diseases (EURO-NMD). We also like to thank Prof. Susan Treves, Basel, for critically reading the manuscript. Publisher Copyright: © 2023

PY - 2023/9/15

Y1 - 2023/9/15

N2 - Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in a wide range of tissues, non-skeletal muscle manifestations associated with RYR1 mutations have only been rarely reported. Here, we report three patients with a diagnosis of Central Core Disease (CCD), King-Denborough Syndrome (KDS) and Malignant Hyperthermia Susceptibility (MHS), respectively, who in addition to their (putative) RYR1-related disorder also developed symptoms and signs of acute pancreatitis. In two patients, episodes were recurrent, with severe multisystem involvement and sequelae. RyR1-mediated calcium signalling plays an important role in normal pancreatic function but has also been critically implicated in the pathophysiology of acute pancreatitis, particularly in bile acid- and ethanol-induced forms. Findings from relevant animal models indicate that pancreatic damage in these conditions may be ameliorated through administration of the specific RyR1 antagonist dantrolene and other compounds modifying pancreatic metabolism including calcium signalling. These observations suggest that patients with RYR1 gain-of-function variants may be at increased risk of developing acute pancreatitis, a condition which should therefore be considered in the health surveillance of such individuals.

AB - Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in a wide range of tissues, non-skeletal muscle manifestations associated with RYR1 mutations have only been rarely reported. Here, we report three patients with a diagnosis of Central Core Disease (CCD), King-Denborough Syndrome (KDS) and Malignant Hyperthermia Susceptibility (MHS), respectively, who in addition to their (putative) RYR1-related disorder also developed symptoms and signs of acute pancreatitis. In two patients, episodes were recurrent, with severe multisystem involvement and sequelae. RyR1-mediated calcium signalling plays an important role in normal pancreatic function but has also been critically implicated in the pathophysiology of acute pancreatitis, particularly in bile acid- and ethanol-induced forms. Findings from relevant animal models indicate that pancreatic damage in these conditions may be ameliorated through administration of the specific RyR1 antagonist dantrolene and other compounds modifying pancreatic metabolism including calcium signalling. These observations suggest that patients with RYR1 gain-of-function variants may be at increased risk of developing acute pancreatitis, a condition which should therefore be considered in the health surveillance of such individuals.

KW - Acute pancreatitis

KW - Calcium signalling

KW - Ryanodine receptor

KW - RyR1

UR - http://www.scopus.com/inward/record.url?scp=85173175094&partnerID=8YFLogxK

U2 - 10.1016/j.nmd.2023.09.003

DO - 10.1016/j.nmd.2023.09.003

M3 - Article

C2 - 37783627

AN - SCOPUS:85173175094

SN - 0960-8966

VL - 33

SP - 769

EP - 775

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

IS - 10

ER -