RYR1-Related Myopathies

Literature and regulatory information updated: 9 October 2026.

Spectrum of muscle disorders caused by ryanodine receptor type 1 gene variants: central core disease, multiminicore disease, autosomal recessive centronuclear myopathy, congenital fibre type disproportion, King–Denborough syndrome, exertional myalgia and rhabdomyolysis with heat stroke, fetal akinesia and lethal multiple pterygium syndrome, distal, axial and myasthenic-onset myopathies.

0. Initial Reference Table

1. Introduction

1.1. From clinical description to the gene

The history of RYR1-related myopathies begins in 1956, when Magee and Shy published in Brain a description of “a new congenital non-progressive myopathy” in a family whose biopsies showed central muscle fibre regions lacking oxidative activity, later termed “central cores”; central core disease (CCD) was therefore also called Shy–Magee syndrome [3, 26]. The association between this myopathy and malignant hyperthermia (MH), a potentially fatal hypermetabolic reaction triggered by halogenated anaesthetics and suxamethonium, was noted shortly after MH itself was described, in the seventies [7]. RYR1 was sequenced in 1988 and the first variants altering calcium homeostasis and conferring MH susceptibility were identified in 1991 [1].

In 1993, two articles published in the same issue of Nature Genetics established the molecular basis of CCD. By sequencing complementary DNA from one patient, Zhang and colleagues identified the substitution Arg2434His (designated at the time “A to G7301”; historical numbering, = NM_000540.3:c.7304G>A p.(Arg2435His)), linked to the disease with a lod score of 4.8 (θ = 0.0) across 16 informative meioses in a 130-member family [27]. Quane and colleagues described two new variants in different families with CCD, one of which was also present in a family with MH without myopathy, which inaugurated the model of one variant with two phenotypes [28]. Recessive inheritance was demonstrated in 2002 by Jungbluth and colleagues in three patients from two consanguineous families with core myopathy and linkage to the RYR1 locus, one of them homozygous for p.Val4849Ile [29]. Complete gene sequencing, first by Sanger and later by massively parallel sequencing, extended the spectrum to recessive multiminicore, centronuclear and fibre type disproportion forms, and to induced phenotypes in adult life [1, 30].

1.2. Nomenclature and reclassification

Historically, congenital myopathies were classified by the predominant biopsy structural abnormality (cores, nemaline rods, central nuclei, fibre type disproportion), into structural, mixed and non-structural forms [31]. In RYR1, this proved insufficient: the same genotype may produce different histologies depending on biopsied muscle and biopsy age, and typical central cores may emerge only late in patients with childhood type 1 fibre uniformity alone [2, 4]. The CCD and MmD GeneReviews chapters were therefore retired in 2019 because these were histological diagnoses without strong genetic correlation [3, 4].

In 2020, Lawal and colleagues proposed the unified designation “RYR1-related disorders” (RYR1-RD) covering congenital myopathies, episodic phenotypes and pharmacogenetic MH susceptibility [1]. The 277th ENMC workshop (June 2024, published in 2026) adopted CMYO for congenital myopathies and a four-component nomenclature in order: inheritance pattern, gene, congenital myopathy and main histopathological finding [2]. For RYR1, the group further proposed classifying myopathies by inheritance, histological findings (cores, central nuclei, fibre disproportion, non-specific or multiple abnormalities) and extraocular muscle involvement, MH susceptibility or King–Denborough syndrome or arthrogryposis features; patients whose main feature is MH susceptibility should be considered a distinct pharmacogenetic phenotype rather than a congenital myopathy [2].

The table reproduces this article's relevant 277th ENMC examples [2]. Current clinical practice continues to use histological designations, retained here for clarity and always linked to inheritance.

1.3. Definition of spectrum entities

CCD is a generally AD, mild congenital myopathy defined by well-demarcated central or peripheral cores extending along a substantial length of type 1 fibres and lacking mitochondria and oxidative activity [3, 9]. Multiminicore disease is a congenital myopathy defined by multiple short focal lesions (a few sarcomeres) with sarcomeric disorganisation and lost oxidative activity in type 1 and 2 fibres; of its four classic clinical forms, RYR1-related forms are particularly the moderate form with hand involvement, ophthalmoplegic form and some antenatal forms with arthrogryposis, whereas the classic form with severe scoliosis is predominantly SELENON-related [4, 10]. AR RYR1-related centronuclear myopathy features internal nuclei, often multiple per fibre, irregular oxidative staining and external ophthalmoparesis [11, 30]. In CFTD, type 1 fibres are at least 12% smaller than the mean type 2 fibre diameter without other significant findings; biallelic RYR1 explains 10% to 20% of cases [4]. CNMDU1, with more than 99% type 1 fibres without cores or rods, may represent early CCD due to C-terminal variants [2, 3]. “Dusty core disease” (DuCD) describes granular-appearing cores, until recently associated only with recessive genotypes with reduced protein [32].

King–Denborough syndrome (KDS) combines congenital myopathy, facial and skeletal dysmorphism and MH susceptibility [12]. RYR1-related exertional myalgia and rhabdomyolysis (exertional rhabdomyolysis/myalgia, ERM) and exertional heat stroke are triggered manifestations of dominant variants, many MH-associated [13, 30]. At the severe end, two null variants cause fetal akinesia and lethal multiple pterygium syndrome (LMPS) [7, 14]. The spectrum also includes late-onset axial myopathy, atypical periodic paralysis, calf-predominant myopathy and distal myopathy with medial gastrocnemius atrophy, congenital myopathy with myasthenic onset and benign Samaritan congenital myopathy [1, 15–17, 30]. Some “core-rod” forms result from RYR1 variants, but the term is not synonymous with CCD because other genes produce the same appearance [3].

1.4. Scope and related entities

This article covers permanent myopathies and episodic muscular phenotypes. MH susceptibility as a pharmacogenetic trait, in vitro contracture testing (IVCT in Europe, CHCT in North America), crisis treatment with intravenous dantrolene and the detailed anaesthetic protocol, as well as the general classification, standards of care and differential diagnosis of congenital myopathies as a whole, are not developed here. Only the MH aspects that alter diagnosis, the genetic report, counselling and management of the patient with myopathy are revisited here.

2. Molecular Genetics and Pathophysiology

2.1. The gene and protein

RYR1 is located at 19q13.2 and comprises 106 exons, two alternatively spliced, spanning approximately 160 kb; it encodes one of the largest human proteins, with 5,038 amino acids [3, 4]. The clinically relevant transcript is NM_000540.3 (transcript 1), MANE Select, with 106 coding exons [6, 7]. RyR1 is expressed predominantly in skeletal muscle, but also B lymphocytes, dendritic cells and, in smaller amounts, arterial smooth muscle [3, 30]. The functional channel is a homotetramer of approximately 565 kDa subunits, with a reported total mass of 2.2–2.4 MDa, forming a macromolecular complex with regulatory proteins exceeding three million daltons [7, 30, 33]. Approximately the first 4,000 amino acids form the large hydrophilic cytoplasmic domain (“foot structure”), bridging sarcoplasmic reticulum (SR) and T-tubule; approximately the last 1,000 form the hydrophobic transmembrane plate containing the pore and selectivity filter [3]. Cryo-electron microscopy structures obtained since 2015 show that RyR1 belongs to the six-transmembrane-segment channel family and have enabled mapping of over 180 pathogenic variants onto the three-dimensional structure [30].

2.2. Excitation–contraction coupling

At the triad, comprising a terminal SR cisterna on either side of a T-tubule, membrane depolarisation activates the dihydropyridine receptor (DHPR, the L-type calcium channel encoded by CACNA1S), mechanically opening RyR1; the adaptor protein STAC3 binds DHPR and is required for activation [18]. Released calcium triggers contraction and is recaptured into SR by the ATP-consuming SERCA pump; calsequestrin buffers luminal calcium, FKBP12 (calstabin 1) stabilises the closed state, low cytosolic calcium stimulates and high calcium inhibits the channel, and magnesium inhibits it [7]. Phosphorylation, nitrosylation, oxidation, glutathionylation and palmitoylation also modulate the channel; with 404 cysteine residues per tetramer, RyR1 is a highly sensitive redox sensor [7, 30].

2.3. Pathogenic mechanisms

The 2026 European Molecular Genetics Quality Network (EMQN) guideline summarises mechanism–phenotype relationships in three groups: drug-triggered gain-of-function variants confer MH susceptibility; dominant-negative variants cause dominant myopathies; loss-of-function variants cause recessive myopathies; a small subset combines dominant MH with dominant myopathy, recessive myopathy or exertional rhabdomyolysis [7].

Gain of function results from variants in regions regulating channel opening, such as the FKBP12 binding site, or interfaces between domains stabilising the closed state; the channel becomes “leaky” and hypersensitive to activators [7, 30]. MH-only variants modestly increase basal activity without altering SR calcium content (“compensated leak”); combined MH/CCD variants increase basal activity sufficiently to deplete SR, raise resting cytosolic calcium and reduce maximal voltage-dependent calcium release (“decompensated leak”) [3]. With volatile anaesthetic exposure, massive calcium release and store-operated calcium entry (SOCE) sustain contraction and crisis hypermetabolism [7].

Most dominant CCD variants lie in the C-terminal transmembrane region, selectivity filter vestibule and pore; mutant subunits are expressed, form heterotetramers with normal subunits and reduce overall function through competition or steric hindrance, a dominant-negative effect [7]. Several, particularly in exon 102, alter calcium permeation and abolish orthograde DHPR activation, termed excitation–contraction uncoupling (“EC uncoupling”), without compensation [3]. The classic example, p.Ile4898Thr, identified in a large Mexican CCD family, helped locate the channel's selectivity filter and reduces calcium release by altering permeation [30]. However, some C-terminal variants also behave as leaky channels, maintaining controversy over strict separation of the mechanisms [3]. CCD features abnormal triad protein distribution: RyR1 is depleted within cores, while calsequestrin, SERCA1/2, triadin and DHPR accumulate within and around lesions [3]. A mouse model suggests that calcium leak generates reactive oxygen species, mitochondrial swelling and early structural changes, a hypothesis for core formation [3].

Complete loss-of-function variants (stop-gain, frameshift, altered splicing) cause protein loss through nonsense-mediated messenger RNA decay or degradation; in recessive forms they typically occur in trans with a partially functional variant [7]. EMQN emphasises that parents heterozygous for a null variant are healthy, so haploinsufficiency is not an RYR1 disease mechanism [7]. Two null variants are incompatible with normal fetal life and cause LMPS and antenatal death [7]. Reduced RyR1 content in recessive forms is aggravated by epigenetic mechanisms: recessive patient biopsies showed reduced muscle-specific microRNAs, hypermethylation of an RYR1 CpG island and increased class II histone deacetylases (HDAC-4 and HDAC-5) [30]. Polymorphic, tissue-specific, developmentally regulated allelic silencing has also been described, potentially producing monoallelic muscle expression and unmasking a recessive variant on the remaining allele; some recessive CNM families have only one identified variant, inherited from an asymptomatic parent, consistent with this mechanism or an undetected second variant [3, 4].

Oxidative stress is a common mechanism: patient myotubes and the ryr zebrafish model have more mitochondrially derived reactive oxygen species and carbonylated proteins, and N-acetylcysteine reduced these markers in models [30]. In 17 RYR1-RM patient biopsies, Kushnir and colleagues observed lost RyR1–calstabin association, SR calcium leak and increased calcium-activated protease activity, normalised ex vivo by a Rycal-class channel stabiliser [33, 34]. In whole blood from 28 National Institutes of Health (NIH) cohort patients, 19 (68%) had systemic NAD+ deficiency (below 21 µM), an observation without therapeutic translation in humans [35].

2.4. Variant distribution and hotspots

By 2014, over 200 CCD-associated variants had been described, predominantly missense and over half private [3]. Three hotspots are described: domain 1 (exons 1–17), domain 2 (exons 39–46) and domain 3 (exons 90–104); in Sarkozy and colleagues' protein numbering, MH1 (amino acids 35–614), MH2 (2163–2458) and MH3 (4550–4940) [3, 8]. MH variants predominate in N-terminal and central hydrophilic regions and CCD variants in the C-terminal pore-forming region, but recessive variants span the entire coding sequence and include at least one truncating variant in most cases [3, 7]. Because pathogenic variants occur in almost every exon, EMQN recommends sequencing all 106 exons with splice regions regardless of phenotype [7]. The gene is also highly polymorphic: rare potentially pathogenic variants occur in up to 6% of control populations, and in a British cohort of 126 MH families half the variants found were of uncertain significance [30, 36].

2.5. Genotype–phenotype correlations

In dominant CCD, C-terminal variants associate with earlier onset and homogeneous pathology, with cores in almost all type 1 fibres, interstitial fibrosis and type 2 fibre deficiency, whereas variants outside the C-terminal region produce milder phenotypes and atypical cores; in a Japanese series of 27 patients, 16 (59%) had a C-terminal hotspot variant [37]. The 277th ENMC adds that AD C-terminal variants with typical cores, type 1 fibre uniformity and reduced calcium-induced calcium release (CICR) do not confer MH susceptibility in most cases, with exceptions such as p.Gly4638Asp, whereas AD variants elsewhere associate with atypical, ill-defined or multiple cores, increased CICR and MH susceptibility [2]. CCD patients with N-terminal variants may have a greater MH likelihood than those with C-terminal variants [3].

In recessive forms, Amburgey and colleagues' analysis of 106 cases (14 new, 92 published) showed approximately half were not core myopathies (CNM, CFTD and others); hypomorphic variants reducing RyR1 quantity were enriched in non-core and severe forms, and at least one hypomorphic allele was significantly associated with greater severity; non-hypomorphic missense variants clustered in hotspots and the selectivity filter; ophthalmoplegia, common to all subtypes, was more frequent with hypomorphic alleles [30, 38]. In Sarkozy and colleagues' British paediatric cohort, 65% of recessive patients (20/31) had one hypomorphic and one non-hypomorphic variant, and 12 of 18 severe or non-ambulant recessive patients (66%) had at least one hypomorphic allele; 41% of hotspot variants associated with severe phenotype versus 22% overall [8]. Gene dosage also matters: p.Arg3772Gln causes MH heterozygously and clinical myopathy homozygously [30]. In an Israeli cohort, Bsol domain variants correlated with severity [39].

2.6. Variants with normalised nomenclature

The table combines this article's variants, normalised on MANE Select, with ClinVar classifications accessed on 9 October 2026. ClinGen RYR1 Variant Curation Expert Panel (VCEP) classifications refer to MH susceptibility; myopathy pathogenicity is assessed separately using American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria [7, 40–42].

Table sources are ClinVar and VariantValidator for normalisation and the clinical sources cited in text for context [3, 4, 6, 7, 18, 21, 30, 40, 43–45].

Three normalisation decisions merit comment. First, the MH susceptibility GeneReviews variant table gives “p.Arg933Thr” for c.2797G>A, but the chapter text and ClinVar give p.Ala933Thr; the arginine designation is a typographical error [18, 40]. Second, p.Met485Val appears benign in one chapter and associated with low protein in another; this is no true contradiction because contexts differ (isolated MH effect versus participation in a recessive combination), and ClinVar currently classifies it as uncertain significance for MH [3, 4, 40]. Third, Zhang and colleagues' Arg2434His probably corresponds to c.7304G>A p.(Arg2435His) because of historical numbering differences, but consulted sources do not document conversion, so the original designation is retained when citing the 1993 article [27, 40]. Historical protein designations p.Ala1832Gly and p.Val2550Leu, lacking matching ClinVar entries under those names, and the deep intronic variant described as “14646+2.99 kb”, not in Human Genome Variation Society (HGVS) nomenclature, remain unnormalised [3, 4]. Sarkozy and colleagues' variant table contains nomenclature errors (e.g. c.14692T>C instead of c.14693T>C for p.Ile4898Thr) and should not be transcribed without normalisation [8, 40].

2.7. Penetrance, expressivity and modifiers

Penetrance of variants associated with dominant CCD is almost complete, with wide intrafamilial variability, ranging from nearly asymptomatic carriers to ventilator-dependent patients [3]. Induced phenotypes have incomplete penetrance and a male predominance among symptomatic individuals; in a Dutch family, the brother of a woman with six episodes of rhabdomyolysis, carrying the same p.Gly2434Arg variant, had only asymptomatic hyperCKaemia up to 1,200 IU/L despite intensive training [30, 43]. MH penetrance is distinct from myopathy penetrance: a multicentre study estimated it at 40.6% for RYR1-related MH, but the population frequency of pathogenic variants suggests values below 5% [18]. The coexistence of independent RYR1 variants in the same family or of a second monogenic disorder (“double trouble”) should be considered when unexpected features are present [30]. Environmental factors modify episodic phenotypes (exercise, heat, viral infections, alcohol, drugs) [21, 46], and RYR1 variants may contribute to statin myopathy [18, 45].

2.8. Allelic disorders and relationship with malignant hyperthermia

RYR1 is associated with at least ten distinct muscle disorders [2]. The MH relationship is asymmetric: RYR1-related myopathies carry increased MH risk, but a variant pathogenic for myopathy may not cause susceptibility, and loss-of-function variants do not confer MH risk [5, 7, 18]. Specific missense variants associate with MH and recessive core myopathy, such as p.(Arg401Cys), p.(Thr2206Met) and p.(Val4849Ile), or dominant CCD and MH, such as p.(Arg163Cys), p.(Tyr522Ser) and p.(Arg4861His), and some behave dominantly for MH and recessively for myopathy in the same family [7, 30]. ERM appears a more common manifestation of MH variants than an anaesthetic crisis itself [30]. CACNA1S and STAC3, encoding other triad components, cause overlapping phenotypes discussed in Section 6 [18].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Overview: dominant and recessive forms

The clinical spectrum extends along two axes. First, permanent myopathies range from lethal fetal to almost asymptomatic forms; second, episodic phenotypes (MH, rhabdomyolysis, myalgia, heat stroke) occur in individuals with normal strength or subtle myopathy [2, 7]. Recessive forms tend to present earlier and more severely, sharing extraocular muscle involvement distinguishing them from dominant forms, together with more generalised weakness and greater bulbar and respiratory compromise [2, 7, 30]. Dominant forms are generally mild with intrafamilial variability; severe dominant forms predominantly arise from de novo variants [7].

The best available longitudinal description is Sarkozy and colleagues' British paediatric cohort: 69 children (38 female) from 53 families followed at the Dubowitz Neuromuscular Centre and Evelina Children's Hospital, London, between 1992 and 2019, with 29 AD, 31 AR, 6 de novo AD and 3 uncertain-inheritance cases; mean follow-up was 6.2 years and median first and last assessment ages 4.0 and 10.8 years [8]. Symptoms were present at birth in 37/67 (55%), began before 12 months in 5 (7%), between 1 and 2 years in 21 (31%) and between 3 and 6 years in 4 (6%); mean presentation age was 1.1 years in AD, 0.6 in AR and 0.2 in de novo AD [8]. This referral cohort is biased towards severe forms and lacks data after transition to adulthood.

The table reproduces Sarkozy and colleagues' Table 2, with SD denoting standard deviation; article text reverses weight Z-scores between groups, but the table and discussion indicate lower weight in AR patients, the interpretation adopted here [8].

3.2. Dominant central core disease

Typical dominant CCD presents with congenital hypotonia and weakness, sometimes hip dislocation at birth; motor milestones are delayed but independent walking is usually acquired, often between ages 3 and 4 [3, 30]. Weakness is symmetrical, proximal and predominantly pelvic girdle and quadriceps, with little facial involvement and normal eye movements; motor function improves during childhood, followed by prolonged stability with possible slow adult progression [30]. Exertional myalgia is frequent and cramps have been documented, possibly associated with MH susceptibility [3, 7]. Orthopaedic complications (scoliosis, congenital hip dislocation, foot deformities, contractures, high palate) predominate over respiratory complications; severe spondylocostal dysostosis-like skeletal malformations occur rarely [3, 7]. Cognition is preserved and life expectancy generally normal; prognosis primarily depends on respiratory status and scoliosis [3, 31]. Creatine kinase (CK) is generally normal but may be elevated, broadening the differential to limb-girdle muscular dystrophies [7, 47].

In Sarkozy's cohort, AD patients had better motor function than AR and de novo AD patients (p <0.01): only 1/28 AD patients never walked unsupported, none lost ambulation or required NIV and only one had respiratory compromise; however, timed tests worsened with age (rising from supine +0.31 s/year, 95% CI 0.12–0.49) and FVC percentage predicted declined by 1.3% annually (95% CI −2.5 to −0.2) [8]. Severe dominant forms exist: some patients with dominant variants and central cores survive the neonatal period with severe motor involvement, sometimes no independent walking and early progressive scoliosis, without facial or extraocular involvement; among patients described by Romero in 2003 whose ventilation was maintained, motor improvement, some respiratory independence and, in one case, independent walking after age 5 occurred [30]. Sarkozy's six de novo AD patients all had facial weakness and four never walked unsupported [8].

3.3. Recessive forms: multiminicore, centronuclear, fibre disproportion and “dusty core”

Recessive forms display diverse phenotypes and histologies, and one patient may have central cores and multiminicores in different muscles or successive biopsies [4, 30]. The 217th ENMC distinguished two clinical groups: with ophthalmoparesis, associated with internal nuclei or a multiminicore pattern, and without ophthalmoparesis, with CCD, congenital muscular dystrophy (CMD) or non-specific histology, marked weakness and early progressive scoliosis [30].

Across genes, multiminicore disease has four forms. The classic form (approximately 75%) has congenital onset with hypotonia, marked axial weakness (trunk and neck flexors 1–2/5 on the Medical Research Council, MRC, scale), progressive cervicothoracic scoliosis with mean onset 8.5 years, spinal rigidity and respiratory compromise in approximately two-thirds; it is predominantly SELENON-related [4]. The moderate form with hand involvement (less than 10%), associated with RYR1, features distal upper-limb weakness with joint hyperlaxity and mild or absent scoliosis and respiratory involvement; in a family homozygous for an exon 71 variant, initial biopsy showed MmD and later biopsy typical CCD lesions [4]. The antenatal form with arthrogryposis (less than 10%) features generalised birth contractures, dolichocephaly, prominent nasal root, oblique palpebral fissures, high palate, low-set ears, short neck and clinodactyly [4]. The ophthalmoplegic form (less than 10%), associated with RYR1, has neonatal onset with marked hypotonia, pronounced axial and proximal weakness, external ophthalmoplegia particularly affecting upward and lateral gaze, ligamentous laxity and moderately compromised respiratory function, generally without nocturnal hypoventilation [4]. Among ten compound heterozygous patients with overlapping central cores and minicores, nine had ophthalmoplegia [4]. RYR1-related disease is generally milder than SELENON-related disease [4].

RYR1-related centronuclear myopathy features variable external ophthalmoparesis, often with facial weakness, ptosis and highly variable proximal weakness [11, 30]. Most patients are compound heterozygotes; some families have only one identified variant [4]. In South Africa (Western Cape), congenital myopathies with central nuclei are the predominant subtype, caused by recurrent, probably founder RYR1 variants, enabling development of a targeted local test [2]. RYR1-related CFTD likewise features ophthalmoplegia, making RYR1 the most likely cause when present; RYR1 is the second CFTD cause after TPM3 [4, 30]. “Dusty core disease” was described in four Italian patients with five variants, two with dominant adult-onset moderately severe presentations, broadening inheritance previously considered exclusively recessive [32].

In Sarkozy's cohort, AR patients had more ophthalmoparesis (39%), ptosis (45%), spinal rigidity (29%), NIV (26%), respiratory compromise (32%) and gastrostomy or tube feeding (32%) than AD patients [8]. A “reverse course” occurred in recessive patients, with reduced NIV after childhood, gastrostomy removal and improved severity scores; FVC percentage declined by only 0.2% annually (95% CI −1.3 to 0.9) [8].

3.4. Severe fetal and neonatal presentations

RYR1-related fetal akinesia occurs with dominant and recessive inheritance: severe hypotonia, multiple congenital arthrogryposis, amyotrophy and respiratory failure requiring mechanical ventilation, with outcomes from early death to survival beyond age 5 [3]. During pregnancy, the affected fetus may cause polyhydramnios and reduced movements, and malpresentation may complicate delivery [4]. At the spectrum's extreme, two null variants cause LMPS with prenatal growth restriction, hypertelorism, epicanthal folds, flat nose, cleft palate, small mouth, micrognathia, multiple contractures and pterygia at almost all joints, frequently with fetal death [7, 48]. In an LMPS and fetal akinesia sequence cohort, recessive RYR1 variants explained 8% of cases, making RYR1 a significant cause warranting inclusion when fetal acetylcholine receptor genes are negative [48, 49]. In genomic cohorts of in utero congenital myopathy presentations, recessive RYR1 loss-of-function variants are among the main contributors after TTN [2].

3.5. King–Denborough syndrome

KDS combines congenital myopathy, dysmorphic features and MH susceptibility: ptosis, downslanting palpebral fissures, hypertelorism, epicanthus, low-set ears, malar hypoplasia, micrognathia, high-arched palate, clinodactyly, single palmar crease, pectus excavatum or carinatum, winged scapula, lumbar lordosis, scoliosis, short stature, webbed neck and cryptorchidism [12, 18]. Ptosis, hypertelorism, webbed neck and short stature overlap with the Noonan syndrome phenotype, which enters the differential diagnosis. Neonatal hypotonia, mild motor delay, joint hyperextensibility and mild proximal weakness are accompanied by a biopsy with minimal changes [18]. A tendency to severe muscle rigidity and hyperthermia even outside anaesthesia, and to rhabdomyolysis after strenuous exertion, viral infection or statins, is characteristic [7, 12]. Orphanet records 18 published cases and AD inheritance, but RYR1 variants have been found in only some patients [12, 18]. In a South African cohort of 67 Black African patients with congenital myopathy, 44 with a clinical diagnosis of KDS, RYR1 and STAC3 were the predominant causes, both with AR inheritance in this population [50]. The Israeli cohort included three patients with KDS [39].

3.6. Triggered and episodic phenotypes

Dlamini and colleagues characterised RYR1-related exertional rhabdomyolysis: among 39 British and Dutch families with rhabdomyolysis or exertional myalgia, nine heterozygous variants were found in 14 families, five already MH-associated; index cases were aged 3–45, strength generally normal and no personal MH history present; heat intolerance and cold-induced stiffness were inconsistent, biopsies showed subtle abnormalities and carrier relatives had similar symptoms or none [21]. According to the 217th and 276th ENMC, MH-associated variants explain 20% to 30% of ERM, frequently in individuals with above-average athletic ability; triggers include exercise, ambient heat, infections in preceding days, alcohol, recreational drugs and medicines (including olanzapine), but, unlike most metabolic causes, not fasting [30, 46]. Rhabdomyolysis may also occur during viral illness without other triggers, mimicking viral myositis as in Section 10 [30, 43]. A fatal MH reaction during anaesthesia shortly after strenuous exercise suggests exertion also contributes to MH [30].

Exertional heat stroke is hyperthermia above 40 °C with encephalopathy, whose incidence increases with temperature and humidity; severe forms feature rhabdomyolysis, tachycardia and multiorgan failure, and RYR1 is the main known susceptibility factor [13]. A five-centre review found 41 MH-susceptible patients with strenuous exercise or fever before an anaesthetic reaction, supporting a continuum between MH, exertional rhabdomyolysis and heat illness [18]. In Leeds, 9 of 62 individuals with exertional heat illness and abnormal thermoregulation on a standardised test had rare potentially pathogenic RYR1 variants [30]. Cases described as human stress syndrome, with muscle hypertrophy and early rigidity during febrile illnesses, should not be called “awake” MH [30].

MH susceptibility-related myopathy is now recognised as a distinct adult phenotype: cramps, stiffness, myalgia, rhabdomyolysis and weakness with non-specific histology and effects on quality of life and employment [51]. Patients positive on halothane but not caffeine contracture testing have a high frequency of these symptoms [18]. In a prospective Dutch patient-reported outcome study, 43 of 50 participants with RYR1-related MH or ERM completed 12 months; many reported fatigue and impaired sleep, walking, daily activities and leisure, with poorer quality of life in those with overt neuromuscular symptoms, anxiety and depression similar to controls and stable outcomes after one year [52]. Late-onset axial myopathy, with progressive paraspinal weakness in previously strong individuals, lumbar hyperlordosis, scapular winging (sometimes asymmetric, mimicking facioscapulohumeral dystrophy) or camptocormia between the third and sixth decades, is a less frequent MH variant manifestation; periodic paralysis is a rare but genuine association [30, 39].

3.7. Other allelic presentations

Calf-predominant distal myopathy with medial gastrocnemius atrophy is AD and adult-onset [1, 17]. AR congenital myopathy with myasthenic onset combines fatigable weakness, fatigable ptosis, feeding difficulties, motor delay and proximal weakness with typical RYR1 magnetic resonance imaging (MRI); two patients were described [15]. Benign Samaritan congenital myopathy features severe neonatal hypotonia with respiratory failure and mild dysmorphism, followed by improvement in the first 2 years and minimal adult manifestations; four cases were described [16]. A 51-year-old woman developed acute respiratory failure as the first congenital myopathy manifestation, with c.5701C>T p.(Gln1901*), and recovered function with ventilation, tracheostomy and rehabilitation [53].

3.8. System-specific manifestations

Respiratory. Neonatal respiratory failure may occur even with mild disease, and severe forms require continuous ventilation from birth [3]. During childhood, respiratory compromise accompanies scoliosis and axial weakness; in recessive forms it may be disproportionate to limb weakness [23]. In Sarkozy's cohort, absolute FVC increased 0.17 L annually, FVC percentage fell 0.89% annually (95% CI −1.64 to −0.14), 11 patients had FVC below 60% and 5 below 40% (mean ages 9.7 and 11.1), 10 began NIV at a median age of 2.5, none required tracheostomy and spinal surgery did not alter FVC [8].

Musculoskeletal. In the same cohort, 13 had developmental hip dysplasia, 21 (29%) developed scoliosis (congenital in two), 8 underwent surgery at median age 8.2 with median Cobb angle 58°, 35 had contractures and 43 hyperlaxity; four of 12 children with hip dysplasia older than 2 never achieved independent walking [8]. In MmD, scoliosis progresses rapidly during the growth spurt [4].

Bulbar and nutrition. Swallowing or feeding difficulties occurred in 3/29 AD and 17/31 AR patients (p <0.01), with gastrostomy at median age 0.5 and three gastrostomies reversed [8]. Short stature and growth failure are frequent in recessive forms, and speech may be hypernasal [4].

Cardiac. Primary cardiac involvement is rare in RYR1 core myopathies, unlike TTN or MYH7 core myopathies; in classic MmD, right ventricular failure is secondary to respiratory compromise and occasional mitral prolapse occurs [4, 7, 47]. Sarkozy's cohort included four children with abnormalities (two septal defects, ventricular bigeminy, mild left ventricular hypertrophy) [8]. In the Dutch cohort, four families had a history of presumably cardiac premature sudden death, including the brother of a patient with axial myopathy (p.Val4849Ile) who died at a marathon finish, and dilated cardiomyopathy attributed to viral infection, bicuspid aortic valve and sinus bradycardia were observed; significance is unresolved because the main cardiac isoform is RyR2 [30]. Table 15.3.3 in a Brazilian textbook attributes “progressive cardiomyopathy” to CCD, but this cell contradicts other sources and appears to reflect table misalignment, so is not reproduced [31, 47].

Bleeding and smooth muscle. A standardised questionnaire showed greater bleeding tendency in gain-of-function carriers, particularly women, with severe menorrhagia and postpartum haemorrhage, sometimes signs of intestinal and bladder smooth muscle involvement; in the Y522S mouse, bleeding time tripled and was normalised by dantrolene [30]. A survey of 66 female RYR1 variant carriers and 88 controls confirmed more frequent pathological bleeding scores, severe menorrhagia, pre-eclampsia, placenta praevia, planned caesarean sections, lower-birthweight newborns and gastrointestinal symptoms, with selection bias from recruitment through a patient organisation [54]. In Sarkozy's cohort, one child had excessive bleeding [8].

Thermoregulation, neurodevelopment and other features. Profuse sweating or heat intolerance occurred in four children (three AD), neurodevelopmental or psychiatric disorders in six and learning difficulties in nine [8]. An adolescent with fatal MH had cerebellar involvement resembling heat stroke [30].

3.9. Adult natural history

In ambulant adults and children in the NIH study, the 6-month pretrial assessment (n = 37) showed stable urinary 15-F2t-isoprostane and six-minute walk test (6MWT) distance; baseline distance was 468 ± 134 m versus 600 ± 58 m in the general population, and isoprostane 3.2 ± 1.5 versus 1.1 ± 1.7 ng/mg creatinine [55]. Physical fatigue measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) is increased (t-scores 55 ± 4 and 64 ± 3 in the two phase 1 trial groups, normal range 20–55) [33]. MRI and CT in 36 Japanese patients showed a common progressive fatty replacement pattern correlated with respiratory failure, walking impairment, scoliosis and pathology [56]. In an international survey of 146 patients, priorities were weakness, fatigue and mobility [57]. The 217th ENMC noted that mouse models suggest progressive RYR1-RM and prospective multicentre natural history data remained lacking [30].

3.10. Natural history and treated disease

Sarkozy's data describe children receiving specialist care including NIV, gastrostomy and spinal surgery; recessive improvement after childhood cannot therefore be interpreted as untreated natural history [8]. Absence of rhabdomyolysis and MH reactions in the same cohort, including eight spinal operations, and normal CK in all 44 tested reflect a paediatric population with anaesthetic precautions rather than zero risk [8].

4. Clinical Recognition and Warning Signs

4.1. Prenatal and neonatal period

Suspicion often begins prenatally. Reduced fetal movements (48% of Sarkozy's recessive cases), polyhydramnios, breech presentation and joint contractures, particularly arthrogryposis or pterygia, warrant inclusion of RYR1 in fetal genetic investigations, particularly after exclusion of fetal acetylcholine receptor genes [8, 48, 49]. In newborns, hypotonia, weakness with reduced reflexes, sucking difficulties, respiratory failure and congenital hip dislocation suggest congenital myopathy; ptosis, ophthalmoparesis and facial weakness suggest a recessive form, whereas hip dislocation with normal face and eyes suggests dominant CCD [3, 8, 30]. Extraocular involvement is rarely evident at birth (two AR patients in Sarkozy) and should be sought during follow-up [8]. No British cohort patient had hydrops, pterygia or cleft palate; these signs in a live newborn broaden the differential [8].

4.2. Infancy and childhood

Motor delay affects approximately 80% of children with RYR1-RM, and 21% never acquire or lose independent walking [8]. In walking children, difficulty rising from the floor, climbing stairs and running, with predominantly lower-limb and pelvic proximal weakness and normal or mildly elevated CK, suggests CCD [3, 30]. At Sarkozy's last assessment, all but one patient had greater proximal than distal and lower- than upper-limb weakness [8]. Scoliosis, spinal rigidity, high palate, joint hyperlaxity and pes cavus complete the presentation [8, 31]. Nocturnal hypoventilation symptoms (morning headaches, daytime drowsiness, poor appetite, declining school performance) require active assessment because respiratory failure may develop silently [3, 4].

4.3. Adolescents and adults

In adolescents and adults, consider RYR1 with exertional myalgia or cramps, rhabdomyolysis without a sufficient acquired cause, repeated episodes, idiopathic hyperCKaemia, heat intolerance, exertional heat stroke or combinations thereof [7, 51]. Late-onset paraspinal weakness, camptocormia or asymmetric scapular winging in a previously athletic individual should also suggest RYR1 [30]. Suspected MH anaesthetic reactions in a patient or family, or unexplained death of a relative with MH signs, indicate investigation [18]. MH variant carriers with neuromuscular symptoms should be informed that these may belong to the same condition, avoiding unnecessary investigations and consultations [46].

4.4. RHABDO criteria suggesting a genetic cause

The 276th ENMC recommends considering a genetic cause of exertional rhabdomyolysis when at least one RHABDO acronym criterion is present [46].

4.5. Warning signs and emergencies

The following require immediate action: acute respiratory failure, including decompensation during lower respiratory tract infections; dark urine or anuria, abnormal vital signs, compartment syndrome or metabolic disturbances during an episode of rhabdomyolysis; hyperthermia above 40 °C with altered consciousness after exertion; and any sign of MH during or after anaesthesia [4, 13, 46]. In recessive forms, a rapid respiratory crisis or unrecognised nocturnal hypoventilation may be fatal, and the need for partial or permanent ventilatory support should be reassessed continuously [4]. In children with RYR1-related myopathy, sudden death has been described after a therapeutic dose of ondansetron, which warrants caution with 5-HT3 antagonists [18].

4.6. Newborn screening

No newborn screening exists for RYR1-related myopathies. ClinGen actionability classifications for RYR1 variants refer to MH susceptibility as a secondary finding in non-diagnostic settings and explicitly exclude newborn and prenatal screening; no myopathy actionability assertion exists [5].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

According to the 277th ENMC, congenital myopathy diagnosis requires compatible symptoms plus an explanatory genetic diagnosis or compatible biopsy; when neither is available, congenital myopathy is termed probable or possible, retaining alternatives [2]. RYR1 diagnosis now rests on pathogenic variant(s) with consistent inheritance: a dominant variant (inherited from an affected parent or de novo) or two variants in trans [7]. Historical GeneReviews CCD criteria (biopsy with characteristic cores in a significant number of fibres and/or a pathogenic RYR1 variant) and MmD criteria (minicores in a large fibre proportion, static or slowly progressive weakness and absence of other disease findings) remain useful for biopsy interpretation but were retired as disease definitions [3, 4]. Biopsy remains important with inconclusive genetic testing, particularly for variants of uncertain significance (VUS) in patients with few clinical signs [2, 3].

For rhabdomyolysis, the 276th ENMC defined three conditions: symptoms (severe muscle swelling, weakness or myalgia); CK above 10,000 IU/L in exertional or 5,000 IU/L in non-exertional rhabdomyolysis; and CK peak 1–4 days after the event with return to baseline within 1–2 weeks of rest. Myoglobinuria establishes diagnosis, and in underlying neuromuscular disease a CK rise exceeding 5–10 times baseline is considered rhabdomyolysis [46].

5.2. Biochemical and neurophysiological investigations

CK is normal or mildly elevated in RYR1 congenital myopathies; CK more than five times normal should suggest muscular dystrophy but may occur in RYR1-RM with CMD pattern or exertional myalgia [2, 3]. During rhabdomyolysis, CK reaches tens of thousands of IU/L (66,413 U/L in Section 10) and may remain elevated at rest [43]. Electromyography shows short, low-amplitude motor unit potentials and early recruitment, excluding denervation, which may also produce core-like lesions; 3 Hz repetitive stimulation and single-fibre electromyography help exclude congenital myasthenic syndromes, remembering that some congenital myopathies have neuromuscular junction abnormalities [2–4]. Testing is less tolerated and harder to interpret in newborns and infants [2].

5.3. Muscle imaging

Muscle MRI, preferably whole-body with T1 or Dixon sequences, is preferred, and the dominant RYR1 myopathy pattern is well characterised [2]. The thigh shows selective consistent involvement of vastus lateralis and intermedius, sartorius and adductor magnus, relatively sparing rectus femoris, gracilis and adductor longus, sometimes hypertrophied; lower-leg involvement affects soleus, lateral gastrocnemius and peroneal group, relatively sparing tibialis anterior; gluteus maximus is also affected [3]. In Sarkozy's cohort, MRI in 19 patients showed anterior thigh predominance (vastus lateralis, sartorius, adductor longus) and gluteal involvement and was normal in four mildly affected children aged 5–6 [8]. Recessive findings are less consistent [3]. In a preliminary study, blinded whole-body MRI agreed with genetic findings in over 80% of 30 children with early myopathy, including 80% of VUS, illustrating its value for variant interpretation [2]. Muscle ultrasound is an alternative in young children to avoid sedation and choose biopsy site [2, 31].

5.4. Muscle biopsy

The table summarises historical GeneReviews, 217th and 277th ENMC and Sarkozy cohort descriptions [2–4, 8, 30]. Among 41 Sarkozy biopsies, 14 showed central cores (4 with nuclear centralisation), 10 minicores or multiminicores, 13 nuclear centralisation (9 AR) and 19 type 1 disproportion or predominance (12 AR) [8].

Biopsy has limitations that must be understood. Cores may vary in size or be absent, are distinguished from the target fibres of neurogenic atrophy by the absence of a dark peripheral rim, and are not specific: they occur with variants in SELENON, MYH7, ACTA1, TNNT1, CFL2 and TTN [3, 4, 30]. Secondary minicores occur in short-chain acyl-coenzyme A dehydrogenase deficiency, cardiomyopathies, hypohidrotic ectodermal dysplasia, Marfan syndrome, after anaesthetic reactions and in denervation [4]. Histology changes over time: serial biopsies have shown central cores developing progressively, and patients with C-terminal variants may show only type 1 fibre uniformity in childhood [2, 30]. The muscle selected also matters, because involvement is differential [30]. Open biopsy for contracture testing has its own requirements [5]. Cores were found in about 50% of patients with MH susceptibility and an RYR1 variant, generally less well demarcated than in CCD, and in patients with MH without myopathy and C-terminal variants the designation “MH with cores” is preferable to CCD [3].

5.5. Genetic strategy

The 277th ENMC advocates “genetics first”, using massively parallel sequencing panels, exome or genome as first line before biopsy where available, after excluding age-appropriate alternatives [2]. For myopathy, EMQN recommends offering non-targeted testing including RYR1, except with strong suspicion of disorders undetectable by short-read sequencing (repeat expansions such as myotonic or facioscapulohumeral dystrophy, duplicated genes such as spinal muscular atrophy); targeted RYR1 testing is an alternative with high suspicion or unavailable broad testing [7]. RHABDO criteria guide exertional rhabdomyolysis testing [7, 46]. In that context, MH GeneReviews proposes a panel including RYR1, CACNA1S, STAC3 and differential genes and discourages testing only the familial variant even in relatives; conversely, EMQN recommends restricting predictive testing to the familial variant to avoid unsolicited findings unless the relative has a more severe phenotype or positive contracture testing without the familial variant [7, 18]. This difference reflects differing aims (detecting another MH cause versus limiting incidental findings) and should be resolved individually with the MH unit.

Test yield depends on population. In the Sanger era, selected-exon sequencing identified variants in 47%–80% of dominant CCD, while full sequencing found variants in 25 of 27 Japanese biopsy-confirmed CCD patients (93%) [3, 37]. In a Dutch MH and myopathy referral centre (2008–2012), 77 of 277 tested patients had RYR1 variants (28%), with 61 distinct variants, 24 novel [30]. In a laboratory cohort of 1,110 congenital myopathy patients from 918 families, 70% had genetic diagnoses and 84% of solved cases had variants in one of nine genes including RYR1 [2]. In an Australian glycogenosis and rhabdomyolysis cohort (n = 765), a neuromuscular panel yielded 17.5%, with RYR1 among the most frequent genes [46]. These proportions describe each study's detections within its population rather than clinical test sensitivity.

5.6. Interpretation and reporting by clinical scenario

The table translates Box 1 of the 2026 EMQN guideline [7]. In recessive myopathy, two variants in cis make RYR1 less likely; with one pathogenic variant and strong suspicion, supplement poorly sequenced coverage, perform CNV analysis or muscle RNA sequencing and, if unavailable, declare limitations in the report [7]. In a sporadic case with one heterozygous variant, test parents to distinguish dominant de novo from recessive disease with an unidentified second allele [3, 7]. EMQN emphasises that IVCT does not inform variant causality for myopathies [7].

Reports should answer the referral question (MH, myopathy or both; diagnostic or predictive testing), state gene, NM_000540.3 transcript, genomic, complementary DNA and protein HGVS nomenclature, zygosity and phase where known, and ACMG/AMP class using “pathogenic”, “likely pathogenic” and “uncertain significance”, without mentioning benign or likely benign variants; consider observed inheritance and recommend action (MH unit, genetic counselling, family studies) [7]. Laboratories should be ISO 15189:2022-accredited and participate in external quality assessment [7].

5.7. Test limitations

Negative results do not exclude diagnosis. Most variants are single nucleotide or small deletions or duplications, and large deletions and duplications are rare, but CNV analysis is good practice in myopathic phenotypes (not MH referrals, where gain of function is the mechanism) [7, 18]. GC-rich exon 91 has reduced coverage with some exome capture reagents (codons 4,209–4,479), potentially causing false negatives; reports should declare coverage and intronic variant and CNV detection limitations [7, 18]. Deep intronic and splicing variants require RNA sequencing; a patient with myopathy and neck stiffness was solved by RNA-seq detection of a retained intron altering RYR1 splicing [2]. Monoallelic expression through epigenetic silencing and regulatory variants may explain single-variant cases [3, 4]. Interpretation is complicated by extensive gene variation: rare potentially pathogenic variants occur in up to 6% of controls and half the variants in a British MH cohort were of uncertain significance [30]. VUS in RYR1, CACNA1S and SCN4A continue to require functional assays [2]. Parental somatic mosaicism with mild symptoms is possible and may escape blood testing [3].

MH variant classification uses VCEP ClinGen-adapted ACMG/AMP criteria, initially classifying 84 and subsequently another 251 variants, and functional data (calcium release in HEK293 cells, RyR1-null mouse myotubes, patient myotubes or microsomes, lymphoblasts) [7, 18, 41, 42]. An in vitro caffeine-induced calcium release sensitivity assay was validated to inform these criteria [18]. Biopsy CICR testing is considered more specific than MH contracture testing [2]. ClinGen has separate guidance for RYR1 myopathy variant curation [7].

5.8. Integrated algorithm

For suspected congenital myopathy, assessment begins with clinical and family evaluation, CK and, according to age and availability, electromyography and muscle imaging [2]. A broad myopathy panel, exome or genome with CNV analysis follows [7]. A dominant variant with consistent phenotype is confirmed and the family studied; with two variants, determine phase; with one variant in suspected recessive disease or VUS, use segregation, muscle MRI, biopsy, RNA sequencing and available functional studies [2, 7]. Every missense or in-frame scenario requires MH risk assessment, communication and referral to an MH unit [7]. For rhabdomyolysis, apply the 276th ENMC definition, assess acute kidney injury risk and request genetic testing if RHABDO criteria apply; MRI, biochemistry, exercise testing and biopsy (over 8 weeks after the episode) complete inconclusive investigations [46]. In Brazil and elsewhere, the reference textbook proposes a common-myopathy panel followed by exome sequencing if negative [31].

5.9. Prenatal and preimplantation diagnosis

Once familial variants are identified, prenatal diagnosis and preimplantation genetic testing are possible in dominant and recessive forms [3, 4, 7]. EMQN permits offering predictive testing, including prenatal testing, for AD and AR myopathies [7]. With ultrasound fetal akinesia signs without previous diagnosis, recessive RYR1 loss-of-function variants are among causes to investigate by fetal exome [2, 49].

6. Differential Diagnosis

The differential diagnosis depends on the mode of presentation: hypotonic infant, child with core or central nuclei myopathy, adult with rhabdomyolysis or axial weakness, fetus with akinesia. The table concentrates on the entities most frequently confused with RYR1-related forms.

Table sources are historical GeneReviews, MH GeneReviews, 217th and 277th ENMC, EMQN, 276th ENMC and cited textbooks [2–4, 7, 18, 30, 31, 46–49].

The most difficult distinction is SELENON myopathy, sharing minicores and redox regulation defects with recessive RYR1 forms; ophthalmoplegia, predominantly pelvic weakness and MRI pattern favour RYR1, while rapidly progressive severe scoliosis with early respiratory failure favours SELENON [4, 30]. CCD and MmD form a histological continuum: marked pelvic girdle weakness, mild facial involvement, absence of significant respiratory compromise, myalgia/cramps and well-demarcated cores confined to type 1 fibres and extending their full length favour CCD [4]. Recessive forms with central nuclei share X-linked myotubular features, probably through common triad assembly defects [30]. Cardiac involvement is the most useful TTN and MYH7 clue because it is typically absent in RYR1 myopathies [7, 47]. Very high baseline CK suggests muscular dystrophy except in dystrophic-pattern or exertional-myalgia RYR1-RM [2].

In rhabdomyolysis, the first differential is physiological response to unaccustomed exercise: in 499 healthy military recruits, CK peaked on training day seven, with 27% above five times and 11% above ten times the upper limit of normal, reaching 35,056 IU/L [46]. Metabolic causes differ in triggers (fasting does not trigger RYR1 rhabdomyolysis) and specific tests; over 75 genes are associated with rhabdomyolysis and available panels contain 66–72 genes [30, 46]. Neuroleptic malignant syndrome may relate to RYR1, given olanzapine-triggered episodes in pathogenic variant carriers [30, 36]. In fetal akinesia, fetal acetylcholine receptor genes explain some LMPS (CHRNG approximately 8% of AR cases, CHRNA1 and CHRND 3% each), and consider RYR1 when negative [48, 49].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no authorised disease-modifying treatment for RYR1-related myopathies; management is supportive, multidisciplinary and complication-driven, always with anaesthetic precautions [5, 31]. The team includes paediatric neurology or neurology, respiratory medicine, orthopaedics, physical and rehabilitation medicine, physiotherapy, occupational and speech therapy, nutrition, clinical genetics and anaesthesiology with access to an MH unit [3, 4, 7]. The following points concentrate on what is specific to RYR1. The RYR-1 Foundation handbook of 2020, reviewed by clinicians and researchers and available in Brazilian Portuguese, is an educational document for patients and families and not a formal guideline; it is used here as a complementary source for practical surveillance intervals [58].

7.2. Initial assessment after diagnosis

After diagnosis, recommended assessments include neurological examination (hypotonia, growth, contractures, scoliosis, weakness, cramps), physiotherapy/occupational therapy, sucking, swallowing, reflux and airway protection, respiratory function (particularly with scoliosis, hypotonia, respiratory difficulty or recurrent infections), nocturnal hypoxia symptoms and sleep studies, spinal and contracture radiographs, cardiac evaluation, speech and language therapy (dysarthria, hypernasal voice), orthodontic palate assessment and genetic consultation [3, 4]. MH risk from the identified variant should be assessed and communicated immediately in report and consultation, with MH unit referral [7].

7.3. Respiratory care

Continuous assessment of partial or permanent ventilatory support needs is critical in recessive forms because rapid respiratory crises and unrecognised nocturnal hypoventilation may be fatal; indicated nocturnal ventilation can significantly improve prognosis [4]. Surveillance includes respiratory rate, peripheral oxygen saturation, peak expiratory flow, FVC and forced expiratory volume in one second (FEV1), with sleep studies for nocturnal hypoxia signs [3, 4]. The RYR-1 Foundation handbook proposes annual respiratory assessment in low-risk forms/variants and six-monthly assessment in severe forms, respiratory function testing from age 5 and assisted cough techniques, with mechanical insufflation–exsufflation typically twice daily routinely and up to hourly during infection [58]. Respiratory severity varies by subtype: typically mild in CCD, severe and sometimes life-threatening in MmD, mild to severe in CNM and severe from birth in some CFTD patients [58]. Prevention includes annual influenza vaccination, pneumococcal vaccination and prompt intensive lower respiratory infection treatment, plus breathing exercises and chest physiotherapy for secretion clearance [3, 4, 58]. In Sarkozy's cohort, NIV began at median age 2.5, was reduced or stopped in two recessive patients at 6 months and no child required tracheostomy [8].

7.4. Rehabilitation, orthopaedics and bone health

Physiotherapy includes stretching, low-impact light-to-moderate exercise avoiding exhaustion and active mobilisation to prevent contractures; walking aids including wheelchairs adapt to disease course [3]. Scoliosis is monitored clinically and radiographically, more frequently during growth spurts because rapid progression is characteristic of MmD [4]. For small scolioses, the RYR-1 Foundation handbook describes approximately annual radiographic surveillance and soft bracing; growing rods in children; spinal fusion in older patients [58]. In Sarkozy's cohort, eight children underwent spinal surgery (four with magnetic growing rods) at median age 8.2 without severe adverse reactions or altered FVC trajectory [8]. Orthopaedic intervention may reduce scoliosis-related respiratory compromise [3]. Congenital hip dislocation and foot deformities may require surgery planned with MH trigger-free anaesthesia [3, 31]. For bone health, the RYR-1 Foundation handbook recommends vitamin D and calcium, annual vitamin D measurement and annual bone densitometry (DEXA) in some patients [58].

7.5. Feeding, growth and speech

Sucking/swallowing difficulties are managed with nasogastric or orogastric feeding, gastrostomy, high-calorie formulas and usual reflux treatment [3, 4]. In Sarkozy's cohort, gastrostomy was placed at median age 0.5 and reversed in three children (at 3.2, 10.8 and 12.8 years), showing nutritional support may be temporary in recessive forms [8]. Growth requires regular monitoring and speech and language therapy addresses dysarthria and hypernasal voice [4].

7.6. Acute rhabdomyolysis and episode prevention

The 276th ENMC recommends tiered management: determine emergency attendance and admission needs from warning signs (abnormal vital signs, dark urine/anuria, compartment syndrome, metabolic disturbances) and comorbidities, and estimate acute kidney injury risk using the McMahon score [46]. Hydration underpins renal failure prevention, but aggressive treatment may be unnecessary without comorbidities, with CK below 15,000 IU/L and low renal risk: many neuromuscular patients have baseline CK 5,000–10,000 IU/L without renal failure, and in a Copenhagen review of 701 patients with CK above 3,000 IU/L, outcomes for 240 without comorbidities were similar with or without treatment [46]. In neuromuscular patients without comorbidities, the workshop proposes starting treatment with CK above 20,000 IU/L, myoglobinuria or creatinine increase exceeding 26 µmol/L in 24 hours or absolute value above 141 µmol/L (the report prints “mmol/L”, a unit typo because values correspond to micromoles) [46]. Treatment comprises normal saline volume replacement and electrolyte correction; bicarbonate urine alkalinisation lacks evidence, and suspected compartment syndrome requires pressure measurement before possible fasciotomy [46]. After episodes, physical activity should resume gradually at least four weeks after symptom resolution, with physiotherapy and support for physical and psychological sequelae [46]. A semi-professional cyclist with RYR1 rhabdomyolysis described the importance of psychological support in changing from sport to sedentary employment [46].

Prevention rests on adequate hydration and nutrition, avoiding unaccustomed/high-risk exercise (including eccentric contractions), attention to hot humid conditions, infections before exercise and medicines altering thermoregulation, and education in early sign recognition; RYR1 forms warrant avoiding temperature extremes [46]. MH GeneReviews recommends susceptible individuals avoid extreme heat without restricting athletics unless frank rhabdomyolysis or heat stroke history exists, when strenuous activity at high temperatures should be avoided or undertaken cautiously [18].

7.7. Off-label and investigational medicines

None of these medicines has an authorised RYR1 myopathy indication; use is off-label and based on observational or pilot evidence except N-acetylcysteine, tested in a negative randomised trial [5, 55, 59].

Oral dantrolene. Dantrolene sodium is an RyR1 antagonist that inhibits calcium release and leak from the sarcoplasmic reticulum [18]. The US capsule label authorises it for chronic spasticity of upper motor neurone origin and for MH, and not for other indications; its use for RYR1-related myalgia, cramps and rhabdomyolysis is off-label, with a risk of hepatotoxicity that prompts a boxed warning, a contraindication in active liver disease and hepatic laboratory monitoring [60]. The available evidence is observational: in a retrospective cohort from the Toronto MH unit, most patients with muscle symptoms and a positive contracture test who started the drug reported improvement in myalgia, fatigue and rhabdomyolysis and continued treatment, without serious adverse effects or irreversible liver injury, and mild-to-moderate adverse effects resolved in most cases with dose reduction [61]. The study is retrospective, without a control group and with subjective assessment of response, so it is hypothesis-generating, and the authors call for a randomised trial [61]. The 276th ENMC cites this cohort in the same sense [46], and the 217th ENMC included dantrolene among compounds tested only in isolated cases that would justify formal trials [30]. The formulations, titration schedules, dose limits and hepatic monitoring from the label and the Toronto cohort are presented below; any prescription requires confirmation against the product information in force in the country. In the European Union there is no centrally authorised oral formulation; the only centrally authorised dantrolene is the intravenous formulation Agilus®, authorised on 29 May 2024 for the treatment of MH in adults and children of all ages; oral formulations have national authorisations, whose summaries of product characteristics were not consulted [62]. Dantrolene may worsen pre-existing muscle weakness, which is particularly relevant in patients with myopathy, and should not be combined with calcium channel blockers [18]. It should not be used during breastfeeding and, in pregnancy, only if clearly needed [60].

Oral dantrolene — dosage. In RYR1-related myopathy, oral dantrolene is used off-label, because none of the indications in the US label for Dantrium® capsules covers myalgia, cramps or rhabdomyolysis of myopathic origin; the only authorised dosages are those for chronic spasticity and for MH, and the latter provides for 4 to 8 mg/kg/day in three or four doses for one to two days before surgery [60]. The capsules are available in 25, 50 and 100 mg strengths [60]. For adult spasticity, the label proposes titration in seven-day steps, starting with 25 mg once daily, then 25 mg three times daily, then 50 mg three times daily and finally 100 mg three times daily; some patients may need four doses daily, but doses above 100 mg four times daily should not be used [60]. In children, the equivalent schedule starts with 0.5 mg/kg once daily and rises, in seven-day steps, to 0.5 mg/kg three times daily, 1 mg/kg three times daily and 2 mg/kg three times daily, with the same absolute limit of 100 mg four times daily; the safety of prolonged use below the age of 5 years has not been established, which makes the balance between benefit and risk particularly important in the paediatric age group [60]. At any age, each step is maintained for seven days to assess response, the dose returns to the previous step if the next brings no additional benefit, the lowest effective dose is prescribed and treatment is stopped if there is no observable benefit after 45 days [60]. The UK SmPC for Dantrium® capsules (25 and 100 mg), the only European reference obtained for the oral form (in Portugal only intravenous dantrolene, Agilus®, is authorised), is more restrictive: it indicates severe chronic spasticity in adults and in children over 5 years of age weighing at least 25 kg; in adults, weekly titration from 25 mg once daily to 50 mg three times daily, not exceeding 200 mg/day in long-term treatment, allowing a temporary increase to 400 mg/day (100 mg four times daily) for a maximum of 2 months; in children, from 25 mg once daily to 75 mg three times daily, with a maximum of 200 mg/day, and use not recommended below the age of 5 years; discontinuation if there is no benefit at 6–8 weeks; contraindications that include liver disease, compromised respiratory function, severe cardiac dysfunction due to myocardial disease, pregnancy and breastfeeding [63].

Hepatic monitoring follows the boxed warning. Symptomatic fatal and non-fatal hepatitis has occurred at various doses, much less frequently at up to 400 mg/day than 800 mg/day or more, predominantly between treatment months three and twelve and more likely in women, individuals over 35 and those taking other medicines [60]. The label recommends baseline liver tests (aspartate/alanine aminotransferases, alkaline phosphatase and total bilirubin), repeat aminotransferases at appropriate intervals and generally stopping if abnormal; active liver disease is contraindicated [60].

In the retrospective Toronto MH unit cohort (1994–2018), the schedule for caffeine–halothane contracture test (CHCT)-confirmed MH susceptibility with muscle symptoms differed from the label: begin 25 mg at bedtime and add 25 mg increments at 6-hour intervals as needed until symptom relief, adverse effects or maximum 400 mg/day, never exceeding 100 mg/dose; if initial dosing failed, first increase bedtime dose to 50 mg, classifying patients as non-responders without reported relief after 6–8 weeks of adjustments [61]. Liver tests (aminotransferases, alkaline phosphatase, bilirubin) were obtained before treatment, quarterly in year one and annually thereafter [61]. Among 164 treated patients, three developed aminotransferases 3–4 times the upper normal limit, normalising one month after discontinuation, and none had irreversible hepatic injury, including those receiving 400 mg/day; median daily dose was 50 mg in responders and 200 mg in non-responders, suggesting escalation after unsuccessful initial adjustments may add no benefit [61]. These retrospective uncontrolled data are not a validated RYR1-RM dosage [61].

N-acetylcysteine. The rationale came from preclinical models, in which N-acetylcysteine reduced markers of oxidative stress and improved strength in mice and endurance in ryr zebrafish [30]. The NIH trial (NCT02362425) included a 6-month natural history phase (n = 37) followed by 1:1 randomisation of 33 participants to oral N-acetylcysteine or placebo for 6 months, with half the dose in the first week (15 mg/kg per day in three doses, not exceeding 1,800 mg per day) and thereafter 2,700 mg per day in participants over 50 kg and 30 mg/kg per day in three doses in those under 50 kg, not exceeding 2,700 mg per day [55, 64]. The drug did not improve the primary biochemical endpoint or the 6-minute walk test, was safe and well tolerated, and the authors classify the result as class I evidence that oral N-acetylcysteine does not reduce oxidative stress in these myopathies [55].

Salbutamol. In a British open-label pilot study, 13 patients (8 with CCD, mean age 17.5 years, and 5 with minicores, mean age 13.6 years) received oral salbutamol 2 mg four times daily, with assessments at 3 and 6 months; two patients with CCD discontinued after one month owing to lack of improvement and one patient with minicores in the fourth month owing to tremor and palpitations, while the remaining ten completed the study without significant adverse effects and with increases in myometry, MRC scale, FVC and functional abilities [65]. The study had no control group and the authors themselves called for a randomised trial, which was not carried out; use is off-label and without demonstrated efficacy [65, 66]. The study dose lies within the range of the oral salbutamol labels for bronchospasm, a different indication: the Portuguese SmPC for Ventilan® syrup (0.4 mg/mL) indicates 4 mg 3 to 4 times daily in adults, up to 8 mg per dose, or 2 mg 3 to 4 times daily in patients sensitive to beta agonists, 2 mg 3 to 4 times daily from 6 to 12 years and 2 to 4 mg 3 to 4 times daily above 12 years [67]; the North American tablet label indicates 2 mg 3 to 4 times daily from 6 to 12 years (maximum 24 mg/day) and 2 to 4 mg 3 to 4 times daily from 12 years (maximum 32 mg/day) [68]. Use in RYR1-related myopathy falls outside the conditions of the label.

Pyridostigmine. Reviews describe exploration without demonstrated efficacy; no dedicated trial was found, and a Dutch natural history study lists it only as a medicine to stop in the 24 hours before assessments [66, 69].

Rycals: surlorian (ARM210, S48168). Rycals are benzothiazepines stabilising closed RyR1 through restored calstabin binding; in 17 RYR1-RM patient biopsies they corrected calcium leak and protease activation ex vivo [18, 34]. The NIH phase 1 trial (NCT04141670, October 2019–December 2021) enrolled six adults aged 18–65 with mono- or biallelic pathogenic variants able to walk 10 metres, treated for 29 days with 120 mg/day (n = 3) or 200 mg/day (n = 4, one re-enrolled after 14 months); the primary outcome was safety [33]. No severe adverse effects or discontinuations occurred, adherence was 100%, 27 treatment-emergent adverse events were recorded, three moderate unrelated events and two possibly related events (grade 1 gastro-oesophageal reflux with pre-existing disease and transient grade 1 hyperglycaemia) [33]. In exploratory 200 mg outcomes, PROMIS fatigue fell 15 ± 8 points on day 14 and 19 ± 13 on day 28, with three of four improving beyond the minimal clinically important difference threshold; shoulder abduction improved in three of four and grip strength increased 5.9% and 5.4% in the two groups; urinary isoprostane did not decrease and neither biallelic patient improved fatigue [33]. This open-label study has a very small heterogeneous sample, and authors considered theoretical MH induction [33].

Preclinical therapies. Gene editing and RNA approaches remain at the preclinical stage, hampered by the size of the gene and protein and by the dispersion of variants [70]. Exon-skipping strategies with antisense U7 small nuclear RNA to neutralise the effect of a recessive splicing variant, with increased protein and restored calcium release in patient cells, and allele-specific silencing with gapmers targeting polymorphisms in linkage disequilibrium with the mutated allele in dominant variants, have been presented [30]. Prime editing to introduce the protective variant RyR1-S2843A (published designation; corresponds to p.(Ser2843Ala) in NP_000531.2), which reduces calcium leak, was achieved in 31% of human myoblasts in vitro [71]. 5-aza-2'-deoxycytidine, 0.05 mg/kg for 15 weeks, improved strength, calcium homeostasis and the proteome in mice with recessive myopathy, and the authors propose a phase 1/2 trial [72]. Two studies were negative: antisense oligonucleotide silencing of Dnm2 in a recessive model brought no benefit in any parameter, and dietary tamoxifen in a model of recessive centronuclear myopathy did not improve function and reduced force during repeated contractions, and may be harmful [73, 74]. Systemic NAD+ deficiency and NAD+ augmentation with nicotinamide riboside in patient myotubes constitute a hypothesis not yet tested in humans [35].

7.8. Regulatory status

7.9. Clinical trials

These trials are not mutually comparable: populations, durations, outcomes and designs differ, and only the N-acetylcysteine trial has power to exclude an effect. Phase 1 surlorian improvement derives from exploratory outcomes in four uncontrolled patients and cannot be interpreted as efficacy. The Cochrane review “Treatments for RYR1-related disorders” (CD014439, December 2024) is only a protocol without results, with standardised outcome definition among its aims [59]. The 217th ENMC had already identified absent prospective multicentre natural history data, lack of assessment tools spanning profoundly weak to ambulant patients and no validated biomarkers as obstacles [30].

7.10. Developments over the past twelve months

Between October 2025 and October 2026, the development with greatest clinical reach is the phase 2 surlorian trial launch: authorised in the EU on 7 April 2026, with first patient recorded in the US system on 9 September 2026, at centres in France, Germany, the Netherlands, Spain and the United Kingdom, estimated primary completion August 2027; status is “recruiting” without results [22, 77]. In standards, the EMQN RYR1 genetic testing/reporting guideline was approved in November 2025 and published in 2026, and the 277th ENMC congenital myopathy workshop report was published in 2026 [2, 7]. New clinical data included Israeli and Turkish cohorts, extension of “dusty core disease” to dominant adult-onset presentations, Japanese muscle imaging as a candidate progression marker and Dutch prospective patient-reported outcomes [32, 39, 44, 52, 56]. Preclinical publications included positive 5-aza-2'-deoxycytidine results, two negative studies (Dnm2 silencing and tamoxifen), prime editing proof of concept and NAD+ dysregulation [35, 71–74]. No new marketing authorisation or regulatory opinion for RYR1-RM occurred during the period.

7.11. Agents to avoid and perioperative management

Everyone with pathogenic missense or in-frame RYR1 variants should be considered MH-at-risk until specialist assessment; susceptibility must be assessed and communicated in all dominant myopathies and recessive forms with missense or in-frame variants, but not loss-of-function variants, which confer no MH risk [3, 7]. ENMC neuromuscular anaesthesia consensus recommends avoiding suxamethonium in known or suspected neuromuscular disease because of hyperkalaemia, continuous temperature monitoring and considering volatile anaesthetics strictly contraindicated in neuromuscular disease with RYR1 variants unless classified benign for MH by ClinGen experts; total intravenous anaesthesia with propofol, short-acting benzodiazepines and dexmedetomidine is the alternative [23]. For congenital myopathies specifically, it recommends assessing fibreoptic intubation need with spinal or craniofacial rigidity, enhanced respiratory attention in recessive forms with compromise disproportionate to weakness, and nutritional surveillance because reduced muscle mass may cause postoperative hypoglycaemia lasting several days; patients should be scheduled first to avoid prolonged fasting [23]. Annual review also recalls perioperative risks and updates alert cards [23, 36].

Extremes of heat should also be avoided and, in those who have already had rhabdomyolysis or heat stroke, strenuous exercise in a hot environment; combining calcium channel blockers with dantrolene may cause potentially fatal hyperkalaemia; 5-HT3 receptor antagonist antiemetics require caution, following a sudden death described in a child with RYR1-related myopathy after a therapeutic dose of ondansetron; and aggressive rewarming during cardiopulmonary bypass should be avoided [18]. Statins warrant caution, because RYR1 variants may contribute to statin-induced myopathy, and the structural basis of simvastatin-induced weakness associated with p.Thr4709Met has been described [18, 45]. Patients should carry an alert card and consider a medical identification bracelet [18, 36].

7.12. Pregnancy, delivery and breastfeeding

Some clinical progression may occur during pregnancy in neuromuscular disease generally, and MmD polyhydramnios and reduced fetal movements indicate an affected fetus [3, 4]. All pregnant women with MH-risk RYR1 variants require trigger-free anaesthesia: continuous epidural analgesia is recommended and caesarean section should use neuraxial block; if general anaesthesia is necessary, use total intravenous anaesthesia with a prepared workstation, without prophylactic dantrolene [18]. When the father is susceptible, the fetus may be affected and volatiles cross the placenta, so they are likewise avoided [18]. A 2026 report describes a 32-year-old woman heterozygous for a splice variant, pregnant through in vitro fertilisation with a partner carrying the same pathogenic variant, managed with early prenatal anaesthetic assessment, trigger-free theatre, MH prevention kit and simulation training; elective caesarean at 39 weeks under spinal anaesthesia was uncomplicated with discharge on day three [78]. A dedicated CCD pregnancy management report also exists [79]. Female carriers have more obstetric and bleeding complications, warranting haematological assessment and delivery planning [54]. Dantrolene should not be used during breastfeeding [60]. Ongoing trials exclude pregnancy/breastfeeding and require contraception [22, 33].

7.13. Transition and care organisation

Transition to adult care should be planned because postadolescent follow-up data are scarce: the British paediatric cohort ended at transition without subsequent data [8]. In adults, RYR1 myopathy is the most common genetic congenital myopathy subtype and MH susceptibility-related myopathy symptoms often emerge late, so adult services should be prepared to receive and recognise these patients [2, 51]. In resource-limited settings, recognition is delayed: South African patients remained undiagnosed for over 25 years, addressed by local founder variant testing [2, 50].

8. Reproductive Options and Family Counselling

8.1. Establish inheritance before calculating risks

Counselling depends on inheritance, which cannot be inferred from variant type alone: the same gene causes dominant and recessive disease, and some variants act dominantly for MH susceptibility and recessively for myopathy, even within one family [3, 30]. Determining variant phase (cis or trans) and parental studies are therefore mandatory before recurrence risk counselling [7]. In sporadic single-heterozygous-variant cases, consider a dominant de novo variant or recessive disease with an unidentified second allele, resolved through parental testing and, if necessary, CNV or non-coding variant investigation [3, 7].

8.2. Recurrence risks

In dominant forms, most probands have an affected or asymptomatic carrier parent; the de novo proportion is unestablished, although severe dominant forms predominantly result from de novo variants [3, 7]. An affected parent has 50% risk for each child, and offspring of an affected individual have 50% risk [3]. When neither parent has the variant, consider parental germline or somatic mosaicism: in RYR1 MH, sibling risk is estimated at approximately 1% in this situation, and somatically mosaic parents may be mildly affected; no CCD germline mosaicism had been reported by 2014 but it is possible [3, 18]. Apparently negative family history may reflect unrecognised mild cases, early death, late onset, reduced penetrance or absent anaesthetic exposure [3, 18]. CCD variant penetrance is almost complete but intrafamilial expressivity highly variable [3].

In recessive forms, parents are obligate heterozygotes and generally asymptomatic; each sibling has 25% affected, 50% asymptomatic carrier and 25% non-carrier risk, so a clinically unaffected sibling has a 2 in 3 carrier probability; parental siblings have 50% carrier probability; offspring of affected individuals are obligate carriers [3, 4]. In two-generation affected families, pseudodominance is likelier than dominant inheritance with consanguinity or high carrier frequency, and establishing dominant inheritance requires transmission in three or more generations or a demonstrated heterozygous variant [4]. Consanguinity increases risk: recessive inheritance was first demonstrated in two consanguineous families [29]. In non-consanguineous populations, recurrence risk is low [7]. In Brazil, two of nine CCD families had two recessively inherited RYR1 variants, asymptomatic heterozygous parents and mildly affected patients, leading authors to suggest recessive CCD may be more common than assumed, with counselling and MH prevention implications [80].

8.3. Cascade testing and carriers

Family studies have two distinct aims: identifying myopathy or risk of developing it and identifying MH risk. EMQN recommends cascade testing with MH-associated variants and permits predictive testing in dominant/recessive myopathies; predictive testing should be limited to relevant variants through exon-restricted sequencing or bioinformatic restriction to avoid unsolicited findings, except with a more severe relative phenotype (e.g. recessive case in a dominant family) or positive contracture susceptibility without the familial variant, warranting full-gene testing [7]. Conversely, MH GeneReviews recommends multigene panels even for relatives to avoid missing another susceptibility cause [18]. One clinically decisive point is agreed: genetic/contracture discordance has been recognised for thirty years and estimated in at least 25% of families, so absence of the familial variant cannot reduce MH risk to population level, and the relative should attend an MH unit [7]. When testing finds neither the familial variant nor any pathogenic RYR1, CACNA1S or STAC3 variant, GeneReviews considers risk probably equal to or below population risk; without accessible testing, close relatives are treated as susceptible [18]. Heterozygous recessive-variant carriers should be told that MH risk for recessive variants is largely unknown and avoiding volatile anaesthetics and suxamethonium is prudent; for loss-of-function variants, explicitly state no increased MH risk [3, 7, 49].

Spousal testing to exclude recessive offspring risk depends on local policy: the UK national health service uses a carrier-frequency threshold above 1 in 70; if performed, report only pathogenic/likely pathogenic variants, clarify that carrier risk is reduced rather than excluded, and discuss MH-related and VUS findings beforehand [7].

8.4. Testing minors and predictive counselling

Testing at-risk relatives, symptomatic or not, for the proband's variant is recommended particularly because it enables warnings about volatile anaesthetics and suxamethonium, immediately valuable for safety including children [3]. Predictive testing in asymptomatic individuals should occur within formal counselling, explaining that it cannot predict onset age, severity, symptom type or progression [3]. ClinGen MH actionability is strong in adults and children, supporting non-diagnostic disclosure, but explicitly excludes newborn/prenatal screening and does not encompass myopathies [5]. In triggered-phenotype families, counselling includes training adaptation and rhabdomyolysis prevention, with psychological support when sport is central to life [46].

8.5. Prenatal diagnosis, preimplantation testing and other options

Once familial variants are identified, prenatal diagnosis by amniocentesis or chorionic villus sampling and preimplantation genetic testing are possible [3, 4, 7]. Perspectives on prenatal testing for pregnancy termination differ between families and professionals and should be explored non-directively [3]. Offer counselling before pregnancy, and bank affected relatives' DNA for future studies [3, 4]. With severe-form pregnancy risk, ultrasound surveillance of fetal movements, amniotic fluid and contractures supports delivery and neonatal care planning [4, 49]. The 2026 case illustrates counselling when both partners carry the same variant: 25% severe recessive myopathy risk, 50% carrier risk and indeterminate fetal MH risk [78]. Non-medical explanations for unexpected results, such as parentage differing from assumptions or undisclosed adoption, should also be considered [3].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each study measures

There is no validated estimate of the population prevalence of RYR1-related myopathies as a whole; the available figures measure different things and are not interchangeable [5, 7]. Three quantities should be separated: the prevalence of patients with myopathy, the frequency of carriers of MH-associated variants in genomic databases and the incidence of MH reactions during anaesthesia.

9.2. Regional data and founder populations

Strongest data come from the US and northwestern Europe. In the US paediatric cohort, RYR1 was the most frequent genetic congenital myopathy cause [19]. In the UK, the 69-patient London paediatric and British MH cohorts are the largest described clinical series [8, 30]. In the Netherlands, 77 of 277 patients at a national MH/myopathy referral centre had RYR1 variants, with 61 variants, and the cohort subsequently expanded to 108 unrelated patients [30]. In France, over 100 patients were characterised for trial preparation by 2016 [30]. The Netherlands also has a well-documented founder effect in another congenital myopathy, KBTBD13 nemaline myopathy [2].

Elsewhere, data are fragmented but growing. In Japan, 36 patients characterised muscle imaging and Tokyo series documented C-terminal variant/histology correlations [37, 56]. In Israel, a multicentre cohort of 36 individuals from 11 families and 5 sporadic cases described 9 asymptomatic carriers with normal CK and 27 affected, including three KDS patients, deterioration, improvement or stability, and heterogeneous histology [39]. In Turkey, an Izmir cohort included 19 patients from 18 families, 63.1% male, presenting with hypotonic infancy, developmental delay or hyperCKaemia, with MH susceptibility most frequent (8 patients) and p.(Val2627Gly) most common (5); four variants were novel [44]. In Italy, four patients defined extension of “dusty core disease” to dominant presentations [32].

The South African cohort is the clearest example of an under-represented population with probable founder variants: among 67 Black African congenital myopathy patients, 44 clinically diagnosed with KDS, RYR1 and STAC3 predominated, both recessive unlike classical dominant KDS; many remained undiagnosed over 25 years [50]. In the Western Cape, centronuclear myopathies predominate and common RYR1 variant identification enabled local testing [2].

9.3. Portugal and Brazil

Consulted sources contain no Portuguese prevalence estimate. Brazil contributes Kossugue and colleagues' nine CCD families, two with demonstrated recessive inheritance, and the Porto Alegre paediatric exertional myalgia/rhabdomyolysis case in Section 10 [43, 80]. A Brazilian textbook dedicates a chapter to congenital myopathies without original epidemiological data [31]. Brazil has an MH emergency line alongside the UK and Germany [18]. The RYR-1 Foundation handbook is translated into Brazilian Portuguese [58]. Absence of data in these sources does not demonstrate absence of published data.

9.4. Special populations

Women had more pathological bleeding scores, severe menorrhagia, pregnancy complications and planned caesareans, with lower-birthweight infants, in a selection-biased survey of 66 carriers and 88 controls [54]. In athletes and military personnel, exertional rhabdomyolysis is frequent, with incidences of 36–43 per 100,000 person-years in US forces, generally following unaccustomed exercise, and RYR1 explains some genetically susceptible cases [30, 46]. Acute childhood rhabdomyolysis is relatively rare; in a review of 534 cases aged 0–18, males predominated (62%–70%) and infection, particularly influenza A and Coxsackie B, was the commonest cause, whereas trauma, unaccustomed exercise and illicit drugs predominated in adolescents [46]. In resource-limited settings, delayed diagnosis reflects poor recognition and limited tertiary care, electromyography, biopsy and genetic testing, often sent abroad at prohibitive cost using panels excluding local variants [2].

9.5. Reference networks, registries and patient organisations

The European neuromuscular reference network is ERN EURO-NMD [24]. For MH, the European Malignant Hyperthermia Group maintains specialist unit listings, with three North American contracture testing centres and fifteen accredited in Europe, Australia and New Zealand; EMQN emphasises scarce, uneven distribution and, where unavailable, following European recommendations and anaesthetic precautions [7, 18, 25]. Organisations and registries include the Pittsburgh RYR-1 Foundation, established for support/advocacy and operating a patient registry and family conferences, Muscular Dystrophy Association, Muscular Dystrophy UK, Cure CMD, Congenital Muscle Disease International Registry, Malignant Hyperthermia Association of the United States and North American MH Registry [3, 4, 18, 30, 58, 82, 83]. Patient involvement forms part of 277th ENMC recommendations; the RYR-1 Foundation representative advocated classification integrating histology, genotype, mechanism, inheritance and clinical severity because current nomenclature separates identical genetic diagnoses and groups different genetic diagnoses [2]. In an international survey of 146 patients, including 30 with trial experience, predominantly Dutch and US, priority outcomes were weakness, fatigue and mobility, participation facilitators were medicine/results access and barriers adverse-effect fears and travel time [57].

Two relevant natural history studies are underway: a prospective single-centre NIH RYR1 disorder study with centralised/decentralised telemedicine arms, approximately 150 US-resident participants aged 7 or above, begun March 2025 with estimated primary completion April 2031; and a two-year congenital myopathy study at Radboudumc and Utrecht university centre, approximately 100 participants aged 2 or above, measuring motor function and shuttle endurance, begun March 2024 [69, 84].

10. Illustrative Clinical Case

The following case was published by de Lima Silva and colleagues in the Journal of Neuromuscular Diseases in 2023 and is summarised faithfully [43].

A boy followed in Porto Alegre, Brazil, developed myalgia and altered gait at age 2 during ordinary age-appropriate activity such as playing, running and jumping. At age 3, during fever of 38.5 °C and severe lower-limb myalgia preventing walking, CK was 66,413 U/L and C-reactive protein 66.7 mg/L without another infectious focus, leading to a viral myositis interpretation; three days later CK was 3,835 U/L. Recurrent myalgia followed intense or minimal activities such as holding a phone, playing with blocks or using a pincer grip, sometimes one to two days after exertion; severe episodes raised temperature to 37–38 °C and CK to 8,145–21,176 U/L, with mean resting CK 2,932 U/L.

At age 4, metabolic and inflammatory investigations were negative and a massively parallel neuromuscular panel identified heterozygous RYR1 c.7076G>A p.(Arg2359Gln), reported on NM_000540.2, classified likely pathogenic, already MH-associated and curated by ClinGen experts; diagnosis was RYR1-related exertional myalgia and rhabdomyolysis. The pedigree in article Figure 1A shows a mother with minimal-exertion cramps, an aunt who stopped football because of cramps, a grandfather with almost daily nocturnal cramps and another aunt with mild cramps considered a possible phenocopy. The variant occurred in the mother, football-playing aunt and grandfather; none had MH despite incompletely documented anaesthetic exposures (maternal spinal anaesthesia for caesarean and unspecified inhaled anaesthetic for nasal surgery, grandfather's general anaesthesia for spinal surgery without documented agents).

Low-dose oral dantrolene was initiated, starting with half the effective dose at night and adjusting to the lowest effective dose, 0.5 mg/kg/day, corresponding to 10 mg given in the morning. Comparing the preceding five months with treatment, median CK fell from 6,153 U/L (interquartile range 8,005) to 1,956 U/L (4,341), a 68% reduction, and mean CK from 6,564 U/L (standard deviation 4,389) to 2,690 U/L (2,410), with post-treatment maximum 6,128 U/L after an episode. Diary-recorded myalgia attacks fell from ten to five monthly and admissions from two to none. Mean aspartate aminotransferase fell from 117.5 to 63.3 U/L and alanine aminotransferase from 40.0 to 25.3 U/L, monitored before each dose adjustment and every one to two months after day thirty. 6MWT distance increased from 295 m, below the expected 3rd centile for 5-year-old boys, to 431 m, between the 10th and 25th centiles, and Borg perceived exertion range fell from 0–0.5 to 0–0. No significant adverse effects occurred.

Article Figure 1, actually consulted, combines pedigree (panel A) and CK evolution before/after dantrolene (panel B), available at https://pmc.ncbi.nlm.nih.gov/articles/PMC10657692/figure/jnd-10-jnd230007-g001/ [43].

The case illustrates several points: RYR1 rhabdomyolysis may mimic viral myositis and present in early childhood; the causal variant may be an “MH” variant with variable penetrance and carrier relatives with cramps alone; and diagnosis changes family-wide anaesthetic counselling. Treatment is not standard practice: oral dantrolene has no approved indication here, available evidence is observational and one uncontrolled open-label case cannot establish efficacy [43, 60, 61]. The report acknowledges these limitations and relies on indirect recommendations for chronic use above age 5, minimum dose 0.5 mg/kg/dose and transaminase monitoring [43].

11. Prognosis and Long-Term Follow-Up

11.1. Form-specific prognosis

In dominant CCD, weakness is usually non-progressive or slowly progressive, cognition preserved and life expectancy generally normal; prognosis depends on respiratory status and scoliosis, and severely affected patients may require wheelchairs [3, 31]. No dominant British paediatric cohort patient lost independent walking or required ventilation, but timed tests worsened and FVC percentage predicted fell 1.3% annually, demonstrating measurable decline alongside apparent clinical stability [8]. Mouse models likewise suggest progression [30]. Adult progression may follow prolonged stability [30].

Recessive prognosis is more variable and severe: in the same cohort, 15% never walked unsupported, 7% lost independent ambulation, 32% had respiratory compromise and 26% needed NIV, begun at median age 2.5; however, a “reverse course” included reduced/stopped ventilation, gastrostomy removal and improved scores after childhood [8]. All 69 were alive at follow-up end without post-transition data [8]. MmD typically shows progressive scoliosis and respiratory loss during middle/late childhood then stabilisation, retaining adult ambulation even with severe scoliosis and ventilation, with slow progression and loss of walking in some severe cases; death frequently follows respiratory infection with severe respiratory failure, and later onset predicts better prognosis [4]. A Brazilian textbook table attributes “less than 2 years of life” to multiminicores, contradicting other sources and apparently reflecting misalignment, so this is not reproduced [4, 31].

Severe fetal/neonatal forms range from antenatal death (LMPS with two null variants) to neonatal death or survival with motor improvement when ventilation is maintained [7, 30]. Benign Samaritan congenital myopathy has favourable evolution, improving hypotonia during the first 2 years and minimal adult manifestations [16].

In triggered phenotypes, survival depends on episode recognition/prevention: rhabdomyolysis may cause acute kidney injury and exertional hyperthermia progress to multiorgan failure [13, 46]. Quality of life is measurably affected: in a prospective 12-month study, RYR1 MH/exertional rhabdomyolysis patients reported fatigue and limited sleep, walking, daily activities and leisure, stable across the year [52]. MH susceptibility-associated myopathy has socioeconomic effects and may require changed professional or sporting activity [46, 51].

11.2. Progression markers

Muscle MRI fatty replacement progresses and correlates with respiratory failure, walking impairment, scoliosis and histological severity, making it a candidate progression and treatment efficacy marker [56]. Among functional measures, 10-metre walking deteriorated by 0.28 units/year (95% CI −0.40 to −0.17) and floor/supine rising times increased in dominant patients, while the Scott functional motor scale showed a ceiling effect; 6MWT also has a ceiling in mildly affected patients [8, 30]. No validated biomarkers exist: urinary isoprostane and reduced/oxidised glutathione ratio reflect oxidative stress and are abnormal but stable at 6 months and unchanged by tested treatments [30, 33, 55].

11.3. Surveillance plan

Annual and six-monthly intervals derive from the RYR-1 Foundation educational handbook; GeneReviews recommends “regular” surveillance without intervals, so periodicity should adapt to severity and local setting [3, 4, 58]. Exclusively triggered phenotypes with normal strength do not require permanent-myopathy respiratory/orthopaedic surveillance but retain annual MH risk review, rhabdomyolysis prevention and CK surveillance if chronically elevated [23, 46].

12. Summary and Final Considerations

RYR1 variants are the most frequent genetic congenital myopathy cause, producing a continuum from fetal death with two null variants to normal-strength adults with exertional myalgia, cramps or rhabdomyolysis [2, 7]. The most clinically useful division is inheritance. Dominant forms, generally C-terminal missense variants, present with predominantly pelvic congenital hypotonia/weakness, hip dislocation, delayed but acquired walking and stable course with measurable slow decline; face and eyes are spared. Recessive forms, usually with at least one truncating or hypomorphic allele, present earlier and more severely, with ophthalmoparesis, ptosis, facial/bulbar weakness, respiratory compromise possibly disproportionate to limb weakness and nutritional/ventilatory support, but may improve after childhood [8, 30, 38].

Traditional histological names, central core, multiminicore, centronuclear, fibre type disproportion and “dusty core”, describe biopsy appearance in one muscle at one time rather than distinct genetic entities: histology changes with age/muscle and the same variant may produce differing appearances. This prompted retirement of CCD and MmD GeneReviews chapters in 2019 and the 277th ENMC inheritance/gene/histology nomenclature [2–4]. Diagnosis is now genetics-first with broad sequencing covering 106 exons/splice regions and CNV analysis in myopathic phenotypes; biopsy and imaging remain valuable for VUS interpretation, and MRI has a selective dominant-form involvement pattern [2, 3, 7].

Two reasoning errors should be avoided. First, equating no variant with no risk: negative testing does not exclude diagnosis because of coverage limitations (particularly exon 91), intronic variants and allelic silencing, and for MH, genotype/contracture discordance in at least one-quarter of families means absence of a familial variant cannot reduce risk to population level [7, 18]. Second, treating MH risk as uniform: loss-of-function variants confer no risk, while missense/in-frame variants not classified benign for MH require anaesthetic precautions and specialist referral, and the relationship is asymmetric because a myopathy-pathogenic variant may not cause susceptibility [5, 7].

No authorised disease-modifying treatment exists. Management rests on respiratory/orthopaedic surveillance, rehabilitation, nutritional support, respiratory infection prevention, rhabdomyolysis prevention through exercise adaptation and avoidance of extreme heat, and anaesthetic precautions avoiding suxamethonium/halogenated volatiles and preferring total intravenous anaesthesia [3, 4, 23, 46]. Oral dantrolene, salbutamol and pyridostigmine are off-label without established efficacy; N-acetylcysteine was formally tested and failed; surlorian, a RyR1 stabiliser, passed phase 1 with favourable exploratory signals and entered a crossover phase 2 trial in dominant-disease adults in 2026, with unknown outcome [22, 33, 55, 61, 65].

Gaps are acknowledged by consensus groups: no validated population prevalence for overall RYR1-RM, no prospective multicentre natural history data, no validated biomarkers or assessment tools spanning the full severity spectrum, and myopathy variant classification remains dependent on poorly accessible functional assays [2, 5, 7, 30]. Ongoing prevalence/natural history studies, new previously under-represented cohorts and the first phase 2 channel-targeted medicine trial are developments to follow. For clinicians, precise genetic RYR1 myopathy diagnosis immediately changes three things: respiratory/orthopaedic surveillance, patient/family anaesthetic safety and access to reproductive counselling and clinical trials.

13. References

1. Lawal TA, Todd JJ, Witherspoon JW, Bönnemann CG, Dowling JJ, Hamilton SL, et al. Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature. Skelet Muscle. 2020;10(1):32. doi:10.1186/s13395-020-00243-4. PMID: 33190635; PMC7667763.
2. Villar-Quiles RN, Hayes LH, Raga S, Bönnemann C, Oates E, Dowling J, et al. 277th ENMC international workshop: Congenital myopathies: revising and revisiting nomenclature and diagnostic guidelines, 21-23 June 2024, Hoofddorp, The Netherlands. Neuromuscul Disord. 2026;60:106328. doi:10.1016/j.nmd.2025.106328. PMID: 41621159.
3. Malicdan MCV, Nishino I. Central Core Disease — RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. In: Adam MP, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–. First published 16 May 2007; last updated 4 December 2014; chapter retired 7 November 2019. PMID: 20301565. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1391/
4. Beggs AH, Agrawal PB. Multiminicore Disease — RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. In: Adam MP, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–. First published 25 March 2003; last updated 24 January 2013; chapter retired 18 April 2019. PMID: 20301467. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1290/
5. GeneGuidance. RYR1 — gene record (clinical curation; record dated 2026-09-26).
6. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. PMID: 28967166; PMC5765404.
7. Robinson RL, Gardeitchik T, Schouten MI, Jungbluth H, Voermans NC, Stowell K, et al. EMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders. Eur J Hum Genet. 2026 [Epub ahead of print]. doi:10.1038/s41431-026-02121-x. PMID: 42120542.
8. Sarkozy A, Sa M, Ridout D, Fernandez-Garcia MA, Distefano MG, Main M, et al. Long-term Natural History of Pediatric Dominant and Recessive RYR1-Related Myopathy. Neurology. 2023;101(15):e1495-e1508. doi:10.1212/wnl.0000000000207723. PMID: 37643885; PMC10585689.
9. Orphanet. Central core disease. ORPHA:597. Available from: https://www.orpha.net/en/disease/detail/597
10. Orphanet. Multiminicore myopathy. ORPHA:598. Available from: https://www.orpha.net/en/disease/detail/598
11. Orphanet. Autosomal recessive centronuclear myopathy. ORPHA:169186. Available from: https://www.orpha.net/en/disease/detail/169186
12. Orphanet. King-Denborough syndrome. ORPHA:99741. Available from: https://www.orpha.net/en/disease/detail/99741
13. Orphanet. Exercise-induced malignant hyperthermia. ORPHA:466650. Available from: https://www.orpha.net/en/disease/detail/466650
14. Orphanet. Lethal multiple pterygium syndrome. ORPHA:33108. Available from: https://www.orpha.net/en/disease/detail/33108
15. Orphanet. Congenital myopathy with myasthenic-like onset. ORPHA:424107. Available from: https://www.orpha.net/en/disease/detail/424107
16. Orphanet. Benign Samaritan congenital myopathy. ORPHA:324581. Available from: https://www.orpha.net/en/disease/detail/324581
17. Orphanet. Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy. ORPHA:700188. Available from: https://www.orpha.net/en/disease/detail/700188
18. Riazi S, Biesecker LG, Rosenberg H, Dirksen RT. Nonsyndromic Malignant Hyperthermia Susceptibility. In: Adam MP, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–. Initial posting 2003 Dec 19; last update 2025 Aug 7. PMID: 20301325. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1146/
19. Amburgey K, McNamara N, Bennett LR, McCormick ME, Acsadi G, Dowling JJ. Prevalence of congenital myopathies in a representative pediatric united states population. Ann Neurol. 2011;70(4):662-665. doi:10.1002/ana.22510. PMID: 22028225.
20. Norwood FL, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain. 2009;132(Pt 11):3175-3186. doi:10.1093/brain/awp236. PMID: 19767415; PMC4038491.
21. Dlamini N, Voermans NC, Lillis S, Stewart K, Kamsteeg EJ, Drost G, et al. Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis. Neuromuscul Disord. 2013;23(7):540-548. doi:10.1016/j.nmd.2013.03.008. PMID: 23628358.
22. RyCarma Therapeutics. A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Efficacy and Safety of Surlorian (ARM210, S48168) in Adults With Autosomal Dominant RYR1-Related Myopathy. ClinicalTrials.gov NCT07560020. Available from: https://clinicaltrials.gov/study/NCT07560020
23. van den Bersselaar LR, Heytens L, Silva HCA, Reimann J, Tasca G, Díaz-Cambronero Ó, et al. European Neuromuscular Centre consensus statement on anaesthesia in patients with neuromuscular disorders. Eur J Neurol. 2022;29(12):3486-3507. doi:10.1111/ene.15526. PMID: 35971866; PMC9826444.
24. European Reference Network for Neuromuscular Diseases (EURO-NMD). Available from: https://ern-euro-nmd.eu/ [accessed 9 October 2026]
25. European Malignant Hyperthermia Group. Available from: https://www.emhg.org/ [accessed 9 October 2026]
26. Magee KR, Shy GM. A new congenital non-progressive myopathy. Brain. 1956;79(4):610-621. doi:10.1093/brain/79.4.610. PMID: 13396066.
27. Zhang Y, Chen HS, Khanna VK, De Leon S, Phillips MS, Schappert K, et al. A mutation in the human ryanodine receptor gene associated with central core disease. Nat Genet. 1993;5(1):46-50. doi:10.1038/ng0993-46. PMID: 8220422.
28. Quane KA, Healy JM, Keating KE, Manning BM, Couch FJ, Palmucci LM, et al. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet. 1993;5(1):51-55. doi:10.1038/ng0993-51. PMID: 8220423.
29. Jungbluth H, Müller CR, Halliger-Keller B, Brockington M, Brown SC, Feng L, et al. Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores. Neurology. 2002;59(2):284-287. doi:10.1212/wnl.59.2.284. PMID: 12136074.
30. Jungbluth H, Dowling JJ, Ferreiro A, Muntoni F; RYR1 Myopathy Consortium. 217th ENMC International Workshop: RYR1-related myopathies, Naarden, The Netherlands, 29–31 January 2016. Neuromuscul Disord. 2016;26(9):624-633. doi:10.1016/j.nmd.2016.06.001
31. Campos IFS, Ribeiro EM. Miopatias congênitas. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 285–288.
32. Zanotti S, Magri F, Salani S, Napoli L, Ripolone M, Pagliarani S, et al. Expanding the genetic landscape of Dusty Core Disease: new RYR1 variants in Italian patients. Eur J Hum Genet. 2026;34(5):609-618. doi:10.1038/s41431-026-02080-3. PMID: 41851258; PMC13171984.
33. Todd JJ, Lawal TA, Chrismer IC, Kokkinis A, Grunseich C, Jain MS, et al. Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial. EClinicalMedicine. 2024;68:102433. doi:10.1016/j.eclinm.2024.102433. PMID: 38318125; PMC10839573.
34. Kushnir A, Todd JJ, Witherspoon JW, Yuan Q, Reiken S, Lin H, et al. Intracellular calcium leak as a therapeutic target for RYR1-related myopathies. Acta Neuropathol. 2020;139(6):1089-1104. doi:10.1007/s00401-020-02150-w. PMID: 32236737; PMC7788518.
35. Lawal TA, Riekhof W, Groom L, Varma P, Chrismer IC, Kokkinis A, et al. NAD+ dyshomeostasis in RYR1-related myopathies. Skelet Muscle. 2025;15(1):22. doi:10.1186/s13395-025-00390-6. PMID: 40846977; PMC12374369.
36. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 524–525 (Sensitivity to anaesthetic agents).
37. Wu S, Ibarra MC, Malicdan MC, Murayama K, Ichihara Y, Kikuchi H, et al. Central core disease is due to RYR1 mutations in more than 90% of patients. Brain. 2006;129(Pt 6):1470-1480. doi:10.1093/brain/awl077. PMID: 16621918.
38. Amburgey K, Bailey A, Hwang JH, Tarnopolsky MA, Bonnemann CG, Medne L, et al. Genotype-phenotype correlations in recessive RYR1-related myopathies. Orphanet J Rare Dis. 2013;8:117. doi:10.1186/1750-1172-8-117. PMID: 23919265; PMC3751094.
39. Ginsberg M, Michelson M, Aharoni S, Sagie L, Michaeli Y, Rotenberg D, et al. The Clinical, Histological, and Genetic Spectrum of RYR1 Variants-A Multi-Center Israeli Cohort Study. J Clin Med. 2026;15(4):1388. doi:10.3390/jcm15041388. PMID: 41753076; PMC12942153.
40. National Center for Biotechnology Information. ClinVar [Internet]. Bethesda (MD): NCBI. VCV records 12966, 573252, 12964, 12982, 12984, 12993, 12977, 93248, 65996, 133076, 93279, 12975, 12983, 65993, 65968, 12988, 133029, 161363, 161374, 4850776, 159834, 65981, 12970, 65980, 590599. Available from: https://www.ncbi.nlm.nih.gov/clinvar/
41. Johnston JJ, Dirksen RT, Girard T, Gonsalves SG, Hopkins PM, Riazi S, et al. Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility. Genet Med. 2021;23(7):1288-1295. doi:10.1038/s41436-021-01125-w. PMID: 33767344; PMC8263483.
42. Johnston JJ, Dirksen RT, Girard T, Hopkins PM, Kraeva N, Ognoon M, et al. Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility. Hum Mol Genet. 2022;31(23):4087-4093. doi:10.1093/hmg/ddac145. PMID: 35849058; PMC9703808.
43. de Lima Silva EV, Donis KC, Machado FRC, Simão Medeiros L, Aschoff CAM, de Souza CFM, et al. Oral Dantrolene Reduces Myalgia and Hyperckemia in a Child with RYR1-Related Exertional Myalgia/Rhabdomyolysis. J Neuromuscul Dis. 2023;10(6):1145-1149. doi:10.3233/jnd-230007. PMID: 37781817; PMC10657692.
44. Sarıkaya Uzan G, Özyılmaz B, Doğan G, Baydan F, Güzin Y, Gençpınar P, et al. Clinical and Genetic Spectrum of RYR1-Related Disease. Mol Syndromol. 2026;17(1):34-42. doi:10.1159/000545612. PMID: 41675683; PMC12890276.
45. Weninger G, Dridi H, Reiken S, Yuan Q, Zhao N, Groom L, et al. Structural basis for simvastatin-induced skeletal muscle weakness associated with type 1 ryanodine receptor T4709M mutation. J Clin Invest. 2025;135(24):e194490. doi:10.1172/jci194490. PMID: 41392983; PMC12700559.
46. Kruijt N, Laforet P, Vissing J, Bhai S, Stemmerik MG, Kleefeld F, et al. 276th ENMC International Workshop: recommendations on optimal diagnostic pathway and management strategy for patients with acute rhabdomyolysis worldwide. 15th-17th March 2024, Hoofddorp, The Netherlands. Neuromuscul Disord. 2025;50:105344. doi:10.1016/j.nmd.2025.105344. PMID: 40220353.
47. Schade van Westrum SM, Wahbi K, Bonne G, van der Kooi AJ. Hereditary Neuromuscular Diseases and Cardiac Involvement. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. p. 371–385. doi:10.1007/978-3-030-45457-9_22
48. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 240–241 (Lethal multiple pterygium syndrome).
49. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 724–727 (Fetal akinesia).
50. Schoonen M, Fassad M, Patel K, Bisschoff M, Vorster A, Makwikwi T, et al. Biallelic variants in RYR1 and STAC3 are predominant causes of King-Denborough Syndrome in an African cohort. Eur J Hum Genet. 2025;33(4):421-431. doi:10.1038/s41431-025-01795-z. PMID: 39966651; PMC11985997.
51. Ibarra Moreno CA, Silva HCA, Voermans NC, Jungbluth H, van den Bersselaar LR, Rendu J, et al. Myopathic manifestations across the adult lifespan of patients with malignant hyperthermia susceptibility: a narrative review. Br J Anaesth. 2024;133(4):759-767. doi:10.1016/j.bja.2024.05.046. PMID: 39107166; PMC11443134.
52. van den Bersselaar LR, Kruijt N, Kamsteeg EJ, Fernandez-Garcia MA, Treves S, Yang CY, et al. Patient-reported symptoms, fatigue, functional impairment and quality of life in RYR1-related malignant hyperthermia and exertional rhabdomyolysis. Neuromuscul Disord. 2026;67:107373. doi:10.1016/j.nmd.2026.107373. PMID: 42617308.
53. Zhao C, Li Y, Li J, Xiong J. Respiratory Failure Associated With Mutations in the RYR1 Gene: A Case Report. Clin Case Rep. 2025;13(10):e70971. doi:10.1002/ccr3.70971. PMID: 41113287; PMC12534174.
54. Mistry AM, Saldanha G, Bersselaar LRVD, Knock GA, Goldberg MF, Vanegas MI, et al. Obstetric and gynaecological features in females carrying variants in the skeletal muscle ryanodine receptor type 1 (RYR1) gene: a questionnaire study. Neuromuscul Disord. 2025;49:105335. doi:10.1016/j.nmd.2025.105335. PMID: 40020543.
55. Todd JJ, Lawal TA, Witherspoon JW, Chrismer IC, Razaqyar MS, Punjabi M, et al. Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies. Neurology. 2020;94(13):e1434-e1444. doi:10.1212/wnl.0000000000008872. PMID: 31941795; PMC7274912.
56. Shimazaki R, Noguchi S, Yoshioka W, Takizawa H, Takahashi Y, Hayashi S, et al. Muscle imaging of patients with RYR1-related myopathies and its significance to clinical features. Neuromuscul Disord. 2025;56-57:106275. doi:10.1016/j.nmd.2025.106275. PMID: 41270518.
57. Stinissen L, van de Camp SAJH, Simon B, Goldberg L, van Engelen BGM, Bevelander KE, et al. An international patient survey of RYR1-related diseases: The patient perspective on clinical trial participation. J Neuromuscul Dis. 2026 [Epub ahead of print]:22143602261493651. doi:10.1177/22143602261493651. PMID: 42810161; PMC13624179.
58. The RYR-1 Foundation. Clinical Care Guidelines: What patients & families need to know about RYR-1-related diseases. Pittsburgh (PA): The RYR-1 Foundation; last updated August 2020. Available from: https://ryr1.org/wp-content/uploads/2022/03/Clinical-Care-Guidelines_11.11.20.pdf (Brazilian Portuguese version: https://ryr1.org/wp-content/uploads/2023/10/CCG_Booklet_9.13.23_por-BR.pdf)
59. Raga S, Voermans N, Perez-Neri I, Dowling J, Jungbluth H, Baranello G, et al. Treatments for RYR1-related disorders. Cochrane Database Syst Rev. 2024;12:CD014439. doi:10.1002/14651858.cd014439. PMID: 39655671; PMC11629463.
60. Par Health USA. Dantrium (dantrolene sodium) capsules — prescribing information. NDA017443. DailyMed/openFDA SPL set id 57b4eec1-49e1-432c-95ae-0fe36e32d64b, version 2026-08-25. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57b4eec1-49e1-432c-95ae-0fe36e32d64b
61. Ibarra Moreno CA, Kraeva N, Zvaritch E, Jungbluth H, Voermans NC, Riazi S. Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia-Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability. Anesth Analg. 2023;136(3):569-577. doi:10.1213/ane.0000000000006207. PMID: 36201369; PMC9974786.
62. European Medicines Agency. Agilus (dantrolene sodium, hemiheptahydrate) — EPAR. EC authorisation 29/05/2024. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/agilus
63. Norgine Limited. Dantrium Capsules 25 mg (dantrolene sodium): summary of product characteristics, text revised 11 Mar 2025 [Internet]. electronic Medicines Compendium. Accessed 26 Oct 2026.
64. National Institute of Nursing Research. Antioxidant Therapy in RYR1-Related Congenital Myopathy. ClinicalTrials.gov NCT02362425. Available from: https://clinicaltrials.gov/study/NCT02362425
65. Messina S, Hartley L, Main M, Kinali M, Jungbluth H, Muntoni F, et al. Pilot trial of salbutamol in central core and multi-minicore diseases. Neuropediatrics. 2004;35(5):262-266. doi:10.1055/s-2004-821173. PMID: 15534757.
66. Ogasawara M, Nishino I. Update on RYR1-related myopathies. Curr Opin Neurol. 2024;37(5):504-508. doi:10.1097/wco.0000000000001296. PMID: 38994695.
67. INFARMED. Ventilan 0,4 mg/mL xarope (salbutamol): resumo das características do medicamento, approved 17 Sep 2021 [Internet]. Infomed. Accessed 26 Oct 2026.
68. Amneal Pharmaceuticals NY. Albuterol tablets, USP (ANDA 208804): US label, version of 14 Apr 2026 [Internet]. DailyMed. Accessed 26 Oct 2026.
69. Radboud University Medical Center. Trial Readiness and Trial Fitness for Congenital Myopathies: a 2-year Prospective Natural History Study. ClinicalTrials.gov NCT06157268. Available from: https://clinicaltrials.gov/study/NCT06157268
70. Marty I, Beaufils M, Fauré J, Rendu J. Gene therapies for RyR1-related myopathies. Curr Opin Pharmacol. 2023;68:102330. doi:10.1016/j.coph.2022.102330. PMID: 36529094.
71. Godbout K, Dugas M, Reiken SR, Ramezani S, Falle A, Rousseau J, et al. Universal Prime Editing Therapeutic Strategy for RyR1-Related Myopathies: A Protective Mutation Rescues Leaky RyR1 Channel. Int J Mol Sci. 2025;26(7):2835. doi:10.3390/ijms26072835. PMID: 40243436; PMC11988564.
72. Ruiz A, Noreen F, Meier H, Buczak K, Zorzato F, Treves S. 5-aza-2-deoxycytidine improves skeletal muscle function in a mouse model for recessive RYR1-related congenital myopathy. Hum Mol Genet. 2025;34(9):790-805. doi:10.1093/hmg/ddaf021. PMID: 39946277.
73. Onofre-Oliveira P, Groom L, Liang C, Cowling B, Ghahramani-Seno MM, Dirksen RT, et al. Evaluation of dynamin 2 knockdown as a therapeutic strategy for RYR1 related myopathy. Neuromuscul Disord. 2025;50:105339. doi:10.1016/j.nmd.2025.105339. PMID: 40273816.
74. Gineste C, Reiss D, Laporte J. Tamoxifen treatment fails to improve muscle dysfunction in a model of recessive RYR1-linked centronuclear myopathy. Dis Model Mech. 2025;18(12):dmm052462. doi:10.1242/dmm.052462. PMID: 41459639; PMC12805646.
75. Hoffman M. ARM210 granted orphan drug designation for RYR1-RM treatment. NeurologyLive. 2018 Sep 6. Available from: https://neurologylive.com/view/arm210-granted-orphan-drug-designation-ryr1rm-treatment
76. ARMGO Pharma. ARMGO Pharma publishes positive phase 1b trial results of Rycal ARM210 for the treatment of ryanodine receptor 1 related myopathies [press release]. 2024 Jan 29. Available from: https://www.biospace.com/armgo-pharma-publishes-positive-phase-1b-trial-results-of-rycal-arm210-for-the-treatment-of-ryanodine-receptor-1-related-myopathies
77. Rycarma Therapeutics Inc. Trial 2025-522343-18-00 (protocol CL2-210-02). EU Clinical Trials Information System. Available from: https://euclinicaltrials.eu/ (record 2025-522343-18-00, accessed via ctis.eu)
78. Murphy C, Melvin M. Anaesthetic considerations for delivery in an obstetric patient with a RYR1 gene variant: a case report. Int J Obstet Anesth. 2026;65:104838. doi:10.1016/j.ijoa.2025.104838. PMID: 41421292.
79. Niki A, Ochiai D, Iwai M, Sato Y, Yoshino K, Yamada T. Management of pregnancy complicated by central core disease. Int J Obstet Anesth. 2020;43:25-26. doi:10.1016/j.ijoa.2020.05.004. PMID: 32570046.
80. Kossugue PM, Paim JF, Navarro MM, Silva HC, Pavanello RC, Gurgel-Giannetti J, et al. Central core disease due to recessive mutations in RYR1 gene: is it more common than described?. Muscle Nerve. 2007;35(5):670-674. doi:10.1002/mus.20715. PMID: 17226826.
81. King's College London. The Prevalence of RYR1-related Disease — an International, Collaborative Multicentre Study. ClinicalTrials.gov NCT06791369. Available from: https://clinicaltrials.gov/study/NCT06791369
82. Cure CMD. Available from: https://www.curecmd.org/ [accessed 9 October 2026]
83. Congenital Muscle Disease International Registry (CMDIR). Available from: https://www.cmdir.org/ [accessed 9 October 2026]
84. National Institutes of Health Clinical Center. A Single-Center Prospective Natural History Study of RYR1-Related Disorders. ClinicalTrials.gov NCT06287762. Available from: https://clinicaltrials.gov/study/NCT06287762