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Conditions associated with malignant hyperthermia or rhabdomyolysis

Conditions associated with malignant hyperthermia or rhabdomyolysis
Condition Clinical features Problems with anesthetics Inheritance Recommendations
Volatile anesthetics Succinylcholine
Myopathies
Normal phenotype No apparent muscle symptoms. Unexpected MH reactions; patients often have RYR1 or CACNA1S mutations on diagnostic testing. Dominant RYR1 or (dominant and recessive) CACNA1S variants. Contraindicated Contraindicated
Central core myopathy[1-5] Hypotonia in infancy, delayed motor development, proximal lower-limb muscle weakness, associated musculoskeletal abnormalities. RYR1 receptor abnormality; high incidence of MHS. Autosomal dominant with variable penetrance. Contraindicated Contraindicated
Multiminicore myopathy[6] Similar to central core myopathy. RYR1 receptor abnormalities; high incidence of MHS. Autosomal recessive. Contraindicated Contraindicated
King-Denborough syndrome[7,8] Hypotonia at birth, mild proximal muscle weakness, delayed motor development, dysmorphic facial features (ptosis, low-set ears, malar hypoplasia, micrognathia, and a high-arched palate), pectus excavatum, winged scapulae, lumbar lordosis, and thoracic scoliosis. RYR1 receptor abnormality; high incidence of MHS. Autosomal recessive. Contraindicated Contraindicated
Native American myopathy[9] Affects Lumbee Indians of North Carolina; congenital weakness, arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis. STAC3 receptor abnormality; high incidence of MHS. Autosomal recessive. Contraindicated Contraindicated
Congenital myopathy with cores and rods Varying degrees of severity of hypotonia during infancy. One report of a compound heterozygosity (triplet of RYR1 variants in one allele and fourth RYR1 variant on the other allele) resulted in a complex phenotype of MH and core myopathy.[10] Most typically dominant de novo RYR1 variants, as well as variants in NEB, ACTA1, and TPM2. Contraindicated with RYR1 mutations Contraindicated with RYR1 mutations
Centronuclear myopathy (CNM) Muscle weakness that may begin at birth and affect different muscle groups. May have ophthalmoparesis. MH episodes likely only in patients with RYR1 variants (and possibly CACNA1S, though these patients also typically have cores) and not in other subtypes.[11] There are no reports of MH in patients with CNM but precautions advisable because of possible RYR1 variant before genetic testing performed. Variants in DNM2, MTM1, BIN1, CCDC78, TTN, SPEG, CACNA1S, and RYR1. Contraindicated with RYR1 mutations Contraindicated with RYR1 mutations
Congenital fiber type disproportion (CFTD) Non-progressive or slowly progressive myopathy with weakness and hypotonia during infancy. Clinical features include failure to thrive, developmental delays of gross motor skills, limb weakness, joint contractures, and scoliosis. One study reported between 10 and 20% of congenital fiber-type disproportion is caused by variants in RYR1.[12] There are no reports of MH in patients with CFTD, but precautions advisable because of possible RYR1 variant before genetic testing performed. Variants in ACTA1, SEPN1, LMNA, RYR1, MYH7, CACNA1S, or TPM3. Contraindicated with RYR1 mutations Contraindicated with RYR1 mutations
Periodic paralysis Periods of extreme muscle weakness or paralysis based on fluctuating serum potassium levels. Consider MHS if RYR1, CACNA1S, or unknown genotype.[13-17] Variants in RYR1, CACNA1S, or SCN4A. Contraindicated with RYR1 mutations Contraindicated with RYR1 mutations
Nemaline rod myopathy Primarily proximal muscle weakness, delayed motor development beginning in early childhood, variable in severity and progression. Consider MHS if RYR1 or unknown genotype. Mainly associated with variants in ACTA1, NEB, TPM3, TPM2, TNNT1, and CFL2. Rarely associated with RYR1.[18] Contraindicated with RYR1 mutations Contraindicated with RYR1 mutations
Idiopathic hyperCKemia Persistent elevations in serum creatine kinase (CK) levels without evidence of other neuromuscular disease. Reports of patients with hyperCKemia and RYR1 variants have developed clinical MH.[19,20] Associated with many different entities such as undiagnosed Duchenne, variants in CAV3, RYR1, and others. Contraindicated with RYR1 mutations Contraindicated with RYR1 mutations
Conditions associated with rhabdomyolysis
Exertional rhabdomyolysis[21-26] Extreme exercise and/or hot/humid conditions leading to muscle injury (increased CK, hyperkalemia, myoglobinemia, myoglobinuria). Some individuals have RYR1 receptor abnormalities; increased incidence of MHS. Unknown; heterogenous condition. Contraindicated with RYR1 mutations or rhabdomyolysis in unexpected situations Contraindicated with RYR1 mutations or rhabdomyolysis in unexpected situations
Dystrophinopathies[27-38] Progressive weakness from about age two years, dilated cardiomyopathy, conduction abnormalities. While this clinical syndrome can closely resemble acute MH and is related to abnormal calcium release in the muscle, the etiology is thought to be different. Some experts recommend administration of non-triggering anesthetics to these patients; however, many patients with dystrophinopathies have received halogenated volatile agents safely. Severe hyperkalemia from upregulated acetylcholine receptors following succinylcholine; possible rhabdomyolysis following volatile anesthetics.

Duchenne: X-linked recessive.

Becker: X-linked recessive. 		Only if essential, in limited amounts Contraindicated
Myoadenylate deaminase deficiency[39] Muscles cramps, elevated CK levels (baseline and increased after exercise), and occasionally rhabdomyolysis. May develop rhabdomyolysis. Autosomal recessive. Try to avoid Try to avoid
McArdle disease (muscle phosphorylase deficiency, glycogen storage disease V)[40,41] Muscle cramping, exercise intolerance, rhabdomyolysis. May exacerbate underlying symptoms. Autosomal recessive. Try to avoid Try to avoid
Carnitine palmitoyl transferase type 2 deficiency[42,43] Muscle weakness or cramps and exercise intolerance sometimes associated with rhabdomyolysis. Perioperative rhabdomyolysis. Autosomal recessive. Try to avoid Try to avoid
Other conditions
Osteogenesis imperfecta[44-48] Multiple fractures with minimal or no trauma. Some reports of fever with anesthesia. Inherited connective tissue disorder. OK to use OK to use
Arthrogryposis multiplex congenita[48-50] Congenital joint contractures; occurs in a variety of inherited neurogenic or myogenic syndromes. Some reports of fever with anesthesia. Heterogenous disorders. OK to use OK to use
Myotonia[51,52] Incomplete muscle relaxation, weakness. Exposure to succinylcholine or anticholinesterase (reversal agent) may induce prolonged muscle rigidity. Heterogenous disorders. OK to use Avoid succinylcholine or anticholinesterase reversal agents
Neuroleptic malignant syndrome[53-57] Muscular rigidity, hyperthermia, mental status change, autonomic instability, rhabdomyolysis, and acidosis. May be triggered by neuroleptics used as antiemetics (dopamine antagonists), usually more than 24 hours after administration. Unclear. OK to use OK to use
MH: malignant hyperthermia; RYR1: ryanodine receptor 1; CACNA1S: calcium voltage-gated channel subunit alpha1 S; MHS: susceptibility to malignant hyperthermia; STAC3: SH3 and cysteine-rich domains 3; NEB: nebulin; ACTA1: actin, alpha, skeletal muscle 1; TPM2: tropomyosin 2; DNM2: dynamin 2; MTM1: myotubularin; BIN1: bridging integrator 1; CCDC78: coiled-coil domain-containing protein 78; TTN: titin; SPEG: SPEG complex locus; SEPN1: selenoprotein N; LMNA: lamin A/C; MYH7: myosin heavy chain 7; TPM3: tropomyosin 3; SCN4A: sodium voltage-gated channel alpha subunit 4; TNNT1: troponin T1; CFL2: cofilin 2; CAV3: caveolin 3.
References:
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With additional data from:
  • Litman RS, Griggs SM, Dowling JJ, Riazi S. Malignant hyperthermia susceptibility and related diseases. Anesthesiology 2018; 128:159.
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