Dantrolene as a possible prophylactic treatment for<i>RYR1</i>‐related rhabdomyolysis

Scalco, R.; Voermans, Nicol C.; Piercy, Richard J.; Jungbluth, Heinz; Quinlivan, R.

doi:10.1111/ene.13051

Cited by 11 publications

(13 citation statements)

References 11 publications

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“…Third, our results suggest broad genetic heterogeneity for rhabdomyolysis. To the best of our knowledge, only few rhabdomyolysis cohorts were systematically analyzed by means of next generation sequencing and or whole exome sequencing [32–35]. Given the rarity and the high number of genes that can cause rhabdomyolysis if mutated, WES should be the genetic method of choice for molecular diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

et al. 2017

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Background Rhabdomyolysis is a clinical emergency that may cause acute kidney injury (AKI). It can be acquired or due to monogenic mutations. Around 60 different rare monogenic forms of rhabdomyolysis have been reported to date. In the clinical setting, identifying the underlying molecular diagnosis is challenging, due to nonspecific presentation, the high number of causative genes, and current lack of data on the prevalence of monogenic forms. Methods We employed whole exome sequencing (WES) to reveal the percentage of rhabdomyolysis cases explained by single-gene (monogenic) mutations in one of 58 candidate genes. We investigated a cohort of 21 unrelated families with rhabdomyolysis. in whom no underlying etiology had been previously established. Results Using WES, we identified causative mutations in candidate genes in nine of the 21 families (43%). We detected disease-causing mutations in eight of 58 candidate genes, grouped into the following categories: 1) disorders of fatty acid metabolism (CPT2), 2) disorders of glycogen metabolism (PFKM and PGAM2), 3) disorders of abnormal skeletal muscle relaxation and contraction (CACNA1S, MYH3, RYR1 and SCN4A), and 4) disorders of purine metabolism (AHCY). Conclusions Our findings demonstrate a very high detection rate for monogenic etiologies using WES and reveal broad genetic heterogeneity for rhabdomyolysis. These results highlight the importance of molecular genetic diagnostics for establishing an etiologic diagnosis. Because these patients are at risk for recurrent episodes of rhabdomyolysis and subsequent risk for AKI, WES allows adequate prophylaxis and treatment for these patients and their family members and enables a personalized medicine approach.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

et al. 2017

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“…Additionally, to prevent further fatalities caused by inevitable delays in administration of dantrolene, oral dantrolene supplies may be offered to MHS patients and their relatives, so that it can be administered at the earliest possible time should an awake MH episode be suspected. [26][27][28] It is our hope that these case reports will help reverse the view on MH exclusively as an ''anesthetic'' disorder and provide a strong incentive for developing efficient guidelines aimed at early recognition and treatment of awake MH episodes.…”

Section: Discussionmentioning

confidence: 99%

“…24 Oral dantrolene has successfully been used offlabel for many MHS patients and has been shown to be effective in preventing or diminishing the severity of musclerelated symptoms. 8,17,25,26 Dantrolene has also effectively been used in the treatment of conditions symptomatically similar to MH, such as neuroleptic malignant syndrome, 25 exercise-induced rhabdomyolysis and muscle pain, 8,27 exertional heat stroke, 28 and alcohol and drug intoxication. 9,29 Successful management of MH relies on early diagnosis and aggressive treatment.…”

Section: Discussionmentioning

confidence: 99%

Fatal awake malignant hyperthermia episodes in a family with malignant hyperthermia susceptibility: a case series

Zvaritch

Gillies

Kraeva

et al. 2019

Can J Anesth/J Can Anesth

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Purpose The present report of two fatal awake malignant hyperthermia (MH) episodes in an MH susceptible (MHS) family is intended to raise awareness among medical personnel and MHS individuals to the possibility of lifethreatening non-anesthesia-triggered MH episodes and to provide a strong incentive for development of effective preventive measures.Clinical features Two young athletic males (28 and 16 yr old), members of the same extended family with a history of anesthesia-related MH episodes and deaths, succumbed ten years apart on two different continents, with symptoms unrelated to anesthesia but strikingly similar to typical anesthetic-induced MH. Both suffered an abrupt surge in body temperature, tachycardia, tachypnea, muscle rigidity, hyperkalemia, and respiratory and metabolic acidosis. Despite aggressive resuscitation attempts, both developed cardiac arrest and died shortly upon arrival to hospital emergency departments. Autopsy analyses were negative for drugs, alcohol, or bacterial infection. Individual and familial genetic analyses revealed a novel, potentially pathogenic RYR1 variant (p.Gly159Arg) that co-segregates with the MHS phenotype in the family. Both fatal awake MH episodes are hypothesized to have been triggered by physical exertion compounded with a febrile illness that in one case was due to influenza type A. Conclusions Life-threatening awake MH episodes may develop in some MHS individuals in the absence of anesthetic triggers. Potential triggers can be physical exertion in combination with a febrile illness. Malignant hyperthermia susceptible patients are recommended to be vaccinated against flu and restrict physical activities when febrile, wear an MH alert bracelet, and inform medical personnel of their MH history. Oral dantrolene is suggested to be available to MHS patients for administration with the early signs of awake MH. RésuméObjectif Ce compte-rendu de deux épisodes fatals d'hyperthermie maligne (HM) survenus en communauté, sans anesthésie, dans une famille susceptible à l'HM

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“…Firstly, in line with a personalized medicine approach, an informed decision can be made to avoid certain pharmacological agents in individuals where those may be harmful due to a specific genetic predisposition. Secondly, specific measures may be taken (for example, prescription of the specific ryanodine receptor antagonist Dantrolene in cases where RYR1 has been implicated) to prevent recurrent episodes [34]. Thirdly, in cases where diagnostic MH variants in RYR1 have been identified, genetic counseling of the patient and their families may prevent life-threatening MH events.…”

Section: Discussionmentioning

confidence: 99%

HyperCKemia and rhabdomyolysis in the neuroleptic malignant and serotonin syndromes: A literature review

Kruijt

Bersselaar

Wijma

et al. 2020

Neuromuscular Disorders

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Dantrolene as a possible prophylactic treatment forRYR1‐related rhabdomyolysis

Cited by 11 publications

References 11 publications

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases

Fatal awake malignant hyperthermia episodes in a family with malignant hyperthermia susceptibility: a case series

HyperCKemia and rhabdomyolysis in the neuroleptic malignant and serotonin syndromes: A literature review

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