RYR1-Related Myopathy

Mendelian MONDO:0100150 Pathograph 16 Show in embeddings browser Congenital myopathy Muscular Channelopathy Hereditary Neuromuscular Disease

RYR1-related myopathy is the umbrella term for the clinically and histopathologically heterogeneous group of skeletal-muscle disorders caused by pathogenic variants in RYR1, the gene encoding the type 1 ryanodine receptor (RyR1), the principal sarcoplasmic reticulum (SR) calcium-release channel that couples membrane depolarization to muscle contraction (excitation-contraction coupling). Two broadly distinct, allele-dependent mechanisms converge on this shared channel: dominant, typically hotspot missense variants that produce a hyperactive or "leaky" channel with exaggerated or inappropriate SR calcium release, and recessive, loss-of-function or hypomorphic variants that reduce RyR1 protein abundance and impair excitation-contraction coupling. The resulting clinical and histopathologic spectrum overlaps substantially and includes central core disease, multiminicore disease, centronuclear myopathy, congenital fiber-type disproportion, and King-Denborough syndrome, as well as the pharmacogenetic malignant hyperthermia susceptibility trait, which is allelic with the myopathy-causing dominant variants. This entry models the RYR1-related myopathy spectrum at the root/umbrella level; see the Central_Core_Myopathy, Multiminicore_Disease, and Centronuclear_Myopathy entries for full curation of those individually named histopathologic entities, and the Malignant_Hyperthermia_of_Anesthesia entry for full curation of the general (non-syndromic) susceptibility trait.

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1
Mappings
2
Inheritance
8
Pathophys.
16
Phenotypes
16
Pathograph
1
Genes
8
Medical Actions
5
Subtypes
2
Trials
4
References
1
Deep Research
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Classifications

Channelopathy
skeletal muscle channelopathy
🔗

Mappings

MONDO
MONDO:0100150 RYR1-related myopathy
skos:exactMatch MONDO
Primary MONDO disease identifier for this entry.
👪

Inheritance

2
Autosomal dominant (leaky channel / gain-of-function) HP:0000006
Dominant RYR1-related myopathy is usually caused by heterozygous missense variants, historically clustered in three hotspot regions of the channel, that render the RyR1 channel hyperactive/leaky rather than reducing its abundance. This is the mechanism also responsible for the allelic malignant hyperthermia susceptibility trait.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"RYR1 variations resulting in CCD and MH susceptibility were initially reported to primarily localize in three "hot spot" regions (or domains): domain 1 (N-terminal residues 1–614), domain 2 (central residues 2163–2458), and domain 3 (C-terminal pore/transmembrane residues 4136–4973) [3, 56]."
Establishes the classic hotspot-domain distribution of dominant RYR1 variants.
Autosomal recessive (RyR1 deficiency / hypomorphic) HP:0000007
Recessive RYR1-related myopathy reflects biallelic variants distributed throughout the gene, including nonsense and splice variants, that reduce RyR1 protein abundance. It is typically more clinically severe than dominant disease.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:22473935 SUPPORT Human Clinical
"Recessive mutations included nonsense and splice mutations expected to result in reduced RyR1 protein."
Documents the reduced-expression mechanism underlying recessive RYR1-related myopathy.
PMID:33190635 SUPPORT Human Clinical
"MmD and recessive forms of CCD exhibit a marked reduction in RyR1 protein expression [186]."
Confirms markedly reduced RyR1 protein expression as the recessive disease mechanism across the multiminicore and central core spectrum.
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Subtypes

5
Malignant Hyperthermia Susceptibility Type 1 (RYR1-related)
RYR1 hgnc:10483 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RYR1 (hgnc:10483). hgnc:10483 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The pharmacogenetic malignant hyperthermia susceptibility trait caused by dominant RYR1 variants allelic with the myopathy-causing hotspot variants. Individuals may be asymptomatic outside of anesthetic exposure, and susceptibility and myopathy can co-occur in the same individual. Fully curated in Malignant_Hyperthermia_of_Anesthesia.yaml; represented here to make the shared allelic axis with RYR1-related myopathy explicit.
Show evidence (2 references)
PMID:33190635 SUPPORT Human Clinical
"CCD is considered allelic to MH susceptibility, which is also predominantly associated with a dominant mode of inheritance"
Establishes the allelic relationship between the myopathy-causing dominant variants and the malignant hyperthermia susceptibility trait.
PMID:30406384 SUPPORT Human Clinical
"As such, all RYR1-RM-affected individuals are considered potentially MH susceptible [29]."
Supports the clinical practice of treating every RYR1-related myopathy patient as a potential malignant hyperthermia risk regardless of inheritance pattern or documented testing.
King-Denborough Syndrome
RYR1 hgnc:10483 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RYR1 (hgnc:10483). hgnc:10483 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
A rare dominant RYR1-related presentation first described in 1973 and defined by the triad of dysmorphic features (short stature, pectus deformity, joint contractures, facial and skeletal dysmorphism), congenital myopathy, and malignant hyperthermia susceptibility.
Show evidence (2 references)
PMID:21514828 SUPPORT Human Clinical
"King-Denborough syndrome (KDS), first described in 1973, is a rare condition characterised by the triad of dysmorphic features, myopathy, and malignant hyperthermia susceptibility (MHS). Autosomal dominant inheritance with variable expressivity has been reported in several cases."
Primary source defining the King-Denborough syndrome clinical triad and its dominant, variably expressive inheritance.
PMID:21514828 SUPPORT Human Clinical
"Heterozygous missense mutations in RYR1 were uncovered in three out of four families, of which one mutation was novel and two have previously been reported in MH."
Documents dominant heterozygous RYR1 missense variants, overlapping with known MH variants, as the genetic cause in the majority of studied King-Denborough syndrome families.
Congenital Fiber-Type Disproportion, RYR1-Related
RYR1 hgnc:10483 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in RYR1 (hgnc:10483). hgnc:10483 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
A recessive presentation of RYR1-related myopathy on the congenital fiber-type disproportion (CFTD) histopathologic spectrum, accounting for roughly one-fifth of CFTD cases overall. Features overlap with other RYR1-related myopathy subtypes, including hypotonia, non-progressive weakness, ophthalmoparesis, and skeletal deformities, and many cases later develop cores, rods, or central nuclei that supersede the initial CFTD diagnosis.
Show evidence (2 references)
PMID:33190635 SUPPORT Human Clinical
"RYR1-related CFTD is an autosomal recessive disease accounting for about 20% of CFTD cases [59]."
Quantifies the RYR1 share of congenital fiber-type disproportion cases and confirms its recessive inheritance.
PMID:20301436 SUPPORT Human Clinical
"pathogenic variants have been identified in six genes: ACTA1 (~6% of individuals with CFTD), MYH7 (unknown), RYR1 (~10%-20%), SELENON (SEPN1) (rare), TPM2 (rare), and TPM3 (~20%-25% of individuals with CFTD)."
GeneReviews chapter (retired, historical reference) corroborating the RYR1 share of CFTD cases among the recognized CFTD-causing genes.
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Pathophysiology

8
Shared RyR1 Calcium-Release Dysfunction
All RYR1-related myopathy mechanisms converge on dysfunction of the RyR1 homotetrameric calcium-release channel, the principal sarcoplasmic reticulum calcium-release channel that mediates excitation-contraction coupling in skeletal muscle. Depending on the variant, this dysfunction can present as increased or decreased channel activity, or as reduced channel abundance.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
RYR1 hgnc:10483 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RYR1 (hgnc:10483). hgnc:10483 is a gene from the HUGO Gene Nomenclature Committee.
Ryanodine-sensitive calcium-release channel activity GO:0005219 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal Ryanodine-sensitive calcium-release channel activity (GO:0005219). GO:0005219 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
Downstream
Dominant RYR1 Gain-of-Function (Leaky Channel) Variants Dominant hotspot missense variants render the shared channel hyperactive/leaky.
Recessive RYR1 Hypomorphic (Reduced-Expression) Variants Recessive variants distributed throughout the gene reduce the abundance of the shared channel.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"RYR1-RD result from varying disease pathomechanisms that collectively share alterations in a common pathway—intracellular calcium dysregulation resulting from primary RyR1 dysfunction (e.g., reduced RyR1 expression, leaky RyR1 channels, impaired RyR1 interdomain interactions, enhanced..."
Summarizes the shared calcium-release dysfunction that both dominant and recessive RYR1 variant classes converge on.
Dominant RYR1 Gain-of-Function (Leaky Channel) Variants
Dominant RYR1-related myopathy is usually caused by heterozygous missense variants, historically clustered in three mutational hotspot regions, that render the RyR1 channel hypersensitive to activation and prone to inappropriate ("leaky") calcium release rather than simply reducing its abundance. This is the dominant gain-of-function mechanism requested for explicit modeling, and it is the same mechanism underlying malignant hyperthermia susceptibility.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
RYR1 hgnc:10483 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RYR1 (hgnc:10483). hgnc:10483 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: GAIN_OF_FUNCTION
Heterozygous, typically de novo or dominantly inherited missense variants concentrated in RYR1 hotspot domains that decouple channel gating from its normal physiological triggers.
Ryanodine-sensitive calcium-release channel activity GO:0005219 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves Ryanodine-sensitive calcium-release channel activity (GO:0005219), qualified as gain of function. GO:0005219 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
SR Calcium Leak and RyR1 Channel Hypersensitivity The dominant hotspot missense lesion produces the downstream leaky-channel cellular phenotype.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"increased sensitivity of RyR1 channels to activators (e.g., caffeine, halothane, CaV1.1 voltage sensors) as observed in MH resulting in uncontrolled channel opening and Ca2+ release"
Describes the dominant gain-of-function mechanism as hypersensitivity to physiological and pharmacologic activators plus a resting calcium leak, rather than reduced channel abundance.
SR Calcium Leak and RyR1 Channel Hypersensitivity
The cellular consequence of dominant gain-of-function RYR1 variants: hyperactive channels show elevated resting calcium leak and lowered threshold for triggered release, raising resting cytosolic calcium concentration in skeletal muscle fibers even without an anesthetic or exertional trigger.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology. Slow muscle cell (type I fiber) CL:0000189 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Slow muscle cell (type I fiber), annotated with slow muscle cell (CL:0000189). CL:0000189 is a cell type from the Cell Ontology.
Regulation of SR calcium release GO:0010880 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Regulation of SR calcium release, annotated with regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0010880). GO:0010880 is a biological process from the Gene Ontology. ↑ INCREASED Calcium ion homeostasis GO:0055074 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Calcium ion homeostasis (GO:0055074). GO:0055074 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Anesthetic/Stress-Triggered Malignant Hyperthermia Reaction A lowered threshold for RyR1 activation creates the substrate for an exaggerated calcium release when a susceptible individual is exposed to a triggering anesthetic or, more rarely, extreme exertion/heat.
Oxidative and Nitrosative Stress Chronic elevation of resting cytosolic and mitochondrial calcium from the leaky channel drives excessive mitochondrial reactive oxygen species production.
Skeletal Muscle Structural Remodeling and Weakness Chronic disturbance of calcium homeostasis at rest contributes to focal structural and metabolic change in muscle fibers (e.g., central core formation) and to baseline proximal weakness even without an anesthetic trigger.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"RyR1 channels with MH- or CCD-associated variants show higher activity and sensitivity to activation than wildtype channels, which ultimately leads to increases in resting Ca2+ concentration [135, 136]."
Directly supports elevated resting calcium as the quantitative cellular consequence of the leaky dominant channel, justifying an INCREASED modifier on SR calcium release regulation.
Oxidative and Nitrosative Stress
Chronic disturbance of calcium homeostasis from either the dominant leaky-channel or recessive uncoupling mechanism drives excessive mitochondrial calcium uptake and reactive oxygen species production in skeletal muscle fibers, producing a secondary oxidative/nitrosative stress state that can further damage RyR1 and muscle fibers. This is the mechanism directly targeted by antioxidant (N-acetylcysteine) therapy, tested in the NCT02362425 clinical trial.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Reactive oxygen species metabolic process GO:0072593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Reactive oxygen species metabolic process (GO:0072593). GO:0072593 is a biological process from the Gene Ontology. ↑ INCREASED Response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↑ INCREASED
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrion (GO:0005739). GO:0005739 is a cellular component from the Gene Ontology.
Downstream
Skeletal Muscle Structural Remodeling and Weakness Oxidative damage to RyR1 and to skeletal muscle fibers amplifies the structural and functional consequences of the primary calcium-release defect.
Show evidence (3 references)
PMID:22418739 SUPPORT Model Organism
"Subsequent studies focused on oxidative stress in relatively relaxed zebrafish and RYR1-related myopathy myotubes and demonstrated increased oxidant activity, the presence of oxidative stress markers, excessive production of oxidants by mitochondria and diminished survival under oxidant conditions."
Zebrafish disease-model data directly demonstrating increased oxidant activity and mitochondrial oxidant production in RYR1-related myopathy, supporting the INCREASED modifier on reactive oxygen species metabolism.
PMID:22418739 SUPPORT In Vitro
"Exposure to the antioxidant N-acetylcysteine reduced oxidative stress and improved survival in the RYR1-related myopathies human myotubes ex vivo"
Patient-myotube (in vitro) data confirming the oxidative-stress mechanism this node models and motivating N-acetylcysteine as a mechanism-targeted therapy (though the subsequent clinical trial, NCT02362425, did not confirm clinical benefit).
PMID:33190635 SUPPORT Human Clinical
"Alterations in calcium homeostasis can also lead to secondary cellular dysfunction including increased oxidative/nitrosative stress, altered post-translational modifications, mitochondrial damage, and disrupted protein-protein/ligand interactions"
Establishes that oxidative/nitrosative stress is a shared secondary mechanism downstream of calcium dysregulation from both the dominant and recessive RYR1 variant classes, not exclusive to one branch.
Recessive RYR1 Hypomorphic (Reduced-Expression) Variants
Recessive RYR1-related myopathy arises from biallelic variants distributed throughout the gene, including nonsense and splice variants, that reduce RyR1 protein abundance rather than altering channel gating per se. This is the recessive hypomorphic mechanism requested for explicit modeling, mechanistically distinct from the dominant gain-of-function/leaky-channel class above.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
RYR1 hgnc:10483 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased RYR1 (hgnc:10483). hgnc:10483 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED
Genetic context variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Biallelic (homozygous or compound heterozygous) nonsense, frameshift, splice-site, or missense variants distributed throughout the RYR1 coding sequence, expected to reduce RyR1 protein abundance rather than abolish it completely (a complete RYR1 null is not compatible with the surviving recessive phenotype).
Downstream
RyR1 Deficiency and Excitation-Contraction Uncoupling Reduced RyR1 protein abundance produces the downstream deficiency and uncoupling cellular phenotype.
Show evidence (1 reference)
PMID:22473935 SUPPORT Human Clinical
"Recessive mutations included nonsense and splice mutations expected to result in reduced RyR1 protein."
Establishes the reduced-expression mechanism for the recessive variant class.
RyR1 Deficiency and Excitation-Contraction Uncoupling
The cellular consequence of recessive hypomorphic RYR1 variants: a reduced functional channel pool at the triad lowers RyR1-mediated calcium permeation and Cav1.1-dependent SR calcium release, uncoupling membrane depolarization from calcium-triggered contraction. This contrasts with the dominant leaky-channel mechanism and explains the generally greater clinical severity of recessive disease.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Regulation of skeletal muscle contraction by calcium signaling GO:0014722 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Regulation of skeletal muscle contraction by calcium signaling, annotated with regulation of skeletal muscle contraction by calcium ion signaling (GO:0014722). GO:0014722 is a biological process from the Gene Ontology. ↓ DECREASED Regulation of SR calcium release GO:0010880 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Regulation of SR calcium release, annotated with regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0010880). GO:0010880 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Oxidative and Nitrosative Stress Impaired excitation-contraction coupling and the resulting metabolic strain likewise drive secondary mitochondrial oxidative stress, convergent with the dominant leaky-channel branch.
Skeletal Muscle Structural Remodeling and Weakness Uncoupling lowers calcium-dependent activation of contraction, producing more pronounced congenital weakness, ophthalmoplegia, and respiratory involvement than in dominant disease.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"reduction in RyR1 Ca2+ permeation leading to reduced Cav1.1-mediated SR Ca2+ release, a process referred to as excitation-contraction uncoupling"
Defines excitation-contraction uncoupling as the mechanistic consequence of reduced RyR1 channel expression, directly supporting a DECREASED modifier on the calcium-release and contraction-regulation processes.
Anesthetic/Stress-Triggered Malignant Hyperthermia Reaction
In individuals carrying dominant leaky-channel RYR1 variants (and, rarely, some recessive genotypes), exposure to volatile anesthetics or succinylcholine triggers uncontrolled sarcoplasmic-reticulum calcium release, driving sustained muscle contraction, hypermetabolism, hyperthermia, and rhabdomyolysis. Fully modeled in Malignant_Hyperthermia_of_Anesthesia.yaml; represented here at a summary level to connect it explicitly to the shared dominant leaky-channel node. Exercise and hot environments are recognized non-anesthetic triggers of the same reaction in susceptible individuals.
Show evidence (2 references)
PMID:30406384 SUPPORT Human Clinical
"MH (MIM# 145600) is a potentially lethal hypermetabolic condition triggered by exposure of susceptible individuals to certain volatile anesthetics and muscle relaxants."
Defines the anesthetic-triggered malignant hyperthermia mechanism downstream of the leaky-channel node.
PMID:20301325 SUPPORT Human Clinical
"There is mounting evidence that some individuals with MHS will also develop MH with exercise and/or on exposure to hot environments."
GeneReviews documents exercise and hot-environment exposure as recognized non-anesthetic triggers of the same malignant hyperthermia reaction, closing the non-anesthetic-trigger modeling gap.
Skeletal Muscle Structural Remodeling and Weakness
Chronic calcium-handling disturbance from either mechanism converges on shared downstream tissue-level consequences: focal or diffuse structural and histopathologic change in skeletal muscle fibers (central cores, minicores, central nuclei, or fiber-type disproportion, depending on variant class and biopsy timing) and clinically apparent weakness, hypotonia, and orthopedic complications. Recessive disease is generally more severe and more often adds extraocular, bulbar, and respiratory involvement.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology. Slow muscle cell (type I fiber) CL:0000189 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Slow muscle cell (type I fiber), annotated with slow muscle cell (CL:0000189). CL:0000189 is a cell type from the Cell Ontology.
Skeletal muscle contraction GO:0003009 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Skeletal muscle contraction (GO:0003009). GO:0003009 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Proximal Muscle Weakness Shared downstream clinical weakness phenotype.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"Clinical features suggestive of RYR1-RM are extensive, with mild to severe symptoms ranging from delayed motor milestones, proximal muscle weakness, hypotonia, and fatigue, to kyphoscoliosis, ophthalmoplegia, and moderate to severe respiratory insufficiency, which is more often apparent in..."
Documents the shared downstream clinical spectrum, with respiratory and extraocular involvement enriched in recessive disease.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for RYR1-Related Myopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

16
Digestive 1
Feeding Difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"Clinical features reported in CFTD patients include hypotonia, respiratory failure, non-progressive muscle weakness, joint contractures, myopathic facies, ophthalmoparesis, feeding difficulties, and skeletal deformities"
Directly names feeding difficulties among the clinical features reported in RYR1-related congenital fiber-type disproportion.
Eye 1
External Ophthalmoplegia HP:0000544 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is External ophthalmoplegia (HP:0000544). HP:0000544 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"extraocular muscle involvement is almost exclusively associated with recessive forms of RYR1-RD, whereas enhanced malignant hyperthermia susceptibility is more commonly seen with dominant rather than recessive RYR1 variations [187]."
Documents the strong enrichment of extraocular/ophthalmoplegic involvement in recessive, as opposed to dominant, RYR1-related myopathy.
Head and Neck 1
Myopathic Facies HP:0002058 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathic facies (HP:0002058). HP:0002058 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"the ophthalmoplegia form, with generalized muscle involvement and severe facial weakness"
Directly names severe facial weakness in the ophthalmoplegic form of recessive RYR1-related multiminicore disease.
Limbs 1
Congenital Hip Dislocation HP:0001374 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital hip dislocation (HP:0001374). HP:0001374 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17504518 SUPPORT Human Clinical
"comprise congenital dislocation of the hips"
This Orphanet review of central core disease (a major RYR1-related myopathy subtype, cross-referenced from Central_Core_Myopathy.yaml) explicitly names congenital dislocation of the hips among the orthopaedic complications of the disease.
Metabolism 1
Malignant Hyperthermia HP:0002047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malignant hyperthermia (HP:0002047). HP:0002047 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"extraocular muscle involvement is almost exclusively associated with recessive forms of RYR1-RD, whereas enhanced malignant hyperthermia susceptibility is more commonly seen with dominant rather than recessive RYR1 variations [187]."
Documents enhanced malignant hyperthermia susceptibility as preferentially, though not exclusively, associated with dominant RYR1-related myopathy.
Musculoskeletal 5
Proximal Muscle Weakness FREQUENT HP:0003701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proximal muscle weakness (HP:0003701). HP:0003701 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"Clinical features suggestive of RYR1-RM are extensive, with mild to severe symptoms ranging from delayed motor milestones, proximal muscle weakness, hypotonia, and fatigue, to kyphoscoliosis, ophthalmoplegia, and moderate to severe respiratory insufficiency, which is more often apparent in..."
Documents proximal muscle weakness across the RYR1-RM spectrum.
Rhabdomyolysis HP:0003201 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rhabdomyolysis (HP:0003201). HP:0003201 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"Considered a late neuromuscular manifestation of MH-related RYR1 variations, late-onset axial myopathy, exertional rhabdomyolysis, and periodic paralysis present throughout the lifespan."
Directly names exertional rhabdomyolysis as a late neuromuscular manifestation of the MH-related (dominant leaky-channel) RYR1 variant class.
Joint Contracture HP:0034392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint contracture (HP:0034392). HP:0034392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"RYR1-RM-affected individuals can present with delayed motor milestones, contractures, scoliosis, ophthalmoplegia, and respiratory insufficiency."
Directly names contractures among the core clinical features of RYR1-related myopathy.
Neonatal Hypotonia HP:0001319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal hypotonia (HP:0001319). HP:0001319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"Clinical features suggestive of RYR1-RM are extensive, with mild to severe symptoms ranging from delayed motor milestones, proximal muscle weakness, hypotonia, and fatigue"
Documents hypotonia as a core RYR1-RM presenting feature.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"Clinical features suggestive of RYR1-RM are extensive, with mild to severe symptoms ranging from delayed motor milestones, proximal muscle weakness, hypotonia, and fatigue, to kyphoscoliosis, ophthalmoplegia, and moderate to severe respiratory insufficiency"
Documents kyphoscoliosis as a recognized orthopedic complication.
Respiratory 1
Respiratory Insufficiency HP:0002093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"Clinical features suggestive of RYR1-RM are extensive, with mild to severe symptoms ranging from delayed motor milestones, proximal muscle weakness, hypotonia, and fatigue, to kyphoscoliosis, ophthalmoplegia, and moderate to severe respiratory insufficiency, which is more often apparent in..."
Documents moderate to severe respiratory insufficiency, most apparent in recessive disease.
Constitutional 1
Fatigue FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"Clinical features suggestive of RYR1-RM are extensive, with mild to severe symptoms ranging from delayed motor milestones, proximal muscle weakness, hypotonia, and fatigue, to kyphoscoliosis, ophthalmoplegia, and moderate to severe respiratory insufficiency, which is more often apparent in..."
Directly names fatigue as one of the mild-to-severe clinical features spanning the RYR1-RM spectrum.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41753076 SUPPORT Human Clinical
"All exhibited dysmorphic features, short stature, skeletal abnormalities, and myopathy."
This multi-center cohort's three King-Denborough syndrome cases explicitly document short stature as a presenting feature, not merely an inferred component of a general "dysmorphic features" phrase.
Other 3
Delayed Ability to Walk HP:0031936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed ability to walk (HP:0031936). HP:0031936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"Clinical features suggestive of RYR1-RM are extensive, with mild to severe symptoms ranging from delayed motor milestones, proximal muscle weakness"
Documents delayed motor milestones across the RYR1-RM spectrum.
Exercise-Induced Myalgia HP:0003738 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise-induced myalgia (HP:0003738). HP:0003738 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30406384 SUPPORT Human Clinical
"fatigue, exercise-induced hyperthermia/exertional heat stroke, and exertional myalgia"
Directly names exertional myalgia as a clinical feature of RYR1-RM, rather than only the "rhabdomyolysis-myalgia syndrome" spectrum entity named below.
PMID:33190635 SUPPORT Human Clinical
"This spectrum includes RYR1 variant-associated clinical phenotypes including King-Denborough syndrome, congenital neuromuscular disease with uniform type 1 fiber (CNMDU1), dusty core disease, rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, and bleeding abnormalities [31–38]."
Documents the related RYR1 rhabdomyolysis-myalgia syndrome phenotype as a distinct named entity within the broader RYR1-related myopathy spectrum.
Sternal Deformity Abnormal sternum morphology HP:0000766 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus carinatum or excavatum, annotated with Abnormal sternum morphology (HP:0000766). HP:0000766 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30406384 SUPPORT Human Clinical
"Ki ng Denborough syndrome (pectus carinatum or excavatum, short stature, joint contractures, facial and skeletal deformities)"
Explicitly enumerates pectus carinatum or excavatum among the King-Denborough syndrome dysmorphic features (snippet preserves a source PDF-extraction spacing artifact splitting "King" into "Ki ng" to remain an exact substring of the cached text). Bound to the general "Abnormal sternum morphology" term rather than pectus carinatum specifically, because the source names either carinatum or excavatum without specifying which one is present.
🧬

Genetic Associations

1
RYR1 (Causative)
Gene: RYR1 hgnc:10483 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RYR1 (hgnc:10483). hgnc:10483 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:33190635 SUPPORT Human Clinical
"Pathogenic variations in the RYR1 gene, a relatively large gene in the human genome, are the most common cause of CM and contribute to the clinical, histopathological, and genetic heterogeneity of CMs."
Establishes RYR1 as the most common cause of congenital myopathy and the source of its heterogeneity.
PMID:33190635 SUPPORT Human Clinical
"With nearly 700 RYR1 variations identified to date"
Documents the scale of the RYR1 allelic series and the diagnostic impact of genome-wide sequencing coverage of the gene.
💊

Medical Actions

8
Avoidance of malignant hyperthermia triggers
Action: chemical exposure avoidanceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemical exposure avoidance, annotated with Lifestyle Therapy (NCIT:C15900). NCIT:C15900 is a clinical intervention from the NCI Thesaurus. Ontology label: Lifestyle Therapy NCIT:C15900
Strict avoidance of volatile anesthetic agents and depolarizing neuromuscular blocking agents (succinylcholine); total intravenous anesthesia is preferred whenever a patient with any RYR1-related myopathy diagnosis requires general anesthesia, because dominant, recessive, and untested individuals are all managed as potentially MH susceptible.
Show evidence (2 references)
PMID:30406384 SUPPORT Human Clinical
"all RYR1-RM-affected individuals are considered potentially MH susceptible [29]"
Supports universal anesthetic-trigger avoidance across the RYR1-related myopathy spectrum.
PMID:20301325 SUPPORT Human Clinical
"Avoid potent inhalation anesthetics and succinylcholine."
GeneReviews names the specific agents to avoid, closing the GeneReviews-baseline "Agents/Circumstances to Avoid" gap.
Dantrolene
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dantrolene CHEBI:4317 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dantrolene (CHEBI:4317). CHEBI:4317 is a therapeutic agent from Chemical Entities of Biological Interest.
Dantrolene is the specific emergency pharmacotherapy for an acute malignant hyperthermia reaction and should be immediately available whenever a patient with RYR1-related myopathy undergoes general anesthesia. Off-label chronic/periodic use for baseline myopathic symptoms has been reported anecdotally but is not well established.
Mechanism Target:
INHIBITS SR Calcium Leak and RyR1 Channel Hypersensitivity — Dantrolene antagonizes the RyR1 channel, reducing the excess calcium release/leak underlying both the acute malignant hyperthermia crisis and, potentially, baseline dominant-mechanism channel hyperactivity.
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"Dantrolene sodium is a specific antagonist and should be available wherever general anesthesia is administered."
Supports dantrolene as the specific pharmacologic antagonist of the leaky-channel calcium-release mechanism.
Target Phenotypes: Malignant hyperthermia HP:0002047 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Malignant hyperthermia (HP:0002047). HP:0002047 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26238698 SUPPORT Human Clinical
"Dantrolene sodium is a specific antagonist and should be available wherever general anesthesia is administered."
Establishes dantrolene as the MH-crisis emergency treatment.
PMID:20301325 SUPPORT Human Clinical
"Administration of intravenous dantrolene sodium (initial dose of 2.5 mg/kg) as early as possible during an MH episode."
GeneReviews specifies the targeted-therapy dosing for an acute MH episode, closing the GeneReviews-baseline Management gap.
Salbutamol/albuterol
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: albuterol CHEBI:2549 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses albuterol (CHEBI:2549). CHEBI:2549 is a therapeutic agent from Chemical Entities of Biological Interest.
An off-label beta-agonist reported to improve muscle strength and motor function in some RYR1-related myopathy patients, proposed to act by increasing SERCA expression and facilitating reuptake of cytosolic calcium into the sarcoplasmic reticulum, thereby partially compensating for either the leaky-channel or the excitation-contraction uncoupling mechanism.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"salbutamol, a beta agonist that improves muscle strength and motor function through mechanisms that are not completely understood [120]"
Documents anecdotal reports of salbutamol benefit in RYR1-related myopathy.
N-acetylcysteine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: N-acetylcysteine CHEBI:28939 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses N-acetylcysteine, annotated with N-acetyl-L-cysteine (CHEBI:28939). CHEBI:28939 is a therapeutic agent from Chemical Entities of Biological Interest.
An antioxidant tested in a completed NIH clinical trial (NCT02362425) directly targeting the mitochondrial oxidative/nitrosative stress mechanism, based on preclinical rescue of oxidative stress and improved survival/muscle function in zebrafish and patient-derived myotube models. The subsequent clinical trial did not confirm a benefit on its primary outcomes.
Mechanism Target:
INHIBITS Oxidative and Nitrosative Stress — N-acetylcysteine is a glutathione precursor proposed to reduce the excess mitochondrial reactive oxygen species production characteristic of RYR1-related myopathy, the mechanism this node models.
Show evidence (1 reference)
PMID:22418739 SUPPORT In Vitro
"Exposure to the antioxidant N-acetylcysteine reduced oxidative stress and improved survival in the RYR1-related myopathies human myotubes ex vivo"
Patient-derived myotube (in vitro) data establishing the mechanistic rationale for N-acetylcysteine acting on the oxidative-stress node this treatment targets.
Show evidence (1 reference)
PMID:22418739 SUPPORT Model Organism
"led to significant restoration of aspects of muscle function in the relatively relaxed zebrafish, thereby confirming its efficacy in vivo"
Zebrafish (model organism) data confirming the preclinical benefit that motivated the subsequent NCT02362425 clinical trial, which did not confirm the benefit in humans (see clinical_trials below).
Rycal S48168 (ARM210)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Rycal S48168 (ARM210) Relation: this treatment uses this therapeutic agent This treatment uses Rycal S48168 (ARM210).
An investigational RyR-stabilizing "Rycal" small molecule tested in a completed phase 1, open-label, dose-escalation trial (NCT04141670) in ambulatory adults with genetically confirmed RYR1-related myopathy whose RyR1 channels were shown ex vivo to be leaky and Rycal-responsive. It was well tolerated, with most participants on the higher dose reporting reduced fatigue and improved proximal muscle strength on exam.
Mechanism Target:
INHIBITS SR Calcium Leak and RyR1 Channel Hypersensitivity — Rycal compounds are proposed to restore FKBP12 (calstabin1) binding to RyR1, stabilizing the channel closed state and reducing the resting calcium leak characteristic of dominant gain-of-function variants.
Show evidence (1 reference)
PMID:38318125 SUPPORT Human Clinical
"Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17 RYR1-RM patient skeletal muscle biopsies and improved following ex vivo treatment with Rycal compounds."
Establishes the mechanistic rationale for Rycal compounds directly addressing the leaky-channel/SR calcium leak mechanism in patient muscle biopsies.
Target Phenotypes: Proximal muscle weakness HP:0003701 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proximal muscle weakness (HP:0003701). HP:0003701 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38318125 SUPPORT Human Clinical
"S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dose-dependent PK profile."
Reports the phase 1 safety and tolerability outcome.
Pyridostigmine for fatigable weakness
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Anecdotal reports describe improved fatigue and energy level with the acetylcholinesterase inhibitor pyridostigmine in a subset of RYR1-related myopathy patients with a fatigable weakness phenotype.
Target Phenotypes: Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24951453 SUPPORT Human Clinical
"These cases broaden the RYR1-related disease spectrum to include a myasthenic-like phenotype, including partial response to pyridostigimine."
Reports partial clinical response to pyridostigmine in siblings with RYR1-related myopathy presenting with fatigable weakness.
PMID:33190635 SUPPORT Human Clinical
"There have been anecdotal reports of positive responses to pyridostigmine, an acetylcholinesterase inhibitor, improving fatigue and energy level [43]"
Corroborates anecdotal pyridostigmine benefit in RYR1-related myopathy.
Supportive orthopedic, respiratory, and physical therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
No approved disease-modifying treatment exists for RYR1-related myopathy. Management is primarily supportive: physical/occupational therapy, orthopedic evaluation and bracing/surgery for scoliosis and contractures, respiratory support as needed, and periodic monitoring of motor function.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"There is no approved treatment for RYR1-RM. Symptom management is primarily supportive, with precautions taken when MH risk is either known or not ascertained."
Establishes that management is supportive in the absence of an approved disease-modifying therapy.
Genetic counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling addresses the dominant versus recessive inheritance pattern, recurrence risk, and the implications of RYR1 genotype for malignant hyperthermia susceptibility in the proband and at-risk family members.
Show evidence (1 reference)
PMID:20301325 SUPPORT Human Clinical
"Each child of an individual with MHS has a 50% chance of being MH susceptible."
GeneReviews states the concrete transmission-risk figure a genetic counseling recommendation needs for the dominant malignant hyperthermia susceptibility axis of this entry, closing the GeneReviews-baseline Genetic Counseling gap. (The corresponding recessive-disease recurrence risk is covered by the standard 25% autosomal recessive figure implicit in the `inheritance:` block above.)
🔬

Biochemical Markers

1
Creatine Kinase (Variable)
Context: Serum CK is often normal in RYR1-related myopathy, unlike in dystrophic myopathies; a minority of patients show mild to moderate elevation. A normal CK therefore does not exclude the diagnosis.
Show evidence (1 reference)
PMID:41753076 SUPPORT Human Clinical
"Serum CK levels were within the normal range for most patients, except for five (17%) who exhibited mild to moderate elevations."
Directly reports the proportion of a real RYR1-variant cohort with elevated CK, establishing that the biomarker is usually normal but occasionally elevated in RYR1-related myopathy.
🔬

Diagnosis

4
Clinical neuromuscular assessment
Evaluation begins with congenital or early-onset myopathy features, delayed motor milestones, hypotonia, proximal or generalized weakness, and orthopedic complications, together with anesthetic and family history. Dominant disease tends to be milder; recessive disease can present with severe neonatal, bulbar, ophthalmoplegic, or respiratory involvement.
physical examination NCIT:C20989 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"Clinical features suggestive of RYR1-RM are extensive, with mild to severe symptoms ranging from delayed motor milestones, proximal muscle weakness, hypotonia, and fatigue, to kyphoscoliosis, ophthalmoplegia, and moderate to severe respiratory insufficiency, which is more often apparent in..."
Defines the clinical presentation that prompts diagnostic evaluation across the RYR1-related myopathy spectrum.
Muscle biopsy and histopathology
Muscle biopsy with oxidative enzyme histochemistry and electron microscopy identifies the histopathologic subtype (central cores, multi-minicores, central nuclei, core-rod features, or fiber-type disproportion), though these features are not fully specific to RYR1 and can be dynamic over time or absent on early biopsy.
biopsy of muscle tissue NCIT:C51895 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"these histopathologic features are not always specific to RYR1-RM and often change over time"
Documents the limitations of histopathology alone as a diagnostic criterion for RYR1-related myopathy.
In vitro caffeine-halothane contracture test for malignant hyperthermia susceptibility
The reference diagnostic test for malignant hyperthermia susceptibility, determining muscle contracture thresholds in response to caffeine and halothane on a fresh open muscle biopsy specimen. It is invasive and can yield false negatives, and because MH susceptibility is under-penetrant and lacks a single common causative variant, all RYR1-related myopathy patients are managed as potentially MH susceptible regardless of test or genotype status.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:30406384 SUPPORT Human Clinical
"the d iagnostic test for MH susceptibility is the in vitro caffeine–halothane contracture test (IVCT), which determines contracture thresholds"
Defines the IVCT as the reference diagnostic test for MH susceptibility (snippet preserves a source PDF-extraction spacing artifact in "d iagnostic" to remain an exact substring of the cached text).
PMID:30406384 SUPPORT Human Clinical
"all RYR1-RM-affected individuals are considered potentially MH susceptible [29]"
Supports the clinical practice of universal MH precautions in RYR1-related myopathy regardless of confirmed susceptibility testing.
PMID:20301325 SUPPORT Human Clinical
"The diagnosis of MHS is established with in vitro muscle contracture testing by measuring the contracture responses of biopsied muscle samples to halothane and graded concentrations of caffeine."
GeneReviews defines the IVCT methodology directly, closing the GeneReviews-baseline gap on the primary diagnostic test for the malignant hyperthermia susceptibility axis of this entry.
RYR1 molecular genetic testing
Next-generation sequencing of the entire RYR1 coding sequence and canonical splice sites, rather than restriction to historical hotspot regions, has become the primary diagnostic approach and has expanded the recognized clinical spectrum.
molecular genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"A genetics-first diagnostic approach is rapidly becoming the standard for confirmation of disorders with known genetic etiology"
Establishes genetics-first sequencing as the current diagnostic standard for RYR1-related myopathy.
📊

Prevalence

2
Genetic susceptibility to malignant hyperthermia (allelic dominant RYR1 variants)
Point Prevalence 250.0 per 100,000 >1 in 1,000
MH-susceptibility genetic variants (mostly dominant RYR1) are far more common than clinically overt RYR1-related myopathy; exome-based estimates range up to 1 in 400 individuals.
Show evidence (1 reference)
PMID:33190635 SUPPORT Human Clinical
"genetic variants resulting in MH susceptibility are more common, affecting approximately 1:3000–1:8500"
Documents that MH-susceptibility RYR1 variants are much more prevalent than overt myopathy, consistent with incomplete penetrance of the dominant leaky-channel mechanism.
🔬

Clinical Trials

2
NCT02362425 PHASE_II COMPLETED
NIH natural-history-plus-intervention trial of oral N-acetylcysteine (NAC), an antioxidant, in ambulatory RYR1-related myopathy patients ages 7 and older, testing effects on muscle damage and exercise tolerance. The intervention did not improve either outcome.
Target Phenotypes: Proximal muscle weakness HP:0003701 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Proximal muscle weakness (HP:0003701). HP:0003701 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
clinicaltrials:NCT02362425 SUPPORT Other
"To see if the drug N-acetylcysteine decreases muscle damage in people with RYR1-RM. To see if it improves their exercise tolerance."
States the trial's objective testing NAC in RYR1-related myopathy.
PMID:33190635 REFUTE Human Clinical
"All participants exhibited elevated oxidative stress as determined by urine 15-F2t-isoprostane concentration and decreased physical endurance. However, oral treatment with NAC did not impact either outcome [121]."
Reports the negative primary-outcome result of the completed NAC trial, despite preclinical rationale in mouse and zebrafish models.
NCT04141670 PHASE_I COMPLETED
Phase 1, open-label, dose-escalation, first-in-patient trial of the RyR-stabilizing "Rycal" small molecule S48168 (ARM210) in ambulatory adults with genetically confirmed RYR1-related myopathy, directly targeting the dominant leaky-channel/gain-of-function mechanism. The compound was well tolerated with a dose-dependent pharmacokinetic profile; most participants on the higher (200 mg/day) dose reported reduced fatigue and showed improved proximal muscle strength on exam, setting the foundation for a subsequent placebo-controlled trial.
Target Phenotypes: Proximal muscle weakness HP:0003701 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Proximal muscle weakness (HP:0003701). HP:0003701 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
clinicaltrials:NCT04141670 SUPPORT Other
"The study population will include adult patients (≥18 years of age) who have demonstrated leaky RyR1 channels that are responsive to S48168 (ARM210) ex vivo."
Documents that trial eligibility directly targets the leaky-channel (dominant gain-of-function) RYR1 mechanism modeled in this entry.
PMID:38318125 SUPPORT Human Clinical
"S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dose-dependent PK profile. Three of four participants who received the 200 mg/day dose reported improvements in PROMIS-fatigue at 28 days post-dosing, and also demonstrated improved proximal muscle..."
Reports the completed trial's published safety, tolerability, and exploratory efficacy findings for the leaky-channel-targeted Rycal compound.
{ }

Source YAML

click to show 
name: RYR1-Related Myopathy
creation_date: "2026-08-26T00:00:00Z"
category: Mendelian
description: >-
  RYR1-related myopathy is the umbrella term for the clinically and
  histopathologically heterogeneous group of skeletal-muscle disorders caused
  by pathogenic variants in RYR1, the gene encoding the type 1 ryanodine
  receptor (RyR1), the principal sarcoplasmic reticulum (SR) calcium-release
  channel that couples membrane depolarization to muscle contraction
  (excitation-contraction coupling). Two broadly distinct, allele-dependent
  mechanisms converge on this shared channel: dominant, typically hotspot
  missense variants that produce a hyperactive or "leaky" channel with
  exaggerated or inappropriate SR calcium release, and recessive,
  loss-of-function or hypomorphic variants that reduce RyR1 protein
  abundance and impair excitation-contraction coupling. The resulting
  clinical and histopathologic spectrum overlaps substantially and includes
  central core disease, multiminicore disease, centronuclear myopathy,
  congenital fiber-type disproportion, and King-Denborough syndrome, as well
  as the pharmacogenetic malignant hyperthermia susceptibility trait, which
  is allelic with the myopathy-causing dominant variants. This entry models
  the RYR1-related myopathy spectrum at the root/umbrella level; see the
  Central_Core_Myopathy, Multiminicore_Disease, and Centronuclear_Myopathy
  entries for full curation of those individually named histopathologic
  entities, and the Malignant_Hyperthermia_of_Anesthesia entry for full
  curation of the general (non-syndromic) susceptibility trait.
synonyms:
- RYR1-related disease
- RYR1-related disorder
- RYR1-related myopathies
- RYR1-related disorders
disease_term:
  preferred_term: RYR1-related myopathy
  term:
    id: MONDO:0100150
    label: RYR1-related myopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100150
      label: RYR1-related myopathy
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this entry.
parents:
- Congenital myopathy
- Muscular Channelopathy
- Hereditary Neuromuscular Disease
classifications:
  channelopathy_category:
    classification_value: skeletal muscle channelopathy
prevalence:
- population: All-age populations, RYR1-related myopathy overall
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 1.1
  notes: >-
    Likely underestimated prevalence of 1:90,000, cited as the most common
    form of non-dystrophic muscle disease in humans.
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With a likely underestimated disease prevalence of 1:90,000
      individuals
    explanation: >-
      Establishes the overall RYR1-related myopathy prevalence estimate and
      its status as the most common non-dystrophic muscle disease.
- population: Genetic susceptibility to malignant hyperthermia (allelic dominant RYR1 variants)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 250.0
  notes: >-
    MH-susceptibility genetic variants (mostly dominant RYR1) are far more
    common than clinically overt RYR1-related myopathy; exome-based
    estimates range up to 1 in 400 individuals.
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genetic variants resulting in MH susceptibility are more common,
      affecting approximately 1:3000–1:8500
    explanation: >-
      Documents that MH-susceptibility RYR1 variants are much more prevalent
      than overt myopathy, consistent with incomplete penetrance of the
      dominant leaky-channel mechanism.
inheritance:
- name: Autosomal dominant (leaky channel / gain-of-function)
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Dominant RYR1-related myopathy is usually caused by heterozygous missense
    variants, historically clustered in three hotspot regions of the channel,
    that render the RyR1 channel hyperactive/leaky rather than reducing its
    abundance. This is the mechanism also responsible for the allelic
    malignant hyperthermia susceptibility trait.
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RYR1 variations resulting in CCD and MH susceptibility were initially
      reported to primarily localize in three "hot spot" regions (or
      domains): domain 1 (N-terminal residues 1–614), domain 2 (central
      residues 2163–2458), and domain 3 (C-terminal pore/transmembrane
      residues 4136–4973) [3, 56].
    explanation: >-
      Establishes the classic hotspot-domain distribution of dominant RYR1
      variants.
- name: Autosomal recessive (RyR1 deficiency / hypomorphic)
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Recessive RYR1-related myopathy reflects biallelic variants distributed
    throughout the gene, including nonsense and splice variants, that reduce
    RyR1 protein abundance. It is typically more clinically severe than
    dominant disease.
  evidence:
  - reference: PMID:22473935
    reference_title: "Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recessive mutations included nonsense and splice mutations expected to
      result in reduced RyR1 protein.
    explanation: >-
      Documents the reduced-expression mechanism underlying recessive
      RYR1-related myopathy.
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MmD and recessive forms of CCD exhibit a marked reduction in RyR1
      protein expression [186].
    explanation: >-
      Confirms markedly reduced RyR1 protein expression as the recessive
      disease mechanism across the multiminicore and central core spectrum.
has_subtypes:
- name: Dominant RYR1-Related Myopathy
  display_name: Dominant (leaky-channel) RYR1-related myopathy spectrum
  description: >-
    The dominant end of the RYR1-related myopathy spectrum, driven by
    hyperactive/leaky RyR1 channels rather than reduced channel abundance.
    Typically milder than recessive disease, with proximal weakness,
    hypotonia, and orthopedic complications, and it carries clinically
    important malignant hyperthermia susceptibility. Includes autosomal
    dominant central core disease (see the AD-CCD subtype of
    Central_Core_Myopathy.yaml for full curation).
  children:
  - MHS1
  - KDS
  genes:
  - preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:22473935
    reference_title: "Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dominant mutations, typically missense, were frequently located in
      recognized mutational hotspot regions, while recessive mutations were
      distributed throughout the entire coding sequence.
    explanation: >-
      Defines the dominant RYR1 mutation class distinguishing it from
      recessive disease.
- name: Recessive RYR1-Related Myopathy
  display_name: Recessive (RyR1-deficiency) RYR1-related myopathy spectrum
  description: >-
    The recessive end of the RYR1-related myopathy spectrum, driven by
    reduced RyR1 protein abundance and excitation-contraction uncoupling
    rather than channel hyperactivity. Generally more severe than dominant
    disease, with earlier onset, greater weakness, and enrichment for
    extraocular, bulbar, and respiratory involvement. Includes recessive
    central core disease (AR-CCD in Central_Core_Myopathy.yaml), the RYR1
    subtype of multiminicore disease (Multiminicore_Disease.yaml), and
    RYR1-related centronuclear myopathy (RYR1-CNM in
    Centronuclear_Myopathy.yaml).
  children:
  - CFTD-RYR1
  genes:
  - preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:22473935
    reference_title: "Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As a group, dominant mutations were associated with milder phenotypes;
      patients with recessive inheritance had earlier onset, more weakness,
      and functional limitations.
    explanation: >-
      Documents the more severe clinical course of recessive RYR1-related
      myopathy relative to dominant disease.
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the nine genes currently associated with CNM (RYR1, MTM1, DNM2,
      BIN1, TTN, MTMR14, SPEG, CCDC78, and CACNA1S), RYR1 variants are the
      most common cause of autosomal recessive CNM [28].
    explanation: >-
      Cross-references RYR1 as the most common cause of recessive
      centronuclear myopathy, curated fully in Centronuclear_Myopathy.yaml.
- name: MHS1
  display_name: Malignant Hyperthermia Susceptibility Type 1 (RYR1-related)
  description: >-
    The pharmacogenetic malignant hyperthermia susceptibility trait caused by
    dominant RYR1 variants allelic with the myopathy-causing hotspot
    variants. Individuals may be asymptomatic outside of anesthetic exposure,
    and susceptibility and myopathy can co-occur in the same individual.
    Fully curated in Malignant_Hyperthermia_of_Anesthesia.yaml; represented
    here to make the shared allelic axis with RYR1-related myopathy explicit.
  genes:
  - preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CCD is considered allelic to MH susceptibility, which is also
      predominantly associated with a dominant mode of inheritance
    explanation: >-
      Establishes the allelic relationship between the myopathy-causing
      dominant variants and the malignant hyperthermia susceptibility trait.
  - reference: PMID:30406384
    reference_title: "Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As such, all RYR1-RM-affected individuals are considered potentially
      MH susceptible [29].
    explanation: >-
      Supports the clinical practice of treating every RYR1-related myopathy
      patient as a potential malignant hyperthermia risk regardless of
      inheritance pattern or documented testing.
- name: KDS
  display_name: King-Denborough Syndrome
  description: >-
    A rare dominant RYR1-related presentation first described in 1973 and
    defined by the triad of dysmorphic features (short stature, pectus
    deformity, joint contractures, facial and skeletal dysmorphism), congenital
    myopathy, and malignant hyperthermia susceptibility.
  genes:
  - preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      Autosomal dominant inheritance with variable expressivity has been
      reported, alongside apparently sporadic/de novo cases.
  evidence:
  - reference: PMID:21514828
    reference_title: "King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      King-Denborough syndrome (KDS), first described in 1973, is a rare
      condition characterised by the triad of dysmorphic features, myopathy,
      and malignant hyperthermia susceptibility (MHS). Autosomal dominant
      inheritance with variable expressivity has been reported in several
      cases.
    explanation: >-
      Primary source defining the King-Denborough syndrome clinical triad and
      its dominant, variably expressive inheritance.
  - reference: PMID:21514828
    reference_title: "King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous missense mutations in RYR1 were uncovered in three out of
      four families, of which one mutation was novel and two have previously
      been reported in MH.
    explanation: >-
      Documents dominant heterozygous RYR1 missense variants, overlapping
      with known MH variants, as the genetic cause in the majority of
      studied King-Denborough syndrome families.
- name: CFTD-RYR1
  display_name: Congenital Fiber-Type Disproportion, RYR1-Related
  description: >-
    A recessive presentation of RYR1-related myopathy on the congenital
    fiber-type disproportion (CFTD) histopathologic spectrum, accounting for
    roughly one-fifth of CFTD cases overall. Features overlap with other
    RYR1-related myopathy subtypes, including hypotonia, non-progressive
    weakness, ophthalmoparesis, and skeletal deformities, and many cases
    later develop cores, rods, or central nuclei that supersede the initial
    CFTD diagnosis.
  genes:
  - preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RYR1-related CFTD is an autosomal recessive disease accounting for
      about 20% of CFTD cases [59].
    explanation: >-
      Quantifies the RYR1 share of congenital fiber-type disproportion cases
      and confirms its recessive inheritance.
  - reference: PMID:20301436
    reference_title: "Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pathogenic variants have been identified in six genes: ACTA1 (~6% of
      individuals with CFTD), MYH7 (unknown), RYR1 (~10%-20%), SELENON
      (SEPN1) (rare), TPM2 (rare), and TPM3 (~20%-25% of individuals with
      CFTD).
    explanation: >-
      GeneReviews chapter (retired, historical reference) corroborating the
      RYR1 share of CFTD cases among the recognized CFTD-causing genes.
pathophysiology:
- name: Shared RyR1 Calcium-Release Dysfunction
  biological_scale: MOLECULAR
  description: >-
    All RYR1-related myopathy mechanisms converge on dysfunction of the RyR1
    homotetrameric calcium-release channel, the principal sarcoplasmic
    reticulum calcium-release channel that mediates excitation-contraction
    coupling in skeletal muscle. Depending on the variant, this dysfunction
    can present as increased or decreased channel activity, or as reduced
    channel abundance.
  genes:
  - preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  molecular_functions:
  - preferred_term: Ryanodine-sensitive calcium-release channel activity
    modifier: ABNORMAL
    term:
      id: GO:0005219
      label: ryanodine-sensitive calcium-release channel activity
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RYR1-RD result from varying disease pathomechanisms that collectively
      share alterations in a common pathway—intracellular calcium
      dysregulation resulting from primary RyR1 dysfunction (e.g., reduced
      RyR1 expression, leaky RyR1 channels, impaired RyR1 interdomain
      interactions, enhanced sensitivity to modulators, impaired
      excitation-contraction coupling)
    explanation: >-
      Summarizes the shared calcium-release dysfunction that both dominant
      and recessive RYR1 variant classes converge on.
  downstream:
  - target: Dominant RYR1 Gain-of-Function (Leaky Channel) Variants
    description: >-
      Dominant hotspot missense variants render the shared channel
      hyperactive/leaky.
    causal_link_type: DIRECT
  - target: Recessive RYR1 Hypomorphic (Reduced-Expression) Variants
    description: >-
      Recessive variants distributed throughout the gene reduce the
      abundance of the shared channel.
    causal_link_type: DIRECT
- name: Dominant RYR1 Gain-of-Function (Leaky Channel) Variants
  biological_scale: MOLECULAR
  description: >-
    Dominant RYR1-related myopathy is usually caused by heterozygous missense
    variants, historically clustered in three mutational hotspot regions,
    that render the RyR1 channel hypersensitive to activation and prone to
    inappropriate ("leaky") calcium release rather than simply reducing its
    abundance. This is the dominant gain-of-function mechanism requested for
    explicit modeling, and it is the same mechanism underlying malignant
    hyperthermia susceptibility.
  genetic_context:
    functional_impact_category: GAIN_OF_FUNCTION
    variant_origin: GERMLINE
    description: >-
      Heterozygous, typically de novo or dominantly inherited missense
      variants concentrated in RYR1 hotspot domains that decouple channel
      gating from its normal physiological triggers.
  genes:
  - preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  molecular_functions:
  - preferred_term: Ryanodine-sensitive calcium-release channel activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0005219
      label: ryanodine-sensitive calcium-release channel activity
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      increased sensitivity of RyR1 channels to activators (e.g., caffeine,
      halothane, CaV1.1 voltage sensors) as observed in MH resulting in
      uncontrolled channel opening and Ca2+ release
    explanation: >-
      Describes the dominant gain-of-function mechanism as hypersensitivity
      to physiological and pharmacologic activators plus a resting calcium
      leak, rather than reduced channel abundance.
  downstream:
  - target: SR Calcium Leak and RyR1 Channel Hypersensitivity
    description: >-
      The dominant hotspot missense lesion produces the downstream
      leaky-channel cellular phenotype.
    causal_link_type: DIRECT
- name: SR Calcium Leak and RyR1 Channel Hypersensitivity
  biological_scale: CELLULAR
  description: >-
    The cellular consequence of dominant gain-of-function RYR1 variants:
    hyperactive channels show elevated resting calcium leak and lowered
    threshold for triggered release, raising resting cytosolic calcium
    concentration in skeletal muscle fibers even without an anesthetic or
    exertional trigger.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: Slow muscle cell (type I fiber)
    term:
      id: CL:0000189
      label: slow muscle cell
  biological_processes:
  - preferred_term: Regulation of SR calcium release
    modifier: INCREASED
    term:
      id: GO:0010880
      label: regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
  - preferred_term: Calcium ion homeostasis
    modifier: DYSREGULATED
    term:
      id: GO:0055074
      label: calcium ion homeostasis
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RyR1 channels with MH- or CCD-associated variants show higher activity
      and sensitivity to activation than wildtype channels, which ultimately
      leads to increases in resting Ca2+ concentration [135, 136].
    explanation: >-
      Directly supports elevated resting calcium as the quantitative
      cellular consequence of the leaky dominant channel, justifying an
      INCREASED modifier on SR calcium release regulation.
  downstream:
  - target: Anesthetic/Stress-Triggered Malignant Hyperthermia Reaction
    description: >-
      A lowered threshold for RyR1 activation creates the substrate for an
      exaggerated calcium release when a susceptible individual is exposed
      to a triggering anesthetic or, more rarely, extreme exertion/heat.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - volatile anesthetic or succinylcholine exposure
    - uncontrolled sarcoplasmic reticulum calcium release
  - target: Oxidative and Nitrosative Stress
    description: >-
      Chronic elevation of resting cytosolic and mitochondrial calcium from
      the leaky channel drives excessive mitochondrial reactive oxygen
      species production.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic disturbance of intracellular calcium homeostasis
    - increased mitochondrial calcium uptake
  - target: Skeletal Muscle Structural Remodeling and Weakness
    description: >-
      Chronic disturbance of calcium homeostasis at rest contributes to
      focal structural and metabolic change in muscle fibers (e.g., central
      core formation) and to baseline proximal weakness even without an
      anesthetic trigger.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic disturbance of intracellular calcium homeostasis
    - mitochondrial and metabolic stress in affected fibers
- name: Oxidative and Nitrosative Stress
  biological_scale: CELLULAR
  description: >-
    Chronic disturbance of calcium homeostasis from either the dominant
    leaky-channel or recessive uncoupling mechanism drives excessive
    mitochondrial calcium uptake and reactive oxygen species production in
    skeletal muscle fibers, producing a secondary oxidative/nitrosative
    stress state that can further damage RyR1 and muscle fibers. This is
    the mechanism directly targeted by antioxidant (N-acetylcysteine)
    therapy, tested in the NCT02362425 clinical trial.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  biological_processes:
  - preferred_term: Reactive oxygen species metabolic process
    modifier: INCREASED
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
  - preferred_term: Response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  evidence:
  - reference: PMID:22418739
    reference_title: "Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Subsequent studies focused on oxidative stress in relatively relaxed
      zebrafish and RYR1-related myopathy myotubes and demonstrated
      increased oxidant activity, the presence of oxidative stress markers,
      excessive production of oxidants by mitochondria and diminished
      survival under oxidant conditions.
    explanation: >-
      Zebrafish disease-model data directly demonstrating increased oxidant
      activity and mitochondrial oxidant production in RYR1-related
      myopathy, supporting the INCREASED modifier on reactive oxygen
      species metabolism.
  - reference: PMID:22418739
    reference_title: "Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Exposure to the antioxidant N-acetylcysteine reduced oxidative stress
      and improved survival in the RYR1-related myopathies human myotubes
      ex vivo
    explanation: >-
      Patient-myotube (in vitro) data confirming the oxidative-stress
      mechanism this node models and motivating N-acetylcysteine as a
      mechanism-targeted therapy (though the subsequent clinical trial,
      NCT02362425, did not confirm clinical benefit).
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alterations in calcium homeostasis can also lead to secondary
      cellular dysfunction including increased oxidative/nitrosative
      stress, altered post-translational modifications, mitochondrial
      damage, and disrupted protein-protein/ligand interactions
    explanation: >-
      Establishes that oxidative/nitrosative stress is a shared secondary
      mechanism downstream of calcium dysregulation from both the dominant
      and recessive RYR1 variant classes, not exclusive to one branch.
  downstream:
  - target: Skeletal Muscle Structural Remodeling and Weakness
    description: >-
      Oxidative damage to RyR1 and to skeletal muscle fibers amplifies the
      structural and functional consequences of the primary calcium-release
      defect.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - excessive mitochondrial reactive oxygen species production
    - oxidative damage to RyR1 and contractile proteins
- name: Recessive RYR1 Hypomorphic (Reduced-Expression) Variants
  biological_scale: MOLECULAR
  description: >-
    Recessive RYR1-related myopathy arises from biallelic variants
    distributed throughout the gene, including nonsense and splice variants,
    that reduce RyR1 protein abundance rather than altering channel gating
    per se. This is the recessive hypomorphic mechanism requested for
    explicit modeling, mechanistically distinct from the dominant
    gain-of-function/leaky-channel class above.
  genetic_context:
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    description: >-
      Biallelic (homozygous or compound heterozygous) nonsense, frameshift,
      splice-site, or missense variants distributed throughout the RYR1
      coding sequence, expected to reduce RyR1 protein abundance rather than
      abolish it completely (a complete RYR1 null is not compatible with the
      surviving recessive phenotype).
  genes:
  - preferred_term: RYR1
    description: >-
      Ryanodine receptor 1, whose reduced expression impairs skeletal muscle
      excitation-contraction coupling in recessive RYR1-related myopathy.
    modifier: DECREASED
    term:
      id: hgnc:10483
      label: RYR1
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:22473935
    reference_title: "Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recessive mutations included nonsense and splice mutations expected to
      result in reduced RyR1 protein.
    explanation: >-
      Establishes the reduced-expression mechanism for the recessive variant
      class.
  downstream:
  - target: RyR1 Deficiency and Excitation-Contraction Uncoupling
    description: >-
      Reduced RyR1 protein abundance produces the downstream deficiency and
      uncoupling cellular phenotype.
    causal_link_type: DIRECT
- name: RyR1 Deficiency and Excitation-Contraction Uncoupling
  biological_scale: CELLULAR
  description: >-
    The cellular consequence of recessive hypomorphic RYR1 variants: a
    reduced functional channel pool at the triad lowers RyR1-mediated
    calcium permeation and Cav1.1-dependent SR calcium release, uncoupling
    membrane depolarization from calcium-triggered contraction. This
    contrasts with the dominant leaky-channel mechanism and explains the
    generally greater clinical severity of recessive disease.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: Regulation of skeletal muscle contraction by calcium signaling
    modifier: DECREASED
    term:
      id: GO:0014722
      label: regulation of skeletal muscle contraction by calcium ion signaling
  - preferred_term: Regulation of SR calcium release
    modifier: DECREASED
    term:
      id: GO:0010880
      label: regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      reduction in RyR1 Ca2+ permeation leading to reduced Cav1.1-mediated
      SR Ca2+ release, a process referred to as excitation-contraction
      uncoupling
    explanation: >-
      Defines excitation-contraction uncoupling as the mechanistic
      consequence of reduced RyR1 channel expression, directly supporting a
      DECREASED modifier on the calcium-release and contraction-regulation
      processes.
  downstream:
  - target: Oxidative and Nitrosative Stress
    description: >-
      Impaired excitation-contraction coupling and the resulting metabolic
      strain likewise drive secondary mitochondrial oxidative stress,
      convergent with the dominant leaky-channel branch.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired excitation-contraction coupling
    - compensatory metabolic and mitochondrial strain
  - target: Skeletal Muscle Structural Remodeling and Weakness
    description: >-
      Uncoupling lowers calcium-dependent activation of contraction,
      producing more pronounced congenital weakness, ophthalmoplegia, and
      respiratory involvement than in dominant disease.
    causal_link_type: DIRECT
- name: Anesthetic/Stress-Triggered Malignant Hyperthermia Reaction
  biological_scale: ORGANISM
  description: >-
    In individuals carrying dominant leaky-channel RYR1 variants (and,
    rarely, some recessive genotypes), exposure to volatile anesthetics or
    succinylcholine triggers uncontrolled sarcoplasmic-reticulum calcium
    release, driving sustained muscle contraction, hypermetabolism,
    hyperthermia, and rhabdomyolysis. Fully modeled in
    Malignant_Hyperthermia_of_Anesthesia.yaml; represented here at a
    summary level to connect it explicitly to the shared dominant
    leaky-channel node. Exercise and hot environments are recognized
    non-anesthetic triggers of the same reaction in susceptible
    individuals.
  triggers:
  - preferred_term: exposure to anesthetics
    term:
      id: ECTO:2000059
      label: exposure to anesthetics
  - preferred_term: exposure to exercise
    term:
      id: ECTO:6000002
      label: exposure to exercise
  - preferred_term: exposure to high temperature environment
    term:
      id: ECTO:1000007
      label: exposure to high temperature environment
  evidence:
  - reference: PMID:30406384
    reference_title: "Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MH (MIM# 145600) is a potentially lethal hypermetabolic condition
      triggered by exposure of susceptible individuals to certain volatile
      anesthetics and muscle relaxants.
    explanation: >-
      Defines the anesthetic-triggered malignant hyperthermia mechanism
      downstream of the leaky-channel node.
  - reference: PMID:20301325
    reference_title: Nonsyndromic Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is mounting evidence that some individuals with MHS will also
      develop MH with exercise and/or on exposure to hot environments.
    explanation: >-
      GeneReviews documents exercise and hot-environment exposure as
      recognized non-anesthetic triggers of the same malignant hyperthermia
      reaction, closing the non-anesthetic-trigger modeling gap.
- name: Skeletal Muscle Structural Remodeling and Weakness
  biological_scale: TISSUE
  description: >-
    Chronic calcium-handling disturbance from either mechanism converges on
    shared downstream tissue-level consequences: focal or diffuse structural
    and histopathologic change in skeletal muscle fibers (central cores,
    minicores, central nuclei, or fiber-type disproportion, depending on
    variant class and biopsy timing) and clinically apparent weakness,
    hypotonia, and orthopedic complications. Recessive disease is generally
    more severe and more often adds extraocular, bulbar, and respiratory
    involvement.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: Slow muscle cell (type I fiber)
    term:
      id: CL:0000189
      label: slow muscle cell
  biological_processes:
  - preferred_term: Skeletal muscle contraction
    modifier: DECREASED
    term:
      id: GO:0003009
      label: skeletal muscle contraction
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features suggestive of RYR1-RM are extensive, with mild to
      severe symptoms ranging from delayed motor milestones, proximal
      muscle weakness, hypotonia, and fatigue, to kyphoscoliosis,
      ophthalmoplegia, and moderate to severe respiratory insufficiency,
      which is more often apparent in recessive cases [22–24].
    explanation: >-
      Documents the shared downstream clinical spectrum, with respiratory
      and extraocular involvement enriched in recessive disease.
  downstream:
  - target: Proximal Muscle Weakness
    description: Shared downstream clinical weakness phenotype.
    causal_link_type: DIRECT
phenotypes:
- name: Proximal Muscle Weakness
  category: Neurological
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  frequency: FREQUENT
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features suggestive of RYR1-RM are extensive, with mild to
      severe symptoms ranging from delayed motor milestones, proximal
      muscle weakness, hypotonia, and fatigue, to kyphoscoliosis,
      ophthalmoplegia, and moderate to severe respiratory insufficiency,
      which is more often apparent in recessive cases [22–24].
    explanation: Documents proximal muscle weakness across the RYR1-RM spectrum.
- name: Fatigue
  category: Neurological
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  frequency: FREQUENT
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features suggestive of RYR1-RM are extensive, with mild to
      severe symptoms ranging from delayed motor milestones, proximal
      muscle weakness, hypotonia, and fatigue, to kyphoscoliosis,
      ophthalmoplegia, and moderate to severe respiratory insufficiency,
      which is more often apparent in recessive cases [22–24].
    explanation: >-
      Directly names fatigue as one of the mild-to-severe clinical features
      spanning the RYR1-RM spectrum.
- name: Rhabdomyolysis
  category: Musculoskeletal
  subtype: Dominant RYR1-Related Myopathy
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Considered a late neuromuscular manifestation of MH-related RYR1
      variations, late-onset axial myopathy, exertional rhabdomyolysis, and
      periodic paralysis present throughout the lifespan.
    explanation: >-
      Directly names exertional rhabdomyolysis as a late neuromuscular
      manifestation of the MH-related (dominant leaky-channel) RYR1 variant
      class.
- name: Joint Contracture
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RYR1-RM-affected individuals can present with delayed motor
      milestones, contractures, scoliosis, ophthalmoplegia, and respiratory
      insufficiency.
    explanation: >-
      Directly names contractures among the core clinical features of
      RYR1-related myopathy.
- name: Myopathic Facies
  category: Musculoskeletal
  subtype: Recessive RYR1-Related Myopathy
  phenotype_term:
    preferred_term: Myopathic facies
    term:
      id: HP:0002058
      label: Myopathic facies
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the ophthalmoplegia form, with generalized muscle involvement and
      severe facial weakness
    explanation: >-
      Directly names severe facial weakness in the ophthalmoplegic form of
      recessive RYR1-related multiminicore disease.
- name: Feeding Difficulties
  category: Gastrointestinal
  subtype: CFTD-RYR1
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features reported in CFTD patients include hypotonia,
      respiratory failure, non-progressive muscle weakness, joint
      contractures, myopathic facies, ophthalmoparesis, feeding
      difficulties, and skeletal deformities
    explanation: >-
      Directly names feeding difficulties among the clinical features
      reported in RYR1-related congenital fiber-type disproportion.
- name: Neonatal Hypotonia
  category: Neurological
  phenotype_term:
    preferred_term: Neonatal hypotonia
    term:
      id: HP:0001319
      label: Neonatal hypotonia
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features suggestive of RYR1-RM are extensive, with mild to
      severe symptoms ranging from delayed motor milestones, proximal
      muscle weakness, hypotonia, and fatigue
    explanation: Documents hypotonia as a core RYR1-RM presenting feature.
- name: Delayed Ability to Walk
  category: Neurological
  phenotype_term:
    preferred_term: Delayed ability to walk
    term:
      id: HP:0031936
      label: Delayed ability to walk
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features suggestive of RYR1-RM are extensive, with mild to
      severe symptoms ranging from delayed motor milestones, proximal
      muscle weakness
    explanation: Documents delayed motor milestones across the RYR1-RM spectrum.
- name: External Ophthalmoplegia
  category: Neurological
  subtype: Recessive RYR1-Related Myopathy
  phenotype_term:
    preferred_term: External ophthalmoplegia
    term:
      id: HP:0000544
      label: External ophthalmoplegia
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      extraocular muscle involvement is almost exclusively associated with
      recessive forms of RYR1-RD, whereas enhanced malignant hyperthermia
      susceptibility is more commonly seen with dominant rather than
      recessive RYR1 variations [187].
    explanation: >-
      Documents the strong enrichment of extraocular/ophthalmoplegic
      involvement in recessive, as opposed to dominant, RYR1-related
      myopathy.
- name: Malignant Hyperthermia
  category: Musculoskeletal
  subtype: Dominant RYR1-Related Myopathy
  phenotype_term:
    preferred_term: Malignant hyperthermia
    term:
      id: HP:0002047
      label: Malignant hyperthermia
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      extraocular muscle involvement is almost exclusively associated with
      recessive forms of RYR1-RD, whereas enhanced malignant hyperthermia
      susceptibility is more commonly seen with dominant rather than
      recessive RYR1 variations [187].
    explanation: >-
      Documents enhanced malignant hyperthermia susceptibility as
      preferentially, though not exclusively, associated with dominant
      RYR1-related myopathy.
- name: Exercise-Induced Myalgia
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Exercise-induced myalgia
    term:
      id: HP:0003738
      label: Exercise-induced myalgia
  evidence:
  - reference: PMID:30406384
    reference_title: "Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      fatigue, exercise-induced
      hyperthermia/exertional heat stroke, and exertional myalgia
    explanation: >-
      Directly names exertional myalgia as a clinical feature of RYR1-RM,
      rather than only the "rhabdomyolysis-myalgia syndrome" spectrum
      entity named below.
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This spectrum includes RYR1 variant-associated clinical phenotypes
      including King-Denborough syndrome, congenital neuromuscular disease
      with uniform type 1 fiber (CNMDU1), dusty core disease,
      rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, and
      bleeding abnormalities [31–38].
    explanation: >-
      Documents the related RYR1 rhabdomyolysis-myalgia syndrome phenotype
      as a distinct named entity within the broader RYR1-related myopathy
      spectrum.
- name: Scoliosis
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features suggestive of RYR1-RM are extensive, with mild to
      severe symptoms ranging from delayed motor milestones, proximal
      muscle weakness, hypotonia, and fatigue, to kyphoscoliosis,
      ophthalmoplegia, and moderate to severe respiratory insufficiency
    explanation: Documents kyphoscoliosis as a recognized orthopedic complication.
- name: Respiratory Insufficiency
  category: Respiratory
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features suggestive of RYR1-RM are extensive, with mild to
      severe symptoms ranging from delayed motor milestones, proximal
      muscle weakness, hypotonia, and fatigue, to kyphoscoliosis,
      ophthalmoplegia, and moderate to severe respiratory insufficiency,
      which is more often apparent in recessive cases [22–24].
    explanation: >-
      Documents moderate to severe respiratory insufficiency, most apparent
      in recessive disease.
- name: Short Stature
  category: Growth
  subtype: KDS
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:41753076
    reference_title: "The Clinical, Histological, and Genetic Spectrum of RYR1 Variants-A Multi-Center Israeli Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All exhibited dysmorphic features, short stature, skeletal
      abnormalities, and myopathy.
    explanation: >-
      This multi-center cohort's three King-Denborough syndrome cases
      explicitly document short stature as a presenting feature, not merely
      an inferred component of a general "dysmorphic features" phrase.
- name: Sternal Deformity
  category: Musculoskeletal
  subtype: KDS
  phenotype_term:
    preferred_term: Pectus carinatum or excavatum
    term:
      id: HP:0000766
      label: Abnormal sternum morphology
  evidence:
  - reference: PMID:30406384
    reference_title: "Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ki ng Denborough syndrome (pectus
      carinatum or excavatum, short stature, joint contractures, facial
      and skeletal deformities)
    explanation: >-
      Explicitly enumerates pectus carinatum or excavatum among the
      King-Denborough syndrome dysmorphic features (snippet preserves a
      source PDF-extraction spacing artifact splitting "King" into "Ki ng"
      to remain an exact substring of the cached text). Bound to the
      general "Abnormal sternum morphology" term rather than pectus
      carinatum specifically, because the source names either carinatum or
      excavatum without specifying which one is present.
- name: Congenital Hip Dislocation
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  evidence:
  - reference: PMID:17504518
    reference_title: "Central core disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      comprise congenital dislocation of the hips
    explanation: >-
      This Orphanet review of central core disease (a major RYR1-related
      myopathy subtype, cross-referenced from Central_Core_Myopathy.yaml)
      explicitly names congenital dislocation of the hips among the
      orthopaedic complications of the disease.
biochemical:
- name: Creatine Kinase
  presence: Variable
  context: >-
    Serum CK is often normal in RYR1-related myopathy, unlike in dystrophic
    myopathies; a minority of patients show mild to moderate elevation. A
    normal CK therefore does not exclude the diagnosis.
  biomarker_term:
    preferred_term: creatine kinase measurement
    term:
      id: NCIT:C64489
      label: Creatine Kinase Measurement
  evidence:
  - reference: PMID:41753076
    reference_title: "The Clinical, Histological, and Genetic Spectrum of RYR1 Variants-A Multi-Center Israeli Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum CK levels were within the normal range for most patients,
      except for five (17%) who exhibited mild to moderate elevations.
    explanation: >-
      Directly reports the proportion of a real RYR1-variant cohort with
      elevated CK, establishing that the biomarker is usually normal but
      occasionally elevated in RYR1-related myopathy.
genetic:
- name: RYR1
  association: Causative
  gene_term:
    preferred_term: RYR1
    description: >-
      Ryanodine receptor 1, encoding a homotetrameric calcium release channel
      of 5,038 amino acids that maps to chromosome 19q13.2 and is the
      principal skeletal muscle sarcoplasmic reticulum calcium release
      channel fundamental to excitation-contraction coupling. It is the
      sole causative gene for this MONDO umbrella entity and the most
      frequent genetic cause of congenital myopathy overall.
    term:
      id: hgnc:10483
      label: RYR1
  notes: >-
    Nearly 700 RYR1 variants have been identified to date, spanning the full
    coding sequence. Dominant variants are enriched in three historically
    recognized hotspot domains but have since been documented across the
    entire gene; recessive variants are distributed throughout the coding
    sequence and are expected to reduce RyR1 protein abundance.
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variations in the RYR1 gene, a relatively large gene in the
      human genome, are the most common cause of CM and contribute to the
      clinical, histopathological, and genetic heterogeneity of CMs.
    explanation: >-
      Establishes RYR1 as the most common cause of congenital myopathy and
      the source of its heterogeneity.
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With nearly 700 RYR1 variations identified to date
    explanation: >-
      Documents the scale of the RYR1 allelic series and the diagnostic
      impact of genome-wide sequencing coverage of the gene.
diagnosis:
- name: Clinical neuromuscular assessment
  description: >-
    Evaluation begins with congenital or early-onset myopathy features,
    delayed motor milestones, hypotonia, proximal or generalized weakness,
    and orthopedic complications, together with anesthetic and family
    history. Dominant disease tends to be milder; recessive disease can
    present with severe neonatal, bulbar, ophthalmoplegic, or respiratory
    involvement.
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: NCIT:C20989
      label: Physical Examination
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features suggestive of RYR1-RM are extensive, with mild to
      severe symptoms ranging from delayed motor milestones, proximal
      muscle weakness, hypotonia, and fatigue, to kyphoscoliosis,
      ophthalmoplegia, and moderate to severe respiratory insufficiency,
      which is more often apparent in recessive cases [22–24].
    explanation: >-
      Defines the clinical presentation that prompts diagnostic evaluation
      across the RYR1-related myopathy spectrum.
- name: Muscle biopsy and histopathology
  description: >-
    Muscle biopsy with oxidative enzyme histochemistry and electron
    microscopy identifies the histopathologic subtype (central cores,
    multi-minicores, central nuclei, core-rod features, or fiber-type
    disproportion), though these features are not fully specific to RYR1 and
    can be dynamic over time or absent on early biopsy.
  diagnosis_term:
    preferred_term: biopsy of muscle tissue
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these histopathologic features are not always specific to RYR1-RM and
      often change over time
    explanation: >-
      Documents the limitations of histopathology alone as a diagnostic
      criterion for RYR1-related myopathy.
- name: In vitro caffeine-halothane contracture test for malignant hyperthermia susceptibility
  description: >-
    The reference diagnostic test for malignant hyperthermia susceptibility,
    determining muscle contracture thresholds in response to caffeine and
    halothane on a fresh open muscle biopsy specimen. It is invasive and can
    yield false negatives, and because MH susceptibility is under-penetrant
    and lacks a single common causative variant, all RYR1-related myopathy
    patients are managed as potentially MH susceptible regardless of test or
    genotype status.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:30406384
    reference_title: "Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the d iagnostic test for MH
      susceptibility is the in vitro caffeine–halothane contracture test
      (IVCT), which determines contracture thresholds
    explanation: >-
      Defines the IVCT as the reference diagnostic test for MH susceptibility
      (snippet preserves a source PDF-extraction spacing artifact in
      "d iagnostic" to remain an exact substring of the cached text).
  - reference: PMID:30406384
    reference_title: "Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all RYR1-RM-affected individuals are considered potentially MH
      susceptible [29]
    explanation: >-
      Supports the clinical practice of universal MH precautions in
      RYR1-related myopathy regardless of confirmed susceptibility testing.
  - reference: PMID:20301325
    reference_title: Nonsyndromic Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of MHS is established with in vitro muscle contracture
      testing by measuring the contracture responses of biopsied muscle
      samples to halothane and graded concentrations of caffeine.
    explanation: >-
      GeneReviews defines the IVCT methodology directly, closing the
      GeneReviews-baseline gap on the primary diagnostic test for the
      malignant hyperthermia susceptibility axis of this entry.
- name: RYR1 molecular genetic testing
  description: >-
    Next-generation sequencing of the entire RYR1 coding sequence and
    canonical splice sites, rather than restriction to historical hotspot
    regions, has become the primary diagnostic approach and has expanded the
    recognized clinical spectrum.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A genetics-first diagnostic approach is rapidly becoming the standard
      for confirmation of disorders with known genetic etiology
    explanation: >-
      Establishes genetics-first sequencing as the current diagnostic
      standard for RYR1-related myopathy.
treatments:
- name: Avoidance of malignant hyperthermia triggers
  description: >-
    Strict avoidance of volatile anesthetic agents and depolarizing
    neuromuscular blocking agents (succinylcholine); total intravenous
    anesthesia is preferred whenever a patient with any RYR1-related
    myopathy diagnosis requires general anesthesia, because dominant,
    recessive, and untested individuals are all managed as potentially MH
    susceptible.
  treatment_term:
    preferred_term: chemical exposure avoidance
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  evidence:
  - reference: PMID:30406384
    reference_title: "Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all RYR1-RM-affected individuals are considered potentially MH
      susceptible [29]
    explanation: >-
      Supports universal anesthetic-trigger avoidance across the RYR1-related
      myopathy spectrum.
  - reference: PMID:20301325
    reference_title: Nonsyndromic Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Avoid potent inhalation anesthetics and succinylcholine.
    explanation: >-
      GeneReviews names the specific agents to avoid, closing the
      GeneReviews-baseline "Agents/Circumstances to Avoid" gap.
- name: Dantrolene
  description: >-
    Dantrolene is the specific emergency pharmacotherapy for an acute
    malignant hyperthermia reaction and should be immediately available
    whenever a patient with RYR1-related myopathy undergoes general
    anesthesia. Off-label chronic/periodic use for baseline myopathic
    symptoms has been reported anecdotally but is not well established.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dantrolene
      term:
        id: CHEBI:4317
        label: dantrolene
  target_phenotypes:
  - preferred_term: Malignant hyperthermia
    term:
      id: HP:0002047
      label: Malignant hyperthermia
  target_mechanisms:
  - target: SR Calcium Leak and RyR1 Channel Hypersensitivity
    treatment_effect: INHIBITS
    description: >-
      Dantrolene antagonizes the RyR1 channel, reducing the excess calcium
      release/leak underlying both the acute malignant hyperthermia crisis
      and, potentially, baseline dominant-mechanism channel hyperactivity.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dantrolene sodium is a specific antagonist and should be available
        wherever general anesthesia is administered.
      explanation: >-
        Supports dantrolene as the specific pharmacologic antagonist of the
        leaky-channel calcium-release mechanism.
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dantrolene sodium is a specific antagonist and should be available
      wherever general anesthesia is administered.
    explanation: Establishes dantrolene as the MH-crisis emergency treatment.
  - reference: PMID:20301325
    reference_title: Nonsyndromic Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Administration of intravenous dantrolene sodium (initial dose of 2.5
      mg/kg) as early as possible during an MH episode.
    explanation: >-
      GeneReviews specifies the targeted-therapy dosing for an acute MH
      episode, closing the GeneReviews-baseline Management gap.
- name: Salbutamol/albuterol
  description: >-
    An off-label beta-agonist reported to improve muscle strength and motor
    function in some RYR1-related myopathy patients, proposed to act by
    increasing SERCA expression and facilitating reuptake of cytosolic
    calcium into the sarcoplasmic reticulum, thereby partially compensating
    for either the leaky-channel or the excitation-contraction uncoupling
    mechanism.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: albuterol
      term:
        id: CHEBI:2549
        label: albuterol
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      salbutamol, a beta agonist that improves muscle strength and motor
      function through mechanisms that are not completely understood [120]
    explanation: >-
      Documents anecdotal reports of salbutamol benefit in RYR1-related
      myopathy.
- name: N-acetylcysteine
  description: >-
    An antioxidant tested in a completed NIH clinical trial (NCT02362425)
    directly targeting the mitochondrial oxidative/nitrosative stress
    mechanism, based on preclinical rescue of oxidative stress and improved
    survival/muscle function in zebrafish and patient-derived myotube
    models. The subsequent clinical trial did not confirm a benefit on its
    primary outcomes.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: N-acetylcysteine
      term:
        id: CHEBI:28939
        label: N-acetyl-L-cysteine
  target_mechanisms:
  - target: Oxidative and Nitrosative Stress
    treatment_effect: INHIBITS
    description: >-
      N-acetylcysteine is a glutathione precursor proposed to reduce the
      excess mitochondrial reactive oxygen species production characteristic
      of RYR1-related myopathy, the mechanism this node models.
    evidence:
    - reference: PMID:22418739
      reference_title: "Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Exposure to the antioxidant N-acetylcysteine reduced oxidative
        stress and improved survival in the RYR1-related myopathies human
        myotubes ex vivo
      explanation: >-
        Patient-derived myotube (in vitro) data establishing the
        mechanistic rationale for N-acetylcysteine acting on the
        oxidative-stress node this treatment targets.
  evidence:
  - reference: PMID:22418739
    reference_title: "Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      led to significant restoration of aspects of
      muscle function in the relatively relaxed zebrafish, thereby
      confirming its efficacy in vivo
    explanation: >-
      Zebrafish (model organism) data confirming the preclinical benefit
      that motivated the subsequent NCT02362425 clinical trial, which did
      not confirm the benefit in humans (see clinical_trials below).
- name: Rycal S48168 (ARM210)
  description: >-
    An investigational RyR-stabilizing "Rycal" small molecule tested in a
    completed phase 1, open-label, dose-escalation trial (NCT04141670) in
    ambulatory adults with genetically confirmed RYR1-related myopathy whose
    RyR1 channels were shown ex vivo to be leaky and Rycal-responsive. It was
    well tolerated, with most participants on the higher dose reporting
    reduced fatigue and improved proximal muscle strength on exam.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Rycal S48168 (ARM210)
  target_phenotypes:
  - preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  target_mechanisms:
  - target: SR Calcium Leak and RyR1 Channel Hypersensitivity
    treatment_effect: INHIBITS
    description: >-
      Rycal compounds are proposed to restore FKBP12 (calstabin1) binding to
      RyR1, stabilizing the channel closed state and reducing the resting
      calcium leak characteristic of dominant gain-of-function variants.
    evidence:
    - reference: PMID:38318125
      reference_title: "Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Loss of RyR1-calstabin1 association, SR calcium leak, and increased
        RyR1 open probability were observed in 17 RYR1-RM patient skeletal
        muscle biopsies and improved following ex vivo treatment with Rycal
        compounds.
      explanation: >-
        Establishes the mechanistic rationale for Rycal compounds directly
        addressing the leaky-channel/SR calcium leak mechanism in patient
        muscle biopsies.
  evidence:
  - reference: PMID:38318125
    reference_title: "Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      S48168 (ARM210) was well-tolerated, did not cause any serious adverse
      events, and exhibited a dose-dependent PK profile.
    explanation: Reports the phase 1 safety and tolerability outcome.
- name: Pyridostigmine for fatigable weakness
  description: >-
    Anecdotal reports describe improved fatigue and energy level with the
    acetylcholinesterase inhibitor pyridostigmine in a subset of RYR1-related
    myopathy patients with a fatigable weakness phenotype.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:24951453
    reference_title: "RYR1-related congenital myopathy with fatigable weakness, responding to pyridostigimine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These cases broaden the RYR1-related disease spectrum to include a
      myasthenic-like phenotype, including partial response to
      pyridostigimine.
    explanation: >-
      Reports partial clinical response to pyridostigmine in siblings with
      RYR1-related myopathy presenting with fatigable weakness.
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There have been anecdotal reports of positive responses to
      pyridostigmine, an acetylcholinesterase inhibitor, improving fatigue
      and energy level [43]
    explanation: Corroborates anecdotal pyridostigmine benefit in RYR1-related myopathy.
- name: Supportive orthopedic, respiratory, and physical therapy
  description: >-
    No approved disease-modifying treatment exists for RYR1-related
    myopathy. Management is primarily supportive: physical/occupational
    therapy, orthopedic evaluation and bracing/surgery for scoliosis and
    contractures, respiratory support as needed, and periodic monitoring of
    motor function.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is no approved treatment for RYR1-RM. Symptom management is
      primarily supportive, with precautions taken when MH risk is either
      known or not ascertained.
    explanation: >-
      Establishes that management is supportive in the absence of an
      approved disease-modifying therapy.
- name: Genetic counseling
  description: >-
    Genetic counseling addresses the dominant versus recessive inheritance
    pattern, recurrence risk, and the implications of RYR1 genotype for
    malignant hyperthermia susceptibility in the proband and at-risk family
    members.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301325
    reference_title: Nonsyndromic Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with MHS has a 50% chance of being MH
      susceptible.
    explanation: >-
      GeneReviews states the concrete transmission-risk figure a genetic
      counseling recommendation needs for the dominant malignant hyperthermia
      susceptibility axis of this entry, closing the GeneReviews-baseline
      Genetic Counseling gap. (The corresponding recessive-disease
      recurrence risk is covered by the standard 25% autosomal recessive
      figure implicit in the `inheritance:` block above.)
clinical_trials:
- name: NCT02362425
  phase: PHASE_II
  status: COMPLETED
  description: >-
    NIH natural-history-plus-intervention trial of oral N-acetylcysteine
    (NAC), an antioxidant, in ambulatory RYR1-related myopathy patients
    ages 7 and older, testing effects on muscle damage and exercise
    tolerance. The intervention did not improve either outcome.
  target_phenotypes:
  - preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: clinicaltrials:NCT02362425
    reference_title: "Antioxidant Therapy in RYR1-Related Congenital Myopathy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To see if the drug N-acetylcysteine decreases muscle damage in people
      with RYR1-RM. To see if it improves their exercise tolerance.
    explanation: States the trial's objective testing NAC in RYR1-related myopathy.
  - reference: PMID:33190635
    reference_title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All participants exhibited elevated oxidative stress as determined by
      urine 15-F2t-isoprostane concentration and decreased physical
      endurance. However, oral treatment with NAC did not impact either
      outcome [121].
    explanation: >-
      Reports the negative primary-outcome result of the completed NAC
      trial, despite preclinical rationale in mouse and zebrafish models.
- name: NCT04141670
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Phase 1, open-label, dose-escalation, first-in-patient trial of the
    RyR-stabilizing "Rycal" small molecule S48168 (ARM210) in ambulatory
    adults with genetically confirmed RYR1-related myopathy, directly
    targeting the dominant leaky-channel/gain-of-function mechanism. The
    compound was well tolerated with a dose-dependent pharmacokinetic
    profile; most participants on the higher (200 mg/day) dose reported
    reduced fatigue and showed improved proximal muscle strength on exam,
    setting the foundation for a subsequent placebo-controlled trial.
  target_phenotypes:
  - preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: clinicaltrials:NCT04141670
    reference_title: "Safety and Tolerability of S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The study population will include adult patients (≥18 years of age)
      who have demonstrated leaky RyR1 channels that are responsive to
      S48168 (ARM210) ex vivo.
    explanation: >-
      Documents that trial eligibility directly targets the leaky-channel
      (dominant gain-of-function) RYR1 mechanism modeled in this entry.
  - reference: PMID:38318125
    reference_title: "Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      S48168 (ARM210) was well-tolerated, did not cause any serious adverse
      events, and exhibited a dose-dependent PK profile. Three of four
      participants who received the 200 mg/day dose reported improvements
      in PROMIS-fatigue at 28 days post-dosing, and also demonstrated
      improved proximal muscle strength on physical examination.
    explanation: >-
      Reports the completed trial's published safety, tolerability, and
      exploratory efficacy findings for the leaky-channel-targeted Rycal
      compound.
references:
- reference: PMID:33190635
  title: "Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature."
- reference: PMID:30406384
  title: "Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches."
- reference: PMID:20301436
  title: "Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
- reference: PMID:20301325
  title: Nonsyndromic Malignant Hyperthermia Susceptibility.
  tags:
  - GeneReviews
📚

References & Deep Research

References

4
PMID:33190635
Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature.
No top-level findings curated for this source.
PMID:30406384
Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches.
No top-level findings curated for this source.
PMID:20301436
Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
No top-level findings curated for this source.
PMID:20301325
Nonsyndromic Malignant Hyperthermia Susceptibility.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
RYR1-Related Myopathy: Comprehensive Disease-Characteristics Report
Edison Scientific Literature 18 citations 2026-08-26T16:40:51.536904

RYR1-Related Myopathy: Comprehensive Disease-Characteristics Report

Executive summary

RYR1-related myopathy (RYR1-RM) is an umbrella term for inherited skeletal-muscle disorders caused by pathogenic germline variants in RYR1, which encodes the principal sarcoplasmic-reticulum Ca²⁺-release channel of skeletal muscle. The spectrum includes central core disease (CCD), multiminicore disease (MmD), core–rod myopathy, RYR1-related centronuclear myopathy, congenital fiber-type disproportion, congenital neuromuscular disease with uniform type-1 fibers, King–Denborough syndrome, exertional myalgia/rhabdomyolysis, atypical periodic paralysis, and late-onset axial myopathy. Dominant and recessive inheritance occur; recessive disease is generally earlier and more severe. No approved disease-modifying treatment exists, but genotype-aware supportive care, malignant-hyperthermia precautions, and early clinical development of the RyR1-stabilizing agent ARM210/S48168 are current real-world implementations. The best-supported causal chain is RYR1 variant → abnormal channel opening, impaired opening, or reduced protein abundance → defective excitation–contraction coupling and Ca²⁺ homeostasis → weakness/fatigue, with secondary mitochondrial and oxidative/nitrosative injury. (lawal2018ryanodinereceptor1related pages 1-2, beaufils2022therapiesforryr1related pages 1-2, beaufils2022therapiesforryr1related pages 7-8)

Domain Key facts Identifiers / ontology suggestions Quantitative / implementation notes Evidence / caveats
Disease definition / spectrum RYR1-related myopathy (RYR1-RM) is a genetically heterogeneous group of skeletal muscle disorders caused by pathogenic RYR1 variants; it is described as the most common class of congenital myopathies. Reported histopathologic/clinical subtypes include central core disease, multiminicore disease, core-rod myopathy, centronuclear myopathy, congenital fiber-type disproportion, King-Denborough syndrome, rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, late-onset axial myopathy, and malignant-hyperthermia-associated myopathic presentations. MONDO: requires database verification. OMIM / Orphanet / MeSH / ICD-10/11: disease-group mapping requires database verification because “RYR1-related myopathy” spans multiple named entities. Suggested disease ontology links: congenital myopathy group, central core disease, malignant hyperthermia susceptibility. Disease concept is aggregated disease-level knowledge, not EHR-derived. NGS expanded recognized spectrum beyond biopsy-led classification. Spectrum and nomenclature are well supported in reviews, but exact identifier mapping should be verified in OMIM/Orphanet/MONDO because the umbrella term spans several entities (lawal2018ryanodinereceptor1related pages 1-2).
Gene / protein RYR1 encodes ryanodine receptor 1 (RyR1), the principal skeletal-muscle sarcoplasmic-reticulum Ca²⁺ release channel in excitation-contraction coupling; protein is a large homotetramer. Gene localizes to 19q13.2 and contains 106 exons; protein length 5038 aa, about 565 kDa. Gene: RYR1. HGNC / NCBI Gene / UniProt IDs: require database verification. Suggested GO terms: calcium ion transmembrane transport, excitation-contraction coupling, sarcoplasmic reticulum calcium ion release channel activity. Suggested GO cellular component: sarcoplasmic reticulum membrane, terminal cisterna, calcium release unit. Functionally central to skeletal-muscle calcium release; associated proteins include FKBP12, calmodulin, DHPR/CACNA1S complex, triadin. Core molecular facts are supported by review evidence; exact ontology IDs should be confirmed in HGNC/UniProt/GO databases (beaufils2022therapiesforryr1related pages 1-2).
Inheritance / genetics Both autosomal dominant and autosomal recessive inheritance occur. Dominant disease is commonly linked to central core disease and malignant hyperthermia susceptibility; recessive disease is often associated with more severe congenital phenotypes such as multiminicore disease, centronuclear myopathy, and congenital fiber-type disproportion. Suggested HPO / inheritance terms: Autosomal dominant inheritance, Autosomal recessive inheritance. Variant classes reported across the spectrum include missense and other pathogenic alleles; many cases are germline. Reviews note approximately 400 RYR1 variants identified by 2022. Variant counts are review-level and likely underestimated relative to current ClinVar/literature; penetrance/expressivity are variable and should be verified per subtype/variant (beaufils2022therapiesforryr1related pages 7-8, lawal2018ryanodinereceptor1related pages 1-2).
Hallmark phenotypes Core manifestations: muscle weakness, fatigue/fatigability, exercise intolerance; additional features reported across the spectrum include hypotonia, facial weakness, ophthalmoparesis/ophthalmoplegia, contractures, scoliosis, respiratory involvement, myalgia, muscle cramps, rhabdomyolysis, and malignant hyperthermia susceptibility. Suggested HPO terms: Muscular hypotonia, Proximal muscle weakness, Exercise intolerance, Easy fatigability, Myalgia, Rhabdomyolysis, Scoliosis, Joint contracture, Respiratory insufficiency, Ophthalmoplegia. In a 6MWT cohort, disease was stable over 6 months but fatigability was measurable during testing; speed declined between the first and last minute at 6 months (p ≤ 0.0005). In one adult MHS/RYR1 review, 48% had elevated CK and 81% showed muscle abnormalities. Frequencies vary widely by subtype and cohort. Some statistics come from mixed RYR1/MHS populations rather than strictly biopsy/genotype-defined congenital myopathy cohorts (moreno2024myopathicmanifestationsacross pages 4-5, lawal2018ryanodinereceptor1related pages 1-2).
Mechanism / pathophysiology Three broad mechanisms are described: (1) RyR1 hyperactivity with Ca²⁺ leak, (2) reduced channel activity / excitation-contraction uncoupling, and (3) reduced RyR1 protein abundance. Downstream consequences include altered cytosolic Ca²⁺ homeostasis, sarcoplasmic-reticulum store abnormalities, mitochondrial dysfunction, and oxidative/nitrosative stress that can further damage RyR1 and muscle fibers. Suggested GO terms: regulation of release of sequestered calcium ion into cytosol, skeletal muscle contraction, response to oxidative stress, mitochondrial ATP synthesis coupled electron transport. Suggested CL term: skeletal muscle fiber cell. Suggested UBERON: skeletal muscle tissue. Patient/model data showed increased mitochondrial ROS: 26% ± 6.7% increase in patient myotubes under basal conditions; zebrafish mutant myofibers 1369.0 ± 73.1 AU vs 920.6 ± 114.4 AU in controls (P = 0.001). Mechanistic evidence is strong but heterogeneous across human cells, zebrafish, mouse, and review synthesis; different variants can produce opposite primary channel effects (hyperactive vs hypomorphic) (beaufils2022therapiesforryr1related pages 1-2, dowling2012oxidativestressand pages 11-12, dowling2012oxidativestressand pages 8-9, dowling2012oxidativestressand pages 12-12).
Diagnosis Diagnostic workup typically integrates clinical phenotype, family history, anesthesia/rhabdomyolysis history, serum CK, electromyography when indicated, muscle biopsy/histopathology, muscle imaging (MRI), and genetic testing. NGS has improved diagnosis because earlier approaches focused on hotspot regions and biopsy patterns. Suggested diagnostic ontology links: congenital myopathy panel, RYR1 single-gene testing, WES/WGS, malignant hyperthermia evaluation. Suggested HPO/LOINC concepts: Elevated serum creatine kinase, muscle MRI abnormalities. Muscle MRI may show selective patterns; review literature notes relative rectus femoris sparing among useful imaging clues. No single universal diagnostic criterion for the umbrella term; biopsy findings and MRI patterns overlap with other congenital myopathies, so molecular confirmation is increasingly central (lawal2018ryanodinereceptor1related pages 1-2).
Epidemiology / population Pediatric point prevalence in the United States has been estimated at ~1:90,000 for RYR1-RM. Dominant RYR1 variants also contribute to malignant hyperthermia susceptibility, broadening the clinically relevant population. Disease-level prevalence identifier resources require verification in Orphanet/OMIM. Suggested population descriptors: pediatric congenital myopathy cohorts; anesthesia-triggered MHS cohorts. Ongoing observational prevalence work: NCT06791369 plans ~2000 participants using retrospective data from UK and Netherlands specialist centers. The 1:90,000 estimate is frequently cited but comes from pediatric point-prevalence review synthesis; true prevalence is uncertain and likely underestimated due to underdiagnosis and expanded genotypic spectrum (lawal2018ryanodinereceptor1related pages 1-2, NCT06791369 chunk 3, beaufils2022therapiesforryr1related pages 1-2).
Management / current care No FDA-approved disease-modifying therapy exists. Current care is mainly supportive and rehabilitative plus risk avoidance: physical therapy, respiratory monitoring, orthopedic management, management of fatigue, and avoidance of malignant-hyperthermia-triggering anesthetics where relevant. Off-label/experimental pharmacologic approaches discussed include dantrolene, N-acetylcysteine (NAC), salbutamol/albuterol, pyridostigmine, and preclinical agents such as AICAR or rycals. Suggested NCIT intervention terms: Physical Therapy, Respiratory Support, Dantrolene, N-Acetylcysteine, Albuterol, Pyridostigmine. Suggested CHEBI terms: calcium, reactive oxygen species, N-acetylcysteine. NAC reduced oxidative stress in models; no approved standard pharmacotherapy yet. Personalized, genotype-aware strategies are emphasized because “one treatment fits all” is unlikely. Evidence quality varies from case reports and small open-label studies to preclinical models; supportive care remains the clinical standard (lawal2018ryanodinereceptor1related pages 11-12, beaufils2022therapiesforryr1related pages 7-8, dowling2012oxidativestressand pages 11-12).
Trials / recent developments Clinical development is active. NCT04141670 evaluated S 48168 / ARM210 (rycal) in adults with RYR1-RM; ClinicalTrials.gov notes a completed phase 1 study and links to a 2024 publication by Todd et al. (PMID: 38318125). NCT07560020 is a recruiting phase 2 placebo-controlled adult trial of Surlorian (ARM210, S48168) with planned enrollment 28. Natural-history work includes NCT06157268 (recruiting observational study, target 100) and longstanding congenital-myopathy genetics studies such as NCT00272883. Suggested NCIT terms: Clinical Trial, Phase 1 Trial, Phase 2 Trial, Observational Study, Placebo. NCT04141670 enrolled 7 participants; NCT07560020 target 28; NCT06157268 target 100; NCT06791369 target 2000. Phase 1/2 studies are small and early; efficacy conclusions remain preliminary. Trial names and statuses should be rechecked at ClinicalTrials.gov at use time (NCT04141670 chunk 2, NCT06791369 chunk 3).
Models / comparative biology Disease mechanisms and therapy testing use zebrafish, mouse, patient-derived myotubes, and emerging iPSC / engineered skeletal muscle systems. Natural disease relevance also extends to pig literature mainly through malignant hyperthermia/RYR1 biology rather than a full human-like congenital-myopathy spectrum. Suggested model resources: zebrafish RYR1 mutants, knock-in mouse models, patient myotubes, iPSC-derived skeletal muscle. Suggested CL terms: myoblast, myotube, skeletal muscle fiber cell. In zebrafish and patient myotubes, NAC improved oxidative-stress phenotypes; mouse models have been used for calcium-leak, heat sensitivity, and rycal/AICAR studies. Model evidence is highly informative mechanistically but does not fully recapitulate human phenotypic heterogeneity. The iPSC evidence cited in current context is preprint/future-dated and should not be treated as established clinical evidence (dowling2012oxidativestressand pages 11-12, dowling2012oxidativestressand pages 8-9, rossi2026advancedmodellingof pages 1-5).

Table: This compact table summarizes the core knowledge-base elements for RYR1-related myopathy, including spectrum, mechanisms, diagnosis, epidemiology, management, trials, and models. It also flags where identifier mappings or quantitative estimates require external database verification.

1. Disease information

Definition and scope

RYR1-RM is best treated as a molecularly defined disease family, rather than one uniform clinicopathologic entity. Historically, classification depended on muscle-biopsy patterns; sequencing of the entire large RYR1 coding region has shown extensive overlap among biopsy patterns and clinical presentations. As Lawal and colleagues state in the abstract, “RYR1-RM are the most common class of congenital myopathies,” and the expanded spectrum is partly attributable to next-generation sequencing beyond historical hotspot testing. Published October 2018; DOI: https://doi.org/10.1007/s13311-018-00677-1. (lawal2018ryanodinereceptor1related pages 1-2)

Identifiers and synonyms

  • Gene: RYR1; chromosome 19q13.2; 106 exons; protein 5,038 amino acids and approximately 565 kDa. (beaufils2022therapiesforryr1related pages 1-2)
  • Common names: RYR1-related myopathy, ryanodine receptor 1-related myopathy, RYR1-related congenital myopathy, RYR1-RM.
  • Relevant OMIM phenotypic entries: central core disease (OMIM 117000), malignant hyperthermia susceptibility 1 (OMIM 145600), and multiminicore disease with external ophthalmoplegia (OMIM 255320). These are subtype entries, not exact synonyms for the entire umbrella.
  • MONDO: a single stable umbrella mapping could not be verified from the retrieved sources. A production knowledge base should map the umbrella to its constituent MONDO subtype records rather than assign an unverified ID.
  • ICD: ICD-10/ICD-11 generally classify these under congenital myopathy/other specified myopathy and, separately, malignant hyperthermia; no retrieved source established one specific code encompassing the full RYR1-RM spectrum.
  • MeSH: “Central Core Disease” and “Malignant Hyperthermia” are relevant subtype concepts; “RYR1-related myopathy” is not reliably represented as one umbrella descriptor in the evidence reviewed.

The information in this report is aggregated disease-level evidence from publications, registries, and ClinicalTrials.gov—not individual-patient EHR data.

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

The cause is pathogenic germline RYR1 variation. Mechanistic classes include: (1) channel hyperactivity and resting SR Ca²⁺ leak; (2) reduced stimulus-coupled Ca²⁺ release or excitation–contraction uncoupling; and (3) reduced RyR1 abundance, particularly in some recessive genotypes. Approximately 400 variants had been reported by the 2022 therapeutic review, but this is not a current ClinVar count. (beaufils2022therapiesforryr1related pages 1-2, beaufils2022therapiesforryr1related pages 7-8)

Variants are predominantly missense, although nonsense, frameshift, splice-altering, in-frame indel, and structural/deep-intronic alleles occur. Clinical classification must be variant-specific under ACMG/AMP criteria; many rare RYR1 missense variants remain VUS because RYR1 is large and missense variation exists in reference populations. Pathogenic causal alleles are expected to be rare or absent in population databases, but no universal allele-frequency threshold is valid across dominant, recessive, and reduced-penetrance malignant-hyperthermia phenotypes.

Risk factors

  • Genetic: one pathogenic dominant allele or biallelic pathogenic/hypomorphic alleles; family history of congenital myopathy, unexplained anesthesia reaction, heat illness, exertional rhabdomyolysis, or persistently raised CK.
  • Environmental triggers: volatile anesthetics and succinylcholine can precipitate malignant hyperthermia in susceptible people. Heat, fever/pyrexia, and intense or prolonged exercise can precipitate myalgia, hyperCKemia, rhabdomyolysis, or heat illness. A 2024 review described 41 contracture- or genetically confirmed malignant-hyperthermia-susceptible individuals in whom intense exercise or pyrexia preceded reactions, supporting a continuum between anesthesia-triggered and non-anesthetic RYR1 disease. (moreno2024myopathicmanifestationsacross pages 4-5)
  • Age and sex: both sexes and all ages are affected. No robust sex-specific causal risk was established in the retrieved evidence.
  • Noncausal exposures: smoking, alcohol, diet, infection, pollution, and occupation are not established primary causes.

Protective factors

No reproducible human genetic protective allele is established. Practical environmental protection consists of avoiding trigger anesthetics, preventing dehydration/overheating, pacing exercise, promptly treating fever, and using individualized emergency plans. These reduce episodes but do not prevent inheritance or constitutive myopathy. Antioxidants are mechanistically plausible but are not proven preventive therapy.

3. Phenotypes

Clinical expression ranges from fetal hypokinesia and severe neonatal hypotonia to childhood weakness, apparently static congenital myopathy, episodic adult rhabdomyolysis, or late-onset axial weakness. Dominant CCD is often mild or slowly progressive; recessive disease more often includes generalized weakness, ophthalmoparesis, bulbar/respiratory involvement, scoliosis, and contractures. (lawal2018ryanodinereceptor1related pages 1-2)

Phenotype Type, onset, course and impact Suggested HPO term
Hypotonia Sign; congenital/neonatal; variable severity; delays motor milestones Muscular hypotonia, HP:0001252
Proximal/generalized weakness Sign; congenital through adult; often stable or slowly progressive; impairs stairs, rising, lifting and ambulation Proximal muscle weakness, HP:0003701; generalized muscle weakness, HP:0001324
Fatigue/fatigability Symptom; common and activity-limiting; may occur despite stable strength Easy fatigability, HP:0003388; exercise intolerance, HP:0003546
Delayed motor development Developmental manifestation, principally congenital forms Motor delay, HP:0001270
Myalgia/cramps Episodic or increasingly persistent in adult MHS-associated disease Myalgia, HP:0003326; muscle cramp, HP:0003394
Rhabdomyolysis/hyperCKemia Episodic laboratory/clinical phenotype, frequently exercise-, heat-, illness-, or anesthesia-associated Rhabdomyolysis, HP:0003201; elevated CK, HP:0003236
Scoliosis/contractures Musculoskeletal signs, more consequential in severe recessive disease; can worsen ventilation and mobility Scoliosis, HP:0002650; joint contracture, HP:0034392
Facial/bulbar weakness Signs; feeding, speech, airway-clearance and aspiration impact Facial muscle weakness, HP:0002058; dysphagia, HP:0002015
External ophthalmoparesis Sign, especially recessive MmD-spectrum disease External ophthalmoplegia, HP:0000544
Respiratory insufficiency Sign/functional abnormality; may be disproportionate to limb weakness Respiratory insufficiency, HP:0002093
Malignant-hyperthermia susceptibility Latent/episodic pharmacogenetic phenotype Malignant hyperthermia, HP:0002047

In a mixed RYR1-rhabdomyolysis/MHS-myopathy population summarized in 2024, 48% had elevated CK and 81% had muscle abnormalities; these figures should not be generalized to every congenital subtype. (moreno2024myopathicmanifestationsacross pages 4-5)

Quality-of-life impact is dominated by fatigue, weakness, limited walking/endurance, pain/cramps, recurrent acute-care episodes, respiratory/orthopedic complications, and anxiety surrounding anesthesia and exertion. A longitudinal 6-minute-walk study found no significant change in total distance over six months but detected within-test fatigability, consistent with a stable/slowly progressive baseline plus activity-related performance decline. Robust EQ-5D, SF-36, survival, and subtype-specific frequency estimates remain limited.

4. Genetic and molecular information

RYR1 is the sole defining causal gene for this disease umbrella. RyR1 forms a homotetrameric channel in the terminal sarcoplasmic-reticulum membrane and interacts functionally with the voltage sensor CaV1.1/DHPR, FKBP12, calmodulin, triadin, calsequestrin, and related triadic proteins. (beaufils2022therapiesforryr1related pages 1-2)

Dominant alleles frequently produce channel gain of function/Ca²⁺ leak or altered gating and are associated with CCD, malignant-hyperthermia susceptibility, and exertional rhabdomyolysis. Recessive combinations can cause reduced protein expression, impaired channel activation, or mixed functional effects and generally produce more severe congenital disease. Both penetrance and expressivity are variable; malignant-hyperthermia penetrance is incomplete and exposure-dependent. No repeat-expansion mechanism, aneuploidy, recurrent translocation, or disease-defining somatic mutation is established.

Potential modifiers include other excitation–contraction-coupling and redox genes, but no modifier is sufficiently validated for routine prognostication. A 2024 candidate-locus study supports a threshold/polygenic model for malignant hyperthermia, but this remains supplementary rather than diagnostic. Disease-specific DNA-methylation, histone, or chromatin signatures are not validated clinically.

5. Environmental and lifestyle information

RYR1-RM is not infectious, toxic, or autoimmune in origin. The clinically important environment is trigger exposure: anesthetic agents, heat, fever, and intense exercise interact with abnormal channel gating. Sustained Ca²⁺ release increases ATP demand, heat production, contracture, acidosis, membrane injury, CK release, and—at extremes—rhabdomyolysis or malignant hyperthermia. Exercise is not categorically contraindicated; individualized moderate activity, cooling, hydration, and avoidance of exhaustive exertion are preferable to deconditioning.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream lesion: pathogenic RYR1 allele changes channel gating, stimulus coupling, folding/assembly, or abundance.
  2. Primary cellular defect: excessive resting Ca²⁺ leak, insufficient depolarization-evoked Ca²⁺ release, or depleted functional channel at the triad.
  3. Functional consequence: reduced myoplasmic Ca²⁺ transient and force generation causes weakness and fatigability; hyperactive channels confer heat, exercise, and anesthetic-triggered crises.
  4. Downstream amplification: chronic Ca²⁺ disturbance increases mitochondrial workload and ROS/RNS; oxidative/nitrosative RyR1 modifications can further destabilize the channel.
  5. Tissue pathology: focal sarcomeric/mitochondrial disorganization produces cores or minicores, fiber-type disproportion, central nuclei, muscle injury, atrophy, and secondary fibrosis.

Human myotubes showed a 26% ± 6.7% basal increase in mitochondrial ROS. Mutant zebrafish myofibers showed ROS fluorescence of 1,369.0 ± 73.1 versus 920.6 ± 114.4 AU in controls (P=0.001). NAC normalized oxidant measures and protected patient myotubes from oxidant-induced death, although preclinical improvement does not establish clinical efficacy. Dowling et al., April 2012; DOI: https://doi.org/10.1093/brain/aws036. (dowling2012oxidativestressand pages 11-12, dowling2012oxidativestressand pages 8-9, dowling2012oxidativestressand pages 12-12)

Suggested annotations: GO biological processes—skeletal-muscle contraction, excitation–contraction coupling, calcium-ion transmembrane transport, release of sequestered Ca²⁺ into cytosol, response to oxidative stress, mitochondrial ATP synthesis; GO cellular components—sarcoplasmic-reticulum membrane, terminal cisterna, T-tubule, calcium-release unit, mitochondrion; GO molecular function—ryanodine-sensitive calcium-release-channel activity. Cell Ontology: skeletal muscle fiber (CL:0000188), myoblast (CL:0000056), and skeletal-muscle satellite cell. Multi-omics evidence remains exploratory; no validated transcriptomic, proteomic, metabolomic, lipidomic, single-cell, or spatial diagnostic signature exists.

7. Anatomical structures affected

The primary organ is skeletal muscle (UBERON:0001134), particularly limb-girdle/proximal, axial, paraspinal, respiratory, facial, bulbar, and extraocular muscles depending on genotype. Relative rectus-femoris sparing has been reported as part of a recognizable MRI pattern, but imaging is not independently diagnostic. (lawal2018ryanodinereceptor1related pages 1-2)

At tissue/cell level, multinucleated skeletal myofibers and their triads are affected. Subcellular sites include the sarcoplasmic reticulum, terminal cisternae, T-tubules, RyR1–CaV1.1 calcium-release units, mitochondria, and downstream myofibrils. Weakness is usually bilateral and relatively symmetric; focal/asymmetric disease is atypical and should broaden the differential. The heart is generally spared because cardiac excitation–contraction coupling principally uses RYR2, although cardiac surveillance is appropriate when symptoms or alternative diagnoses warrant it. (beaufils2022therapiesforryr1related pages 1-2)

8. Temporal development

Onset may be prenatal, neonatal, childhood, or adult. Congenital disease is chronic and lifelong, commonly static or slowly progressive; severe recessive disease may progress through respiratory and orthopedic complications. Adult MHS-associated disease may begin with cramps/myalgia and evolve toward persistent symptoms and proximal lower-limb weakness. Rhabdomyolysis and malignant-hyperthermia episodes are acute superimposed events rather than conventional relapses. (moreno2024myopathicmanifestationsacross pages 4-5)

There is no formal staging system. Critical intervention windows are before anesthesia, during fever/heat exposure, after the first rhabdomyolysis episode, and early in respiratory or scoliosis progression. True remission is not expected because the genotype persists, although episodic symptoms can resolve and complications can be prevented.

9. Inheritance and population

Inheritance is autosomal dominant or autosomal recessive. Variable expressivity is pronounced, and penetrance—especially for malignant hyperthermia—is incomplete and exposure-dependent. Genetic anticipation is not established. Parental/germline mosaicism is possible in principle and should be considered when an apparently de novo variant recurs, but its population frequency is unknown. Consanguinity increases the probability of recessive disease. Founder variants exist in some populations, but no single ancestry defines RYR1-RM.

The frequently cited US pediatric point prevalence is approximately 1:90,000. This is probably an underestimate because mildly affected adults, MHS-only carriers, and previously biopsy-negative individuals may escape diagnosis. (lawal2018ryanodinereceptor1related pages 1-2, beaufils2022therapiesforryr1related pages 1-2)

The ongoing prevalence project NCT06791369 plans approximately 2,000 records from UK and Dutch specialist centers and includes congenital myopathy and malignant-hyperthermia subgroups; it uses retrospective 2011–2020 data and therefore is not yet a definitive population incidence study. https://clinicaltrials.gov/study/NCT06791369. (NCT06791369 chunk 3)

No reliable annual incidence, carrier frequency, sex ratio, or ethnicity-specific prevalence was established by the retrieved literature.

10. Diagnostics

Recommended pathway

  1. Document congenital weakness/hypotonia, fatigability, axial or ocular involvement, rhabdomyolysis, anesthesia reactions, exercise/heat intolerance, and a three-generation pedigree.
  2. Measure CK, renal function and urine myoglobin during episodes; baseline CK may be normal or mildly elevated. Obtain pulmonary function—sitting and supine FVC, maximal pressures, sleep assessment when indicated—and orthopedic evaluation.
  3. Muscle MRI can identify selective involvement and guide biopsy but is supportive.
  4. Perform a congenital-myopathy/rhabdomyolysis panel including full RYR1 coding and splice regions with deletion/duplication analysis. Single-gene RYR1 testing is suitable when phenotype/family variant is specific. WES or preferably WGS is useful after negative panel testing, particularly for structural, deep-intronic, or blended diagnoses.
  5. Confirm segregation, phase recessive variants, review gnomAD/ClinVar, and apply ACMG/AMP criteria with phenotype and functional evidence.
  6. Muscle biopsy is now adjunctive: central cores, multiple minicores, core–rod change, central nuclei, type-1 predominance/uniformity, or fiber-type disproportion are suggestive but neither necessary nor specific.

NGS is favored because hotspot-only analysis misses pathogenic variation and histology overlaps among RYR1-RM subtypes. (lawal2018ryanodinereceptor1related pages 1-2)

For malignant-hyperthermia risk, a pathogenic RYR1 variant may establish susceptibility; where genetics is negative or uncertain but clinical risk remains high, specialist in-vitro contracture testing may be considered. CMA, karyotype, FISH, mitochondrial-DNA analysis, and repeat-expansion testing are not first-line unless another diagnosis is suspected. RNA sequencing from muscle can resolve selected splice variants but is not routine screening.

Differential diagnosis: SELENON-related myopathy, ACTA1/NEB-related nemaline myopathy, MTM1/DNM2/BIN1/SPEG-associated centronuclear myopathy, CACNA1S-related channelopathy/MHS, STAC3-related Native American myopathy, TTN congenital myopathy, congenital muscular dystrophies, metabolic rhabdomyolysis disorders, mitochondrial myopathy, periodic paralysis, inflammatory myopathy, motor-neuron disease, and neuromuscular-junction disorders.

11. Outcomes and prognosis

Most mildly affected dominant patients retain ambulation and have near-normal life expectancy, but robust survival curves are unavailable. Morbidity is driven by fatigue, reduced endurance, pain, scoliosis/contractures, respiratory weakness, episodic rhabdomyolysis, and preventable malignant-hyperthermia crises. Severe neonatal recessive disease can be life-threatening through respiratory insufficiency and feeding/bulbar complications.

Prognostic factors include recessive inheritance, prenatal/neonatal onset, respiratory or bulbar involvement, severe scoliosis, recurrent rhabdomyolysis, and low functional baseline. Genotype alone has limited precision because allelic and intrafamilial expressivity is variable. No validated circulating prognostic biomarker exists; CK is an injury marker, not a reliable measure of chronic severity.

12. Treatment and current applications

Standard management

There is no FDA-approved disease-modifying treatment. Current care is multidisciplinary: individualized physiotherapy and moderate aerobic/strength activity, energy conservation, mobility/orthotic support, contracture prevention, scoliosis surveillance, respiratory monitoring and noninvasive ventilation/cough support where needed, swallowing/nutritional support, pain management, and renal monitoring during rhabdomyolysis. (lawal2018ryanodinereceptor1related pages 1-2, beaufils2022therapiesforryr1related pages 7-8)

All affected or potentially susceptible patients should carry an anesthesia alert. Trigger-free anesthesia, machine preparation, monitoring, and immediate dantrolene availability are practical standard implementations. Dantrolene is established for acute malignant hyperthermia; chronic oral use for myalgia/cramps remains off-label and limited by weakness, fatigue, and hepatotoxicity risk. Suggested NCIT concepts include Physical Therapy, Respiratory Support, Noninvasive Ventilation, Dantrolene, N-Acetylcysteine, Albuterol, Pyridostigmine, and Clinical Trial.

Investigational pharmacotherapy

  • N-acetylcysteine (NAC): reduced oxidative stress and improved selected histological/motor measures in zebrafish and patient myotubes, but the subsequent randomized clinical program did not establish an approved therapy. Preclinical evidence must not be equated with clinical benefit. (dowling2012oxidativestressand pages 11-12, dowling2012oxidativestressand pages 8-9)
  • Salbutamol/albuterol and pyridostigmine: small uncontrolled reports suggested symptomatic improvement in selected patients; evidence is insufficient for routine disease-modifying use. Pyridostigmine benefit in RYR1-centronuclear cases was reportedly nonsustained. (lawal2018ryanodinereceptor1related pages 11-12)
  • AICAR: reduced Ca²⁺ leak/ROS-RNS and prevented heat-induced death in an RYR1 mouse model; preclinical only. (lawal2018ryanodinereceptor1related pages 11-12)
  • ARM210/S48168 (surlorian): a Rycal designed to stabilize the RyR1 complex. Phase 1 NCT04141670 enrolled seven adults; the linked 2024 open-label dose-escalation publication is PMID 38318125. The study excluded FVC below 50% predicted and included pharmacokinetic and muscle-biopsy assessments. Small size and open-label design preclude definitive efficacy conclusions. https://clinicaltrials.gov/study/NCT04141670. (NCT04141670 chunk 2)
  • Phase 2: NCT07560020, recruiting, placebo-controlled, planned n=28 adults with autosomal-dominant RYR1-RM. Its identifier indicates a post-2024 development and should not be presented as a 2024 result. https://clinicaltrials.gov/study/NCT07560020.
  • Natural history: NCT06157268, recruiting observational study, planned n=100, studies congenital-myopathy fatigability. https://clinicaltrials.gov/study/NCT06157268.

Advanced therapy

Gene replacement is difficult because the approximately 15-kb RYR1 coding sequence exceeds conventional single-AAV capacity. Proposed approaches include dual-vector systems, allele-specific silencing, splice correction, CRISPR editing, transcriptional activation for hypomorphic alleles, and RNA delivery. As of the reviewed evidence, these remain preclinical; no RYR1 gene, RNA, or cell therapy is approved. The therapeutic review identifies five target levels: DNA correction, RNA/splicing correction, protein folding/SR stress, triadic Ca²⁺ leak, and ROS/RNS regulation. (beaufils2022therapiesforryr1related pages 7-8)

13. Prevention

  • Primary: inherited disease itself cannot presently be prevented after conception. Genetic counseling, carrier/partner testing in recessive families, prenatal diagnosis, and preimplantation genetic testing are reproductive options after familial variants are established.
  • Secondary: cascade testing of relatives; early pulmonary, orthopedic, swallowing and functional assessment; specialist evaluation after unexplained heat illness, rhabdomyolysis, or anesthesia reaction. No population newborn screening is available.
  • Tertiary: trigger-free anesthesia, emergency dantrolene access, heat/exertion plans, hydration, fever management, gradual conditioning, avoidance of prolonged immobilization, and surveillance for respiratory/scoliosis complications.
  • Vaccination: no disease-specific vaccine; routine vaccination and prompt infection management may indirectly reduce fever- and respiratory-related complications.

14. Other species and natural disease

The clearest naturally occurring comparative disease is porcine malignant-hyperthermia/porcine stress syndrome caused by RYR1 variation in domestic pig (Sus scrofa, NCBI Taxon 9823). It reproduces stress/anesthetic-triggered Ca²⁺ dysregulation, hypermetabolism, rigidity, and meat-quality effects, but porcine inheritance and variant architecture do not reproduce the complete human congenital-myopathy spectrum. There is no zoonotic transmission.

Naturally occurring or breed-associated RYR1 phenotypes have also been reported in other domestic species, but exact OMIA/VBO mappings were not verified here and should be curated directly from those resources. The mechanism is evolutionarily conserved because RyR1-mediated skeletal-muscle Ca²⁺ release is conserved across vertebrates.

15. Model organisms and experimental systems

  • Zebrafish: ryr1 mutant/knockdown models reproduce abnormal swimming, myofibrillar/SR pathology, Ca²⁺ dysfunction, and oxidative stress. They enabled NAC rescue experiments, but teleost paralogy and developmental physiology limit direct genotype–phenotype translation. (dowling2012oxidativestressand pages 11-12, dowling2012oxidativestressand pages 8-9, dowling2012oxidativestressand pages 1-1)
  • Mouse: knock-in models such as Y522S/Y524S and other humanized alleles reproduce Ca²⁺ leak, heat/anesthetic susceptibility, oxidative/nitrosative stress, core development, and weakness. They are used for dantrolene, AICAR, Rycal, antioxidant, and gene-correction studies; many model one dominant allele and not severe recessive human disease. (lawal2018ryanodinereceptor1related pages 13-13, lawal2018ryanodinereceptor1related pages 11-12)
  • Pig: a valuable large-animal model of malignant hyperthermia and anesthetic physiology, but less representative of multisystem developmental RYR1-RM.
  • Patient myoblasts/myotubes: preserve human genotype and revealed increased mitochondrial ROS and oxidant vulnerability, but lack mature innervation, loading, and whole-body pharmacology. (dowling2012oxidativestressand pages 8-9)
  • iPSC-derived and 3-D engineered muscle: promising for variant-specific Ca²⁺ and contractility assays, genome editing, and personalized drug testing. The retrieved detailed iPSC report was a 2026 preprint and therefore is excluded as established 2023–2024 evidence. (rossi2026advancedmodellingof pages 1-5)

Evidence appraisal and major gaps

The most authoritative recent source retrieved was the October 2024 British Journal of Anaesthesia review of adult myopathic manifestations in malignant-hyperthermia susceptibility (DOI: https://doi.org/10.1016/j.bja.2024.05.046). It strengthens recognition of chronic myalgia, cramps, later weakness, and heat/exercise-triggered rhabdomyolysis as part of an RYR1 continuum. (moreno2024myopathicmanifestationsacross pages 4-5)

Nevertheless, the knowledge base remains limited by heterogeneous subtype definitions, ascertainment through specialist centers, small natural-history cohorts, incomplete penetrance, and scarcity of randomized trials. Reliable annual incidence, carrier frequency, sex/ancestry effects, phenotype percentages by genotype, long-term survival, validated QoL norms, modifier genes, epigenetic signatures, and clinically actionable multi-omics biomarkers are not currently established. Expert interpretation therefore favors a molecular diagnosis plus individualized functional and trigger-risk assessment, rather than predicting outcome solely from biopsy label or variant location. (lawal2018ryanodinereceptor1related pages 11-12, beaufils2022therapiesforryr1related pages 7-8)

References

  1. (lawal2018ryanodinereceptor1related pages 1-2): Tokunbor A. Lawal, Joshua J. Todd, and Katherine G. Meilleur. Ryanodine receptor 1-related myopathies: diagnostic and therapeutic approaches. Neurotherapeutics, 15:885-899, Oct 2018. URL: https://doi.org/10.1007/s13311-018-00677-1, doi:10.1007/s13311-018-00677-1. This article has 130 citations and is from a peer-reviewed journal.

  2. (beaufils2022therapiesforryr1related pages 1-2): Mathilde Beaufils, Lauriane Travard, John Rendu, and Isabelle Marty. Therapies for ryr1-related myopathies: where we stand and the perspectives. Jan 2022. URL: https://doi.org/10.2174/1389201022666210910102516, doi:10.2174/1389201022666210910102516. This article has 15 citations and is from a peer-reviewed journal.

  3. (beaufils2022therapiesforryr1related pages 7-8): Mathilde Beaufils, Lauriane Travard, John Rendu, and Isabelle Marty. Therapies for ryr1-related myopathies: where we stand and the perspectives. Jan 2022. URL: https://doi.org/10.2174/1389201022666210910102516, doi:10.2174/1389201022666210910102516. This article has 15 citations and is from a peer-reviewed journal.

  4. (moreno2024myopathicmanifestationsacross pages 4-5): Carlos A. Ibarra Moreno, Helga C.A. Silva, Nicol C. Voermans, Heinz Jungbluth, Luuk R. van den Bersselaar, John Rendu, Agnieszka Cieniewicz, Philip M. Hopkins, and Sheila Riazi. Myopathic manifestations across the adult lifespan of patients with malignant hyperthermia susceptibility: a narrative review. British Journal of Anaesthesia, 133(4):759-767, Oct 2024. URL: https://doi.org/10.1016/j.bja.2024.05.046, doi:10.1016/j.bja.2024.05.046. This article has 10 citations and is from a highest quality peer-reviewed journal.

  5. (dowling2012oxidativestressand pages 11-12): James J. Dowling, Sandrine Arbogast, Junguk Hur, Darcee D. Nelson, Anna McEvoy, Trent Waugh, Isabelle Marty, Joel Lunardi, Susan V. Brooks, John Y. Kuwada, and Ana Ferreiro. Oxidative stress and successful antioxidant treatment in models of ryr1-related myopathy. Brain : a journal of neurology, 135 Pt 4:1115-27, Apr 2012. URL: https://doi.org/10.1093/brain/aws036, doi:10.1093/brain/aws036. This article has 102 citations.

  6. (dowling2012oxidativestressand pages 8-9): James J. Dowling, Sandrine Arbogast, Junguk Hur, Darcee D. Nelson, Anna McEvoy, Trent Waugh, Isabelle Marty, Joel Lunardi, Susan V. Brooks, John Y. Kuwada, and Ana Ferreiro. Oxidative stress and successful antioxidant treatment in models of ryr1-related myopathy. Brain : a journal of neurology, 135 Pt 4:1115-27, Apr 2012. URL: https://doi.org/10.1093/brain/aws036, doi:10.1093/brain/aws036. This article has 102 citations.

  7. (dowling2012oxidativestressand pages 12-12): James J. Dowling, Sandrine Arbogast, Junguk Hur, Darcee D. Nelson, Anna McEvoy, Trent Waugh, Isabelle Marty, Joel Lunardi, Susan V. Brooks, John Y. Kuwada, and Ana Ferreiro. Oxidative stress and successful antioxidant treatment in models of ryr1-related myopathy. Brain : a journal of neurology, 135 Pt 4:1115-27, Apr 2012. URL: https://doi.org/10.1093/brain/aws036, doi:10.1093/brain/aws036. This article has 102 citations.

  8. (NCT06791369 chunk 3): The Prevalence of RYR1-related Disease. King's College London. 2025. ClinicalTrials.gov Identifier: NCT06791369

  9. (lawal2018ryanodinereceptor1related pages 11-12): Tokunbor A. Lawal, Joshua J. Todd, and Katherine G. Meilleur. Ryanodine receptor 1-related myopathies: diagnostic and therapeutic approaches. Neurotherapeutics, 15:885-899, Oct 2018. URL: https://doi.org/10.1007/s13311-018-00677-1, doi:10.1007/s13311-018-00677-1. This article has 130 citations and is from a peer-reviewed journal.

  10. (NCT04141670 chunk 2): S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM). RyCarma Therapeutics, Inc.. 2020. ClinicalTrials.gov Identifier: NCT04141670

  11. (rossi2026advancedmodellingof pages 1-5): Lucia Rossi, SungWoo Choi, Isobel Terri Olden, Aude Biehler, Lyn Healy, Francesco Muntoni, Giovanni Baranello, Anna Sarkozy, Valentina Maria Lionello, and Francesco Saverio Tedesco. Advanced modelling of ryr1-related myopathies using human ips cells and 3d engineered skeletal muscles. Unknown journal, Aug 2026. URL: https://doi.org/10.21203/rs.3.rs-10606489/v1, doi:10.21203/rs.3.rs-10606489/v1.

  12. (dowling2012oxidativestressand pages 1-1): James J. Dowling, Sandrine Arbogast, Junguk Hur, Darcee D. Nelson, Anna McEvoy, Trent Waugh, Isabelle Marty, Joel Lunardi, Susan V. Brooks, John Y. Kuwada, and Ana Ferreiro. Oxidative stress and successful antioxidant treatment in models of ryr1-related myopathy. Brain : a journal of neurology, 135 Pt 4:1115-27, Apr 2012. URL: https://doi.org/10.1093/brain/aws036, doi:10.1093/brain/aws036. This article has 102 citations.

  13. (lawal2018ryanodinereceptor1related pages 13-13): Tokunbor A. Lawal, Joshua J. Todd, and Katherine G. Meilleur. Ryanodine receptor 1-related myopathies: diagnostic and therapeutic approaches. Neurotherapeutics, 15:885-899, Oct 2018. URL: https://doi.org/10.1007/s13311-018-00677-1, doi:10.1007/s13311-018-00677-1. This article has 130 citations and is from a peer-reviewed journal.

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