MedGen

Congenital myopathy-1A (CMYO1A) with susceptibility to malignant hyperthermia is an autosomal dominant disorder of skeletal muscle characterized by muscle weakness primarily affecting the proximal muscles of the lower limbs beginning in infancy or early childhood, although later onset of symptoms has been reported. There is significant phenotypic variability, even within families, and the wide clinical diversity most likely depends on the severity of the RYR1 mutation. The disorder is static or slowly progressive; affected individuals typically show delayed motor development and usually achieve independent walking, although many have difficulty running or climbing stairs. Additional features often include mild facial weakness, joint laxity, shoulder girdle weakness, and skeletal manifestations, such as dislocation of the hips, foot deformities, scoliosis, and Achilles tendon contractures. Some patients present with orthopedic deformities. Serum creatine kinase is usually not elevated. Respiratory involvement is rare and there is no central nervous system or cardiac involvement. Patients with dominant mutations in the RYR1 gene are at risk for malignant hyperthermia and both disorders may segregate in the same family. Historically, patients with congenital myopathy due to RYR1 mutations were diagnosed based on the finding of pathologic central cores (central core disease; CCD) on muscle biopsy, which represent areas that lack oxidative enzymes and mitochondrial activity in type 1 muscle fibers. However, additional pathologic findings may also be observed, including cores and rods, central nuclei, fiber type disproportion, multiminicores, and uniform type 1 fibers. These histopathologic features are not always specific to RYR1 myopathy and often change over time (Quinlivan et al., 2003; Jungbluth et al., 2007; Klein et al., 2012; Ogasawara and Nishino, 2021). Some patients with RYR1 mutations have pathologic findings on muscle biopsy, but are clinically asymptomatic (Shuaib et al., 1987; Quane et al., 1993). Rare patients with a more severe phenotype have been found to carry a heterozygous mutation in the RYR1 gene inherited from an unaffected parent. However, in these cases, there is a possibility of recessive inheritance (CMYO1B; 255320) with either a missed second RYR1 mutation in trans or a genomic rearrangement on the other allele that is undetectable on routine genomic sequencing, since the RYR1 gene is very large and genetic analysis may be difficult (Klein et al., 2012). Genetic Heterogeneity of Congenital Myopathy See also CMYO1B (255320), caused by mutation in the RYR1 gene (180901) on chromosome 19q13; CMYO2A (161800), CMYO2B (620265), and CMYO2C (620278), caused by mutation in the ACTA1 gene (102610) on chromosome 1q42; CMYO3 (602771), caused by mutation in the SELENON gene (606210) on chromosome 1p36; CMYO4A (255310) and CMYO4B (609284), caused by mutation in the TPM3 gene (191030) on chromosome 1q21; CMYO5 (611705), caused by mutation in the TTN gene (188840) on chromosome 2q31; CMYO6 (605637), caused by mutation in the MYH2 gene (160740) on chromosome 17p13; CMYO7A (608358) and CMYO7B (255160), caused by mutation in the MYH7 gene (160760) on chromosome 14q11; CMYO8 (618654), caused by mutation in the ACTN2 gene (102573) on chromosome 1q43; CMYO9A (618822) and CMYO9B (618823), caused by mutation in the FXR1 gene (600819) on chromosome 3q28; CMYO10A (614399) and CMYO10B (620249), caused by mutation in the MEGF10 gene (612453) on chromosome 5q23; CMYO11 (619967), caused by mutation in the HACD1 gene (610467) on chromosome 10p12; CMYO12 (612540), caused by mutation in the CNTN1 gene (600016) on chromosome 12q12; CMYO13 (255995), caused by mutation in the STAC3 gene (615521) on chromosome 12q13; CMYO14 (618414), caused by mutation in the MYL1 gene (160780) on chromosome 2q34; CMYO15 (620161), caused by mutation in the TNNC2 gene (191039) on chromosome 20q13; CMYO16 (618524), caused by mutation in the MYBPC1 gene (160794) on chromosome 12q23; CMYO17 (618975), caused by mutation in the MYOD1 gene (159970) on chromosome 11p15; CMYO18 (620246), caused by mutation in the CACNA1S gene (114208) on chromosome 1q32; CMYO19 (618578), caused by mutation in the PAX7 gene (167410) on chromosome 1p36; CMYO20 (620310), caused by mutation in the RYR3 gene (180903) on chromosome 15q13; CMYO21 (620326), caused by mutation in the DNAJB4 gene (611327) on chromosome 1p31; CMYO22A (620351) and CMYO22B (620369), both caused by mutation in the SCN4A gene (603967) on chromosome 17q23; CMYO23 (609285), caused by mutation in the TPM2 gene (190990) on chromosome 9p13; and CMYO24 (617336), caused by mutation in the MYPN gene (608517) on chromosome 10q21. [from OMIM]

Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances cause uncontrolled release of calcium from the sarcoplasmic reticulum and may promote entry of extracellular calcium into the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even cardiac arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some individuals with MHS will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high. [from GeneReviews]

Congenital myopathy-1B (CMYO1B) is an autosomal recessive disorder of skeletal muscle characterized by severe hypotonia and generalized muscle weakness apparent soon after birth or in early childhood with delayed motor development, generalized muscle weakness and atrophy, and difficulty walking or running. Affected individuals show proximal muscle weakness with axial and shoulder girdle involvement, external ophthalmoplegia, and bulbar weakness, often resulting in feeding difficulties and respiratory insufficiency. Orthopedic complications such as joint laxity, distal contractures, hip dislocation, cleft palate, and scoliosis are commonly observed. Serum creatine kinase is normal. The phenotype is variable in severity (Jungbluth et al., 2005; Bharucha-Goebel et al., 2013). Some patients show symptoms in utero, including reduced fetal movements, polyhydramnios, and intrauterine growth restriction. The most severely affected patients present in utero with fetal akinesia, arthrogryposis, and lung hypoplasia resulting in fetal or perinatal death (McKie et al., 2014). Skeletal muscle biopsy of patients with recessive RYR1 mutations can show variable features, including multiminicores (Ferreiro and Fardeau, 2002), central cores (Jungbluth et al., 2002), congenital fiber-type disproportion (CFTD) (Monnier et al., 2009), and centronuclear myopathy (Wilmshurst et al., 2010). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000). [from OMIM]

King-Denborough syndrome (KDS) is an autosomal dominant disorder characterized by the triad of congenital myopathy, dysmorphic features, and susceptibility to malignant hyperthermia (summary by Dowling et al., 2011). [from OMIM]

Congenital fiber-type disproportion is a condition that primarily affects skeletal muscles, which are muscles used for movement. People with this condition typically experience muscle weakness (myopathy), particularly in the muscles of the shoulders, upper arms, hips, and thighs. Weakness can also affect the muscles of the face and muscles that control eye movement (ophthalmoplegia), sometimes causing droopy eyelids (ptosis). Individuals with congenital fiber-type disproportion generally have a long face, a high arch in the roof of the mouth (high-arched palate), and crowded teeth.

Individuals with congenital fiber-type disproportion may have joint deformities (contractures) and an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Approximately 30 percent of people with this disorder experience mild to severe breathing problems related to weakness of muscles needed for breathing. Some people who experience these breathing problems require use of a machine to help regulate their breathing at night (noninvasive mechanical ventilation), and occasionally during the day as well. About 30 percent of affected individuals have difficulty swallowing due to muscle weakness in the throat. Rarely, people with this condition have a weakened and enlarged heart muscle (dilated cardiomyopathy).

The severity of congenital fiber-type disproportion varies widely. It is estimated that up to 25 percent of affected individuals experience severe muscle weakness at birth and die in infancy or childhood. Others have only mild muscle weakness that becomes apparent in adulthood. Most often, the signs and symptoms of this condition appear by age 1. The first signs of this condition are usually decreased muscle tone (hypotonia) and muscle weakness. In most cases, muscle weakness does not worsen over time, and in some instances it may improve. Although motor skills such as standing and walking may be delayed, many affected children eventually learn to walk. These individuals often have less stamina than their peers, but they remain active. Rarely, people with this condition have a progressive decline in muscle strength over time. These individuals may lose the ability to walk and require wheelchair assistance. [from MedlinePlus Genetics]