Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis

Dlamini, Nomazulu; Voermans, Nicol C.; Lillis, S.; Stewart, Ken G.; Kamsteeg, Erik‐Jan; Drost, Gea; Quinlivan, R.; Snoeck, M.M.J.; Norwood, Fiona; Radunović, Aleksandar; Straub, Volker; Roberts, Mark; Vrancken, Alexander F.J.E.; Pol, W. Ludo van der; Coo, I.F.M. de; Manzur, Adnan; Yau, Shu; Abbs, Stephen; King, Andrew; Lammens, Martin; Hopkins, Philip M.; Mohammed, Shehla; Treves, Susan; Muntoni, Francesco; Wraige, Elizabeth; Davis, Mark; Engelen, B.G.M. van; Jungbluth, Heinz

doi:10.1016/j.nmd.2013.03.008

Cited by 169 publications

(203 citation statements)

References 39 publications

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“…Three novel mutations and two variants previously reported in Caucasian MH-Susceptible subjects were found in five patients studied, further emphasizing the importance of performing CHCT and RYR1 mutation screening in patients with unexplained ERM [21]. In our seminal study systematically investigating a possible link between ERM and RYR1 mutations in 2013, RYR1 was sequenced in 39 unrelated families with RM, in whom common metabolic and mitochondrial causes had been excluded [8]. In this series we identified nine heterozygous RYR1 mutations/variants in 14 families, five of them (K1393R; G434R; T4288_A4290dup; A4295V; and R4737Q) previously associated with MH.…”

Section: Ryr1-related (Exertional) Rhabdomyolysis ((E)rm)mentioning

confidence: 80%

“…(patient 7.II.2;also patient 23 in Snoeck et al) had to change her plans to become a sports coach after the second ERM episode with CPK levels up to 378,900 IU/l [1,8]. Similarly, the patient illustrated above (Box 1) stopped cycling semi-professionally only after another episode of RM requiring hospital admission occurred a year after he was diagnosed with RYR1-related RM.…”

Section: Malignant Hyperthermia (Mh)mentioning

confidence: 98%

“…Family counselling is vital to identify potentially MH-susceptible relatives [1] We performed a systematic literature review (including the patients in the studies mentioned above), based on a Pubmed search with "RYR1" and "rhabdomyolysis". This resulted in identification of several case report and small series [1,8,[21][22][23][24][25][26], and two review article [27,28] Subsequently, we also included cases from references of these articles [20,26,[29][30][31][32][33][34] and added our recent letter by Snoeck et al [35]. Finally, we added two patients from our paper on the spectrum of RYR1 related myopathies by Snoeck et al who were not included in any other publication (patients 14 and 52 [1]).…”

Section: Ryr1-related (Exertional) Rhabdomyolysis ((E)rm)mentioning

confidence: 99%

“…We excluded the patients who suffered only from exertional myalgia without clinical or biochemical RM (Family 11 and 14 in Dlamini et al [8]). We identified 37 patients with non-anaesthetic RM due to RYR1 mutation(s) (age range 1 -64 years; 31 males and 6 females).…”

Section: Ryr1-related (Exertional) Rhabdomyolysis ((E)rm)mentioning

confidence: 99%

“…More recently, (MHS-related) RYR1 mutations have also emerged as a common cause of exertional rhabdomyolysis (ERM), accounting for up to 30% of rhabdomyolysis (RM) episodes in otherwise healthy individuals [8]. This review will focus on the features of RYR1-related (E)RM by discussing the key features from cases reported to date, summarizing the proposed pathophysiological mechanism(s) extrapolated from observations in relevant animal models, and suggesting how this probably not uncommon manifestation of RYR1 mutations can be recognized and how it should be managed.…”

Section: Introductionmentioning

confidence: 99%

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RYR1-related rhabdomyolysis: A common but probably underdiagnosed manifestation of skeletal muscle ryanodine receptor dysfunction

2016

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Section: Ryr1-related (Exertional) Rhabdomyolysis ((E)rm)mentioning

confidence: 80%

Section: Malignant Hyperthermia (Mh)mentioning

confidence: 98%

Section: Ryr1-related (Exertional) Rhabdomyolysis ((E)rm)mentioning

confidence: 99%

Section: Ryr1-related (Exertional) Rhabdomyolysis ((E)rm)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RYR1-related rhabdomyolysis: A common but probably underdiagnosed manifestation of skeletal muscle ryanodine receptor dysfunction

2016

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Exome analysis identifies Brody myopathy in a family diagnosed with malignant hyperthermia susceptibility

Sambuughin

Zvaritch

Kraeva

et al. 2014

Molec Gen & Gen Med

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Whole exome sequencing (WES) was used to determine the primary cause of muscle disorder in a family diagnosed with a mild, undetermined myopathy and malignant hyperthermia (MH) susceptibility (MHS). WES revealed the compound heterozygous mutations, p.Ile235Asn and p.Glu982Lys, in ATP2A1, encoding the sarco(endo)plasmic reticulum Ca2+ ATPase type 1 (SERCA1), a calcium pump, expressed in fast-twitch muscles. Recessive mutations in ATP2A1 are known to cause Brody myopathy, a rare muscle disorder characterized by exercise-induced impairment of muscle relaxation and stiffness. Analyses of affected muscles showed the absence of SERCA1, but SERCA2 upregulation in slow and fast myofibers, suggesting a compensatory mechanism that partially restores the diminished Ca2+ transport in Brody myopathy. This compensatory adaptation to the lack of SERCA1 Ca2+ pumping activity within the muscle explains, in part, the mild course of disease in our patient. Diagnosis of MHS in this family was secondary to a loss of SERCA1 due to disease-associated mutations. Although there are obvious differences in clinical expression and molecular mechanisms between MH and Brody myopathy, a feature common to both conditions is elevated myoplasmic Ca2+ content. Prolonged intracellular Ca2+ elevation is likely to have led to MHS diagnosis in vitro and postoperative MH-like symptoms in Brody patient.

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Diagnostic evaluation of rhabdomyolysis

2015

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Rhabdomyolysis is characterized by severe acute muscle injury resulting in muscle pain, weakness, and/or swelling with release of myofiber contents into the bloodstream. Symptoms develop over hours to days following an inciting factor and may be associated with dark pigmentation of the urine. Serum creatine kinase and urine myoglobin levels are markedly elevated. The clinical examination, history, laboratory studies, muscle biopsy, and genetic testing are useful tools for diagnosis of rhabdomyolysis, and they can help differentiate acquired from inherited causes of rhabdomyolysis. Acquired causes include substance abuse, medication or toxic exposures, electrolyte abnormalities, endocrine disturbance, and autoimmune myopathies. Inherited predisposition to rhabdomyolysis can occur with disorders of glycogen metabolism, fatty acid beta-oxidation, and mitochondrial oxidative phosphorylation. Less common inherited causes of rhabdomyolysis include structural myopathies, channelopathies, and sickle cell disease. This review focuses on the differentiation of acquired and inherited causes of rhabdomyolysis and proposes a practical diagnostic algorithm.

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Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis

Cited by 169 publications

References 39 publications

RYR1-related rhabdomyolysis: A common but probably underdiagnosed manifestation of skeletal muscle ryanodine receptor dysfunction

RYR1-related rhabdomyolysis: A common but probably underdiagnosed manifestation of skeletal muscle ryanodine receptor dysfunction

Exome analysis identifies Brody myopathy in a family diagnosed with malignant hyperthermia susceptibility

Diagnostic evaluation of rhabdomyolysis

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