Alternative titles; symbols
SNOMEDCT: 43152001; ICD10CM: G71.29; ORPHA: 178145, 597, 598; DO: 3529;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.2 | Congenital myopathy 1A, autosomal dominant, with susceptibility to malignant hyperthermia | 117000 | Autosomal dominant | 3 | RYR1 | 180901 |
A number sign (#) is used with this entry because of evidence that autosomal dominant congenital myopathy-1A (CMYP1A) with susceptibility to malignant hyperthermia (MHS) is caused by heterozygous mutation in the ryanodine receptor-1 gene (RYR1; 180901) on chromosome 19q13.
Heterozygous mutation in the RYR1 gene also causes susceptibility to malignant hyperthermia-1 (MHS1; 145600); patients with CMYP1A are at risk for MHS.
Biallelic mutations in the RYR1 gene cause autosomal recessive CMYP1B (255320), which shows overlapping features, but is typically more severe.
Congenital myopathy-1A (CMYP1A) 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 (CMYP1B; 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 CMYP1B (255320), caused by mutation in the RYR1 gene (180901) on chromosome 19q13; CMYP2A (161800), CMYP2B (620265), and CMYP2C (620278), caused by mutation in the ACTA1 gene (102610) on chromosome 1q42; CMYP3 (602771), caused by mutation in the SELENON gene (606210) on chromosome 1p36; CMYP4A (255310) and CMYP4B (609284), caused by mutation in the TPM3 gene (191030) on chromosome 1q21; CMYP5 (611705), caused by mutation in the TTN gene (188840) on chromosome 2q31; CMYP6 (605637), caused by mutation in the MYH2 gene (160740) on chromosome 17p13; CMYP7A (608358) and CMYP7B (255160), caused by mutation in the MYH7 gene (160760) on chromosome 14q11; CMYP8 (618654), caused by mutation in the ACTN2 gene (102573) on chromosome 1q43; CMYP9A (618822) and CMYP9B (618823), caused by mutation in the FXR1 gene (600819) on chromosome 3q28; CMYP10A (614399) and CMYP10B (620249), caused by mutation in the MEGF10 gene (612453) on chromosome 5q23; CMYP11 (619967), caused by mutation in the HACD1 gene (610467) on chromosome 10p12; CMYP12 (612540), caused by mutation in the CNTN1 gene (600016) on chromosome 12q12; CMYP13 (255995), caused by mutation in the STAC3 gene (615521) on chromosome 12q13; CMYP14 (618414), caused by mutation in the MYL1 gene (160780) on chromosome 2q34; CMYP15 (620161), caused by mutation in the TNNC2 gene (191039) on chromosome 20q13; CMYP16 (618524), caused by mutation in the MYBPC1 gene (160794) on chromosome 12q23; CMYP17 (618975), caused by mutation in the MYOD1 gene (159970) on chromosome 11p15; CMYP18 (620246), caused by mutation in the CACNA1S gene (114208) on chromosome 1q32; CMYP19 (618578), caused by mutation in the PAX7 gene (167410) on chromosome 1p36; CMYP20 (620310), caused by mutation in the RYR3 gene (180903) on chromosome 15q13; CMYP21 (620326), caused by mutation in the DNAJB4 gene (611327) on chromosome 1p31; CMYP22A (620351) and CMYP22B (620369), both caused by mutation in the SCN4A gene (603967) on chromosome 17q23; CMYP23 (609285), caused by mutation in the TPM2 gene (190990) on chromosome 9p13; and CMYP24 (617336), caused by mutation in the MYPN gene (608517) on chromosome 10q21.
Byrne et al. (1982) described a large Australian kindred in which at least 37 members in 5 generations had a congenital myopathy associated with central cores on skeletal muscle biopsy. The inheritance pattern was clearly autosomal dominant. Although there was some variability in the severity, all patients presented in infancy or early childhood with proximal muscle weakness and difficulty running and climbing stairs; some had delayed walking by a few years. Five patients had congenital hip dislocation, including the index case, which was how the family came to attention. Overall, the disorder appeared to follow a static course without progression. Haan et al. (1990) reported follow-up of this family, noting that muscle weakness was typically more severe in the lower limbs rather than the upper limbs, and affected proximal muscles more than distal muscles. Facial weakness was observed in 4 patients. Additional variable features included high-arched palate, dental malocclusion, hypermobile joints, joint contractures, kyphoscoliosis, pes cavus, and congenital hip dislocation. Three patients had susceptibility to malignant hyperthermia, demonstrated through testing of muscle samples. Through linkage analysis, Haan et al. (1990) mapped the disease locus in this family to chromosome 19q12-q13, which includes the RYR1 gene.
Shuaib et al. (1987) reported a 45-year-old Canadian man (case 7) who came to attention for an episode of malignant hyperthermia during anesthesia. He reported slowly progressive muscle weakness since early childhood with a tendency to dislocate the patellae and fibular heads. Physical examination showed thin muscles, unilateral ptosis, and truncal weakness; reflexes were normal. EMG was myopathic and muscle biopsy was consistent with a pathologic diagnosis of central core disease. Testing also showed susceptibility to malignant hyperthermia. Family history was positive for muscle weakness and musculoskeletal abnormalities, and his sister had had an episode of MHS. Two cousins (cases 10 and 11) of the proband and 2 adult daughters of patient 11 (cases 12 and 13) were subsequently referred for investigation. These family members did not show significant clinical features of a congenital myopathy: the 2 daughters had scoliosis, case 10 had hypermobile knee and fibular head joints, and case 13 reported mild calf aching and weak ankles, but none had come to attention in childhood. All showed central core disease and susceptibility to malignant hyperthermia on muscle biopsy. Three had increased serum creatine kinase. The authors noted that the finding of normal strength during examination does not rule out central core disease of the muscle, which is important for genetic counseling.
Quane et al. (1993) reported an Italian family (4T) in which 2 brothers had features of CCD associated with a heterozygous mutation in the RYR1 gene (I403M; 180901.0005). The 30-year-old proband had a lifelong history of nonprogressive myopathy. Physical examination showed club foot, positive Gowers sign, weakness of the shoulder and pelvic girdle muscles, and areflexia. Serum creatine kinase was elevated and EMG showed a myopathic pattern. Muscle biopsy showed a predominance of type 1 fibers, increased central nuclei, and cores devoid of oxidative activity. His brother had a similar, but less severe, phenotype; muscle biopsy was not performed. The parents were clinically unaffected and refused muscle biopsy, but the father was found to carry the RYR1 mutation. Quane et al. (1993) reported another Italian family (2T) in which a father and 3 of his children carried a heterozygous mutation in the RYR1 gene (R163C; 180901.0004). The father and daughter had classic features of CCD, including weakness of the pelvic girdle muscles, positive Gowers sign, and core structures on muscle biopsy. The father had increased serum creatine kinase, but never experienced anesthetic complications, whereas his daughter had an episode of malignant hyperthermia during surgery. One son had an episode of malignant hyperthermia at age 17, but did not have clinical signs of a myopathy and absence of core structures on muscle biopsy. The other son had elevated serum creatine kinase, but no symptoms of CCD and had not been exposed to anesthesia; skeletal muscle biopsy was not performed. Of note, Quane et al. (1993) identified the same RYR1 mutation (R163C) in a Danish family (D15) in which a mother and her 2 children had MHS without clinical signs of a myopathy and absence of cores on muscle biopsy. These findings demonstrated phenotypic variability, both within families and between families with the same mutation.
Tojo et al. (2000) reported a 27-year-old Japanese man and his 2 sons (ages 20 months and 6 months, respectively), with congenital myopathy transmitted in an autosomal dominant pattern. The father had delayed motor milestones with walking at age 3 years and an inability to perform strenuous exercise. He showed proximal muscle weakness, mild Gowers sign, and normal serum creatine kinase. Skeletal muscle biopsy showed uniform type 1 fiber and core structures, consistent with a diagnosis of central core disease (CCD). His 20-month-old son walked at age 15 months, but with an unsteady gait and inability to run. Skeletal muscle biopsy in the son showed type 1 fibers without core structures: he was diagnosed with congenital neuromuscular disease with uniform type 1 fibers (CNMDU1). The 6-month-old son had generalized muscle weakness, hypotonia, poor sucking, and hip joint dysplasia. Muscle biopsy was not performed. The finding of CCD and CNMDU1 in the same family suggested that the 2 pathologic entities are related or even the same, with core structures appearing with age. Limited sequencing of the RYR1 gene did not identify common mutations, but the authors noted that the possibility of an RYR1 mutation in this family could not be excluded. In the father and 1 son reported by Tojo et al. (2000), Wu et al. (2006) and Sato et al. (2008) identified a heterozygous mutation in the RYR1 gene (180901.0033), indicating that CCD and CNMDU1 are indeed different manifestations of the same disease and likely represent a spectrum of abnormalities.
Monnier et al. (2000) reported a French family in which 5 individuals spanning 3 generations had CMYP1A associated with a heterozygous missense mutation in the RYR1 gene (Y4796C; 180901.0016). The patients, who ranged from 10 months to 50 years of age, presented in infancy with hypotonia and proximal muscle weakness. They had delayed motor development with mildly delayed walking and difficulties running and climbing stairs. Some had congenital hip dislocation. Although the muscle weakness was not progressive, most developed Achilles tendon contractures and lordosis. Serum creatine kinase was normal and there was no cardiac involvement. Muscle biopsy showed a congenital myopathy with cores and rods. One of the patients tested showed susceptibility to malignant hyperthermia, demonstrating that the same RYR1 mutation is responsible for both congenital myopathy and MHS in this family.
Monnier et al. (2001) reported 16 unrelated probands with CMYP1A confirmed by genetic analysis. One of the families (CCD06) had been reported by Monnier et al. (2000). There were several large families and 5 patients with sporadic disease. Most patients had onset of hypotonia and muscle weakness in infancy or early childhood, although several patients had onset in adolescence. Many had delayed walking by a few years, and most had difficulty running and climbing stairs in childhood. More severe cases had hip dislocation and cleft palate. As adults, almost all patients were ambulatory with proximal muscle weakness and tendon contractures; a few had scoliosis. Muscle biopsies showed features of central core disease.
Quinlivan et al. (2003) reported 11 patients from 4 unrelated families with congenital myopathy associated with heterozygous missense mutations in the highly conserved C-terminal domain (region 3) of the RYR1 gene: A4940T in exon 103, R4893W (180901.0044) and Y4864C (180901.0045) in exon 102, and R4861H (180901.0019) in exon 101. The proband in each family came to attention through orthopedic abnormalities apparent in infancy or early childhood, namely congenital dislocation of the hips or scoliosis. In early childhood, the probands showed hypotonia, proximal muscle weakness of the lower limbs, delayed motor development with delayed walking and difficulty running or inability to run, frequent falls, and positive Gowers sign. Hypo- or areflexia, mild facial weakness, high-arched palate, and neck muscle weakness were also observed. Some had upper limb involvement with scapular winging. Three index patients had a family history of the disease consistent with autosomal dominant inheritance, and each inherited the mutation from their mothers who had similar features, although milder. The mutation in the fourth proband (family D) occurred de novo. All 3 individuals in family B and the 33-year-old mother in family C had a mild reduction in forced vital capacity, suggesting respiratory involvement. Serum creatine kinase was normal in all those tested. Skeletal muscle biopsies showed variable abnormalities, including type 1 fiber uniformity, central cores, minicores, and type 1 fiber predominance. The authors noted that not all biopsies were diagnostic for central core disease and that there was intrafamilial variability. The 2 sibs in family B (ages 6 and 16 years) showed type 1 fiber uniformity and multiple minicores, whereas their mother (age 38) had type 1 fiber uniformity and central cores. In family C, an affected 3-month-old girl had uniform type 1 fibers without cores, her 3-year-old brother showed uniform type 1 fibers and classic cores, and their 33-year-old mother had type 1 fiber predominance and multiple minicores. These findings suggested that pathologic changes in the skeletal muscle can occur over time. The pathologic findings in these families were also reported by Sewry et al. (2002). Of note, a 44-year-old male (the uncle of the index case in family C) was found to carry the mutation, but was clinically unaffected. He had a son with congenital foot deformities who was not tested.
Jungbluth et al. (2007) reported a 16-year-old Asian girl with clinical features of a congenital myopathy since infancy and external ophthalmoplegia associated with a de novo heterozygous missense mutation (S4112L) in the RYR1 gene. The pregnancy was complicated by polyhydramnios and decreased fetal movements. She had neonatal hypotonia, muscle weakness, and feeding difficulties in the newborn period, followed by delayed motor development with walking at age 18 months. The disorder was progressive, and she lost the ability to stand unsupported at age 14 years. Other features included talipes equinovarus, scoliosis, dysarthria, respiratory insufficiency with recurrent respiratory infections, and swallowing difficulties requiring gastrostomy insertion at 12 years of age. She also developed mild epilepsy in childhood that was well-controlled and eventually resolved by age 13. Physical examination showed myopathic facies with extraocular weakness and generalized muscle wasting and weakness. Muscle MRI of the lower limbs showed diffuse involvement of the quadriceps and soleus with relative sparing of the rectus femoris, gracilis, and gastrocnemii. Skeletal muscle biopsy at age 1 year showed hypotrophy of type 1 fibers with centralized nuclei and no necrosis. Core-like structures were not apparent at that time, suggesting a clinical diagnosis of centronuclear myopathy, although molecular analysis excluded a mutation in the DNM2 gene (602378). However, biopsy at age 8 years showed fiber type variation, central nuclei in some fibers, and central loss of oxidative enzyme staining resembling central cores. Jungbluth et al. (2007) noted that skeletal muscle biopsy findings such as central cores and central nuclei are nonspecific and can occur in genetically distinct disorders, and that the histologic features of disorders associated with mutations in the RYR1 gene may include mixed pathologic features that may also evolve over time.
Sato et al. (2008) reported 4 unrelated Japanese children (patients 1-4), ranging from 6 months to 11 years of age, with congenital myopathy apparent since birth or early infancy. Skeletal muscle biopsy showed a pattern of uniform type 1 fibers with more than 99% of type 1 fibers; core and core-like structures were not observed. Based on the pathology, the patients were diagnosed with congenital neuromuscular disease with uniform type 1 fiber (CNMDU1). One of the patients (patient 4) had previously been reported by Tojo et al. (2000). All 4 patients reported by Sato et al. (2008) had muscle weakness, delayed motor milestones, and hypo- or areflexia. Three patients had poor sucking, but only 1 had respiratory insufficiency in the neonatal period. One had facial involvement and another had a high-arched palate. Serum creatine kinase was not elevated, and none of the patients had past or family history of malignant hyperthermia. Genetic analysis identified heterozygous mutations in the C terminus of the RYR1 gene (see, e.g., 180901.0019, 180901.0033-180901.0034) in all 4 patients. Two of the mutations had previously been reported in patients with CCD. Sato et al. (2008) noted that distinguishing CCD from CNMDU1 based on clinical features alone is difficult, and that uniform type 1 fibers on biopsy can be found in both. Younger patients may show CNMDU1, whereas older patients in the same family may show CCD, which would suggest that the 2 disorders are part of a phenotypic spectrum.
Klein et al. (2012) reported 40 patients from 35 families with myopathy associated with a heterozygous RYR1 mutation. Severity and age at onset were highly variable: onset ranged from reduced fetal movements and polyhydramnios prenatally to adult-onset muscle weakness. Although most patients could walk, only 14 could run. Bharucha-Goebel et al. (2013) identified putative heterozygous mutations in the RYR1 gene in 4 patients (7-10) from 3 unrelated families with a severe form of congenital myopathy. In some of these severe cases, there is a possibility of recessive inheritance (CMYP1B) 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).
Pattern of Muscle Involvement
Fischer et al. (2006) performed muscle CT imaging in 11 CCD patients with RYR1 mutations. All patients showed a distinct homogeneous pattern of muscle involvement, with prominent involvement of the gluteus maximus, medial and anterior compartments of the thigh muscles, and soleus and lateral gastrocnemius muscles of the lower leg. These patterns of muscle involvement differed from those observed in affected members of 2 additional families unlinked to the RYR1 locus. The results suggested genetic heterogeneity in autosomal dominant core myopathies.
Ogasawara and Nishino (2021) stated that most patients with RYR1 mutations have involvement of the vastus lateralis, adductor magnus, gracilis, and gastrocnemius muscles, with relative sparing of the rectus femoris, adductor longus, sartorius, and soleus muscles.
Clinical Variability
Jungbluth et al. (2009) reported a 77-year-old man who presented with a 5 to 10-year history of increasing difficulty maintaining an erect posture and complaint of a 'wobbly' spine. He had a stooped posture and had to use 2 sticks to stand upright. He had no weakness in the arms or legs but reported that his legs were sometimes tired. Examination did not show weakness or wasting of distal or proximal limb muscles, and muscle tone and tendon reflexes were normal. Serum creatine kinase was mildly increased. EMG showed a myopathic pattern in the lumbar and lower thoracic paraspinal muscles but normal pattern in limb muscles. Skeletal muscle biopsy from the quadriceps showed fiber size variation, increased internal nucleation, marked type 1 fiber predominance, and defined central and eccentric cores on oxidative stains. Genetic analysis revealed a heterozygous missense mutation (G40V) in the RYR1 gene. Jungbluth et al. (2009) noted that the phenotypes associated with RYR1 mutations are highly variable and suggested that genetically determined congenital muscular dystrophies with late onset may be underreported.
Matthews et al. (2018) reported a 49-year-old man (case 3) with periodic paralysis associated with a heterozygous variant in the RYR1 gene (R1043H). He reported episodes of mild muscle weakness after strenuous exercise since age 14, but had his first full attack of muscle paralysis at age 29. Medical history was notable for 2 complicated episodes regarding anesthesia in childhood, suggesting a risk for MHS. He did not have signs of a congenital myopathy. Skeletal muscle biopsy showed variation in fiber size, internal nuclei, and type 1 fiber predominance. He had a positive McManis test for periodic paralysis.
Early clinical reports of families with central core disease of muscle by Shy and Magee (1956), Bethlem et al. (1966), Isaacs et al. (1975), Eng et al. (1978), and others supported autosomal dominant inheritance.
The transmission pattern of CMYP1A in the families reported by Monnier et al. (2001) and Quinlivan et al. (2003) was consistent with autosomal dominant inheritance.
The heterozygous mutations in the RYR1 gene that were identified in some patients with CMYP1A by Quinlivan et al. (2003) and Jungbluth et al. (2007) occurred de novo.
Zhou et al. (2006) presented evidence that the RYR1 gene undergoes polymorphic, tissue-specific, and developmentally regulated allele silencing and that this can unveil recessive mutations in patients with core myopathies. Their data also suggested that imprinting is a likely mechanism for this phenomenon and that similar mechanisms can play a role in human phenotypic heterogeneity and in irregularities of inheritance patterns. Klein et al. (2012) found that some of the patients reported by Zhou et al. (2006) with apparent mutations expressed monoallelically in the skeletal muscle were found to have another stop RYR1 mutation, resulting in nonsense-mediated mRNA decay and lack of expression.
By linkage studies in the large family with congenital core disease reported by Byrne et al. (1982), Haan et al. (1990) mapped the candidate gene to chromosome 19q12-q13.2. Kausch et al. (1991) also mapped the disease locus to proximal 19q13.1 by linkage to markers.
The work of Mulley et al. (1993) supported the possibility that the mutated gene in congenital core disease is RYR1, which maps to the same region of chromosome 19. Two-point linkage analysis in the large kindred reported by Byrne et al. (1982) gave a maximum lod score of 11.8 between CCD and RYR1, with no recombination. Recombination was observed between CCD and the markers flanking RYR1.
In affected members of a large multigenerational Canadian family with CMYP1A and MHS (Shuaib et al., 1987), Zhang et al. (1993) identified a heterozygous mutation in the RYR1 gene (R2435H; 180901.0003).
In 2 Italian brothers (family 4T) with CMYP1A, Quane et al. (1993) identified a heterozygous missense mutation in the RYR1 gene (I403M; 180901.0005). The clinically unaffected father also carried the mutation; he did not undergo muscle biopsy. In 4 members of another Italian family (2T) with variable expression of CMYP1A and malignant hyperthermia, Quane et al. (1993) identified a heterozygous mutation in the RYR1 gene (R163C; 180901.0004). Of note, Quane et al. (1993) also identified the R163C mutation in a Danish family (D15) in which a mother and her 2 children had MHS without clinical signs of a myopathy and absence of cores on muscle biopsy. These findings demonstrated phenotypic variability, both within families and between families with the same mutation.
Lynch et al. (1999) studied a large Mexican kindred in which all affected members had a clinically severe and highly penetrant form of CMYP1A. Sequencing of the entire RYR1 cDNA in an affected member identified a heterozygous mutation in the C-terminal transmembrane/luminal domain of the protein (I4898T; 180901.0012). The introduction of this mutation into a recombinant RyR1 protein expressed in HEK293 cells resulted in loss of channel activation by caffeine and halothane and a significant reduction in ryanodine binding. These and additional findings, which pointed to a high basal activity of the mutant Ca(2+) channel, could explain the muscle weakness and muscle atrophy observed in CCD patients in this family.
Scacheri et al. (2000) identified a heterozygous mutation in the RYR1 gene (T4637A; 180901.0030) in affected members of a large family with CMYP1A. Skeletal muscle biopsies from 2 affected individuals showed the presence of central cores in over 85% of myofibers and nemaline rods in 5 to 25% of myofibers. Scacheri et al. (2000) suggested that nemaline bodies may be a secondary feature in this disorder.
In 5 members of a French family with CMYP1A, Monnier et al. (2000) identified a heterozygous missense mutation in the RYR1 gene (Y4796C; 180901.0016). The mutation occurred in the C-terminal channel-forming domain of the RYR1 protein. Expression of the mutant RYR1 cDNA in rabbit HEK293 cells produced channels with increased caffeine sensitivity, cells with increased resting cytoplasmic Ca(2+) levels, and a significantly reduced maximal level of Ca(2+) release, suggesting an increased rate of Ca(2+) leakage in the mutant channel. The authors hypothesized that the resulting chronic elevation in myoplasmic Ca(2+) concentration may be responsible for the severe phenotype in this family. Haplotype analysis indicated that the mutation arose de novo in the proband.
In affected members of 16 unrelated families with CMYP1A, Monnier et al. (2001) identified 12 different heterozygous missense mutations in the C-terminal domain of RYR1 (see, e.g., I4898T, 180901.0012; V2168M, 180901.0013; a 9-bp del, 180901.0018; R4861H, 180901.0019; and R4893W, 180901.0044). Since the muscle symptoms in the families suggested a defect in Ca(2+) homeostasis, the authors sequenced exons in the C-terminal channel-forming domain of RYR1, which is involved in Ca(2+) movement. V2168M occurred in exon 39, but all of the other mutations occurred in exons 91 through 102. Four de novo mutations were found, indicating that de novo mutations in RYR1 are not rare and may confound genetic studies of families that present with congenital myopathies. Functional studies of the mutations were not performed. Molecular modeling based on a 4-transmembrane domain model suggested that the mutations concentrated mostly in the myoplasmic and luminal loops linking, respectively, transmembrane domains T1 and T2 or T3 and T4 of RYR1 and may therefore affect the excitation-contraction process in skeletal muscle. The patients were ascertained from a cohort of 34 families with congenital myopathy associated with central cores on muscle biopsy who underwent genetic analysis; RYR1 mutations were found in 47% of families.
Tilgen et al. (2001) screened the C-terminal domain of the RYR1 gene for mutations in 50 European patients diagnosed clinically and/or histologically as having congenital myopathy with central cores on muscle biopsy. Five heterozygous missense mutations (see, e.g., 180901.0012 and 180901.0019) were identified in 13 of 25 index patients. The mutations clustered in exons 101 and 102 and replaced conserved amino acids. Lymphoblasts derived from patients carrying these C-terminal RYR1 mutations exhibited a release of calcium from intracellular stores in the absence of any pharmacologic activators of RYR; significantly smaller thapsigargin-sensitive intracellular calcium stores, compared to lymphoblasts from control individuals; and a normal sensitivity of the calcium release to the RYR inhibitor dantrolene. The authors suggested that the C-terminal domain of RYR1 may be a hotspot for mutations leading to the phenotype.
Zorzato et al. (2003) identified a patient with severe CMYP1A and her mother with a milder phenotype who were both heterozygous for a deletion (amino acids 4863-4869; 180901.0024) in the pore-forming region of the RYR1 gene. The deleted amino acids form part of the luminal loop connecting membrane-spanning segments M8 and M10 and are conserved in all known vertebrate RYR1 isoforms. Lymphoblastoid cells carrying the RYR1 deletion exhibited an 'unprompted' calcium release from intracellular stores, resulting in significantly smaller thapsigargin-sensitive intracellular Ca(2+) stores compared with lymphoblastoid cells from controls. Blocking the RYR1 with dantrolene restored the intracellular calcium stores to levels similar to those found in controls. Single-channel and [3H]ryanodine-binding measurements in HEK293 cells heterologously expressing mutant channels revealed a reduced ion conductance and loss of ryanodine binding and regulation by Ca(2+).
In 11 patients from 4 unrelated families with CMYP1A, Quinlivan et al. (2003) identified heterozygous mutations in the RYR1 gene (see, e.g., R4861H, 180901.0019; R4893W, 180901.0044; and Y4864C, 180901.0045). All mutations occurred in region 3 of the RYR1 gene. The mutation was inherited in an autosomal dominant pattern in 3 families (families A, B, and C), whereas the mutation occurred de novo in the proband from family D.
In 4 unrelated Japanese patients with CMYP1A and a pathologic diagnosis of CNMDU1, Sato et al. (2008) identified heterozygous mutations in the RYR1 gene (see, e.g., 180901.0019, 180901.0033-180901.0034). The father of 1 patient had the same mutation as his son (180901.0033) and was diagnosed with CCD (Wu et al., 2006; Tojo et al., 2000), indicating that RYR1 mutations can cause variable findings on skeletal muscle biopsy.
Klein et al. (2012) noted that dominant RYR1 mutations involved in CMYP1A are mostly confined to the C-terminal region of the gene, particularly region 3, whereas mutations involved in MHS1 are mostly detected in regions 1 and 2 within the N terminus. Most dominant mutations are missense.
Shy and Magee (1956) first described a type of congenital myopathy that was nonprogressive in a large family in which 5 individuals in 5 different sibships spanning 3 generations were affected. Some patients presented with hypotonia in infancy, referred to as the 'floppy infant.' Central cores were identified in skeletal muscle biopsies, although the pathologic name was not given until later.
Bethlem et al. (1966) described a nonprogressive myopathy in 3 females of 3 successive generations. The father of the earliest patient may have been affected. Histologic findings of central core disease were found. Muscle cramps followed exercise and no hypotonia was present in infancy, features different from previously reported cases of central core disease. Creatine excretion in the urine was greatly increased. Creatine kinase and oxidative phosphorylation in the muscles were normal. Bethlem et al. (1978) restudied this family (family A), noting that there was another affected female.
Dubowitz and Roy (1970) described 4 cases in 3 generations. The disorder consisted of slowly progressive weakness after the age of 5 years, resembling limb girdle muscular dystrophy. Only type 1 muscle fibers showed central cores. Isaacs et al. (1975) studied a South African kindred with affected members spanning 5 successive generations. Eng et al. (1978) observed autosomal dominant transmission through 5 generations with 2 skips in a kindred ascertained through a child with malignant hyperthermia (MHS; 145600).
Frank et al. (1978) noted that 4 families with central core disease and malignant hyperthermia had been described and added another familial instance of the combination. Creatine kinase blood levels were increased. In vitro muscle contraction studies with caffeine and halothane identified those susceptible to malignant hyperthermia. (See also Frank et al., 1980).
Gamstorp (1982) stated that this disorder is rare in Scandinavia. She described the case of a girl who at age 2 was found to be clumsy and to have weak hip muscles. Her facial expression was normal. The father 'had never been able to carry a heavy burden upstairs' and he was unable to sit up on a chair without the help of his hands. Muscle biopsy showed central core disease in the father as well as in the daughter, whose disorder had remained stationary to age 8 years.
Koch et al. (1985) described the case of a child with minimulticore findings on biopsy who had been hypotonic from birth, developed cardiac failure at age 2.5 years, and died of malignant hyperthermia 26 hours after cardiac catheterization during which lidocaine and ketamine were given.
Paljarvi et al. (1987) suggested autosomal dominant inheritance of minicore myopathy in a mother and son with nonprogressive weakness of both proximal and distal muscles. Paljarvi et al. (1987) pointed to 3 other reported families with multiminicore myopathy with a pattern of inheritance suggesting autosomal dominance. These included a father and 2 sons, all 3 of whom also had cardiomyopathy (Bender, 1979); mother, son, and granddaughter (Bethlem et al., 1978); and mother and 2 daughters (Vanneste and Stam, 1982).
Afifi, A. K., Smith, J. W., Zellweger, H. Congenital nonprogressive myopathy. Central core disease and nemaline myopathy in one family. Neurology 15: 371-381, 1965. [PubMed: 14280602] [Full Text: https://doi.org/10.1212/wnl.15.4.371]
Bender, A. N. Congenital myopathies. In: Vinken, P. J.; Bruyn, G. W. (eds.): Handbook of Clinical Neurology. Diseases of Muscle. Part II. Vol. 41. Amsterdam: North Holland (pub.) 1979. Pp. 1-26.
Bethlem, J., Arts, W. F., Dingemans, K. P. Common origin of rods, cores, miniature cores and focal loss of cross striations. Arch. Neurol. 35: 555-566, 1978. [PubMed: 687182] [Full Text: https://doi.org/10.1001/archneur.1978.00500330003002]
Bethlem, J., Van Gool, J., Hulsmann, W. C., Meijer, A. E. F. H. Familial nonprogressive myopathy with muscle cramps after exercise: a new disease associated with cores in the muscle fibres. Brain 89: 569-588, 1966. [PubMed: 4224150] [Full Text: https://doi.org/10.1093/brain/89.3.569]
Bharucha-Goebel, D. X., Santi, M., Medne, L., Zukosky, K., Dastgir, J., Shieh, P. B., Winder, T., Tennekoon, G., Finkel, R. S., Dowling, J. J., Monnier, N., Bonnemann, C. G. Severe congenital RYR1-associated myopathy: the expanding clinicopathologic and genetic spectrum. Neurology 80: 1584-1589, 2013. Note: Erratum: Neurology 80: 2081 only, 2013. [PubMed: 23553484] [Full Text: https://doi.org/10.1212/WNL.0b013e3182900380]
Byrne, E., Blumbergs, P. C., Hallpike, J. F. Central core disease: study of a family with five affected generations. J. Neurol. Sci. 53: 77-83, 1982. [PubMed: 7057203] [Full Text: https://doi.org/10.1016/0022-510x(82)90081-8]
Dubowitz, V., Roy, S. Central core disease of muscle: clinical, histochemical and electron microscopic studies of an affected mother and child. Brain 93: 133-146, 1970. [PubMed: 5418397] [Full Text: https://doi.org/10.1093/brain/93.1.133]
Eng, G. D., Epstein, B. S., Engel, W. K., McKay, D. W., McKay, R. Malignant hyperthermia and central core disease in a child with congenital dislocating hips: case presentation and review. Arch. Neurol. 35: 189-197, 1978. [PubMed: 637752] [Full Text: https://doi.org/10.1001/archneur.1978.00500280007002]
Engel, W. K., Foster, J. B., Hughes, B. P., Huxley, H. E., Mahler, R. Central core disease--an investigation of a rare muscle cell abnormality. Brain 84: 167-185, 1961. [PubMed: 13696813] [Full Text: https://doi.org/10.1093/brain/84.2.167]
Fischer, D., Herasse, M., Ferreiro, A., Barragan-Campos, H. M., Chiras, J., Viollet, L., Maugenre, S., Leroy, J.-P., Monnier, N., Lunardi, J., Guicheney, P., Fardeau, M., Romero, N. B. Muscle imaging in dominant core myopathies linked or unlinked to the ryanodine receptor 1 gene. Neurology 67: 2217-2220, 2006. [PubMed: 17190947] [Full Text: https://doi.org/10.1212/01.wnl.0000249151.45200.71]
Frank, J. P., Harati, Y., Butler, I. J., Nelson, T. E., Scott, C. I. Central core disease and malignant hyperthermia syndrome. Ann. Neurol. 7: 11-17, 1980. [PubMed: 7362206] [Full Text: https://doi.org/10.1002/ana.410070105]
Frank, J. P., Harati, Y., Butler, I. J., Scott, C. I., Jr. Central core disease (CCD) and the malignant hyperthermia syndrome (MHS). (Abstract) Am. J. Hum. Genet. 30: 51A only, 1978.
Gadoth, N., Margalit, D., Shapira, Y. Myopathy with multiple central cores: a case with hypersensitivity to pyrexia. Neuropadiatrie 9: 239-244, 1978. [PubMed: 581399] [Full Text: https://doi.org/10.1055/s-0028-1091484]
Gamstorp, I. Non-dystrophic, myogenic myopathies with onset in infancy or childhood: a review of some characteristic syndromes. Acta Paediat. Scand. 71: 881-886, 1982. [PubMed: 6760662] [Full Text: https://doi.org/10.1111/j.1651-2227.1982.tb09543.x]
Haan, E. A., Freemantle, C. J., McCure, J. A., Friend, K. L., Mulley, J. C. Assignment of the gene for central core disease to chromosome 19. Hum. Genet. 86: 187-190, 1990. [PubMed: 2265831] [Full Text: https://doi.org/10.1007/BF00197703]
Isaacs, H., Heffron, J. J. A., Badenhorst, M. Central core disease: a correlated genetic, physiochemical, ultramicroscopic, and biochemical study. J. Neurol. Neurosurg. Psychiat. 38: 1177-1186, 1975. [PubMed: 130467] [Full Text: https://doi.org/10.1136/jnnp.38.12.1177]
Jungbluth, H., Lillis, S., Zhou, H., Abbs, S., Sewry, C., Swash, M., Muntoni, F. Late-onset axial myopathy with cores due to a novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromusc. Disord. 19: 344-347, 2009. [PubMed: 19303294] [Full Text: https://doi.org/10.1016/j.nmd.2009.02.005]
Jungbluth, H., Zhou, H., Sewry, C. A., Robb, S., Treves, S., Bitoun, M., Guicheney, P., Buj-Bello, A., Bonnemann, C., Muntoni, F. Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromusc. Disord. 17: 338-345, 2007. [PubMed: 17376685] [Full Text: https://doi.org/10.1016/j.nmd.2007.01.016]
Kausch, K., Lehmann-Horn, F., Janka, M., Wieringa, B., Grimm, T., Muller, C. R. Evidence for linkage of the central core disease locus to the proximal long arm of human chromosome 19. Genomics 10: 765-769, 1991. [PubMed: 1889818] [Full Text: https://doi.org/10.1016/0888-7543(91)90461-m]
Klein, A., Lillis, S., Munteanu, I., Scoto, M., Zhou, H., Quinlivan, R., Straub, V., Manzur, A. Y., Roper, H., Jeannet, P-Y., Rakowicz, W., Jones, D. H., and 20 others. Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies. Hum. Mutat. 33: 981-988, 2012. Note: Erratum: Hum. Mutat. 33: 2012. [PubMed: 22473935] [Full Text: https://doi.org/10.1002/humu.22056]
Koch, B. M., Bertorini, T. E., Eng, G. D., Boehm, R. Severe multicore disease associated with reaction to anesthesia. Arch. Neurol. 42: 1204-1206, 1985. [PubMed: 4062619] [Full Text: https://doi.org/10.1001/archneur.1985.04060110086024]
Lynch, P. J., Tong, J., Lehane, M., Mallet, A., Giblin, L., Heffron, J. J. A., Vaughan, P., Zafra, G., MacLennan, D. H., McCarthy, T. V. A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca(2+) release channel function and severe central core disease. Proc. Nat. Acad. Sci. 96: 4164-4169, 1999. [PubMed: 10097181] [Full Text: https://doi.org/10.1073/pnas.96.7.4164]
Matthews, E., Neuwirth, C., Jaffer, F., Scalco, R. S., Fialho, D., Parton, M., Rayan, D. R., Suetterlin, K., Sud, R., Spiegel, R., Mein, R., Houlden, H., Schaefer, A., Healy, E., Palace, J., Quinlivan, R., Treves, S., Holton, J. L., Jungbluth, H., Hanna, M. G. Atypical periodic paralysis and myalgia: a novel RYR1 phenotype. Neurology 90: e412-e418, 2018. Note: Electronic Article. [PubMed: 29298851] [Full Text: https://doi.org/10.1212/WNL.0000000000004894]
Monnier, N., Romero, N. B., Lerale, J., Landrieu, P., Nivoche, Y., Fardeau, M., Lunardi, J. Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor. Hum. Molec. Genet. 10: 2581-2592, 2001. [PubMed: 11709545] [Full Text: https://doi.org/10.1093/hmg/10.22.2581]
Monnier, N., Romero, N. B., Lerale, J., Nivoche, Y., Qi, D., MacLennan, D. H., Fardeau, M., Lunardi, J. An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum. Molec. Genet. 9: 2599-2608, 2000. [PubMed: 11063719] [Full Text: https://doi.org/10.1093/hmg/9.18.2599]
Mulley, J. C., Kozman, H. M., Phillips, H. A., Gedeon, A. K., McCure, J. A., Iles, D. E., Gregg, R. G., Hogan, K., Couch, F. J., MacLennan, D. H., Haan, E. A. Refined genetic localization for central core disease. Am. J. Hum. Genet. 52: 398-405, 1993. [PubMed: 8430700]
Ogasawara, M., Nishino, I. A review of core myopathy: central core disease, multiminicore disease, dusty core disease, and core-rod myopathy. Neuromusc. Disord. 31: 968-977, 2021. [PubMed: 34627702] [Full Text: https://doi.org/10.1016/j.nmd.2021.08.015]
Paljarvi, L., Kalimo, H., Lang, H., Savontaus, M.-L., Sonninen, V. Minicore myopathy with dominant inheritance. J. Neurol. Sci. 77: 11-22, 1987. [PubMed: 3806134] [Full Text: https://doi.org/10.1016/0022-510x(87)90202-4]
Patterson, V. H., Hill, T. R. G., Fletcher, P. J. H., Heron, J. R. Central core disease: clinical and pathological evidence of progression within a family. Brain 102: 581-594, 1979. [PubMed: 497805] [Full Text: https://doi.org/10.1093/brain/102.3.581]
Quane, K. A., Healy, J. M. S., Keating, K. E., Manning, B. M., Couch, F. J., Palmucci, L. M., Doriguzzi, C., Fagerlund, T. H., Berg, K., Ording, H., Bendixen, D., Mortier, W., Linz, U., Muller, C. R., McCarthy, T. V. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nature Genet. 5: 51-55, 1993. [PubMed: 8220423] [Full Text: https://doi.org/10.1038/ng0993-51]
Quinlivan, R. M., Muller, C. R., Davis, M., Laing, N. G., Evans, G. A., Dwyer, J., Dove, J., Roberts, A. P., Sewry, C. A. Central core disease: clinical, pathological, and genetic features. Arch. Dis. Child. 88: 1051-1055, 2003. [PubMed: 14670767] [Full Text: https://doi.org/10.1136/adc.88.12.1051]
Sato, I., Wu, S., Ibarra, M. C. A., Hayashi, Y. K., Fujita, H., Tojo, M., Oh, S. J., Nonaka, I., Noguchi, S., Nishino, I. Congenital neuromuscular disease with uniform type 1 fiber and RYR1 mutation. Neurology 70: 114-122, 2008. [PubMed: 17538032] [Full Text: https://doi.org/10.1212/01.wnl.0000269792.63927.86]
Scacheri, P. C., Hoffman, E. P., Fratkin, J. D., Semino-Mora, C., Senchak, A., Davis, M. R., Laing, N. G., Vedanarayanan, V., Subramony, S. H. A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy. Neurology 55: 1689-1696, 2000. [PubMed: 11113224] [Full Text: https://doi.org/10.1212/wnl.55.11.1689]
Sewry, C. A., Muller, C., Davis, M., Dwyer, J. S. M., Dove, J., Evans, G., Schroder, R., Furst, D., Helliwell, T., Laing, N., Quinlivan, R. C. M. The spectrum of pathology in central core disease. Neuromusc. Disord. 12: 930-938, 2002. [PubMed: 12467748] [Full Text: https://doi.org/10.1016/s0960-8966(02)00135-9]
Shuaib, A., Paasuke, R. T., Brownell, K. W. Central core disease: clinical features in 13 patients. Medicine (Baltimore) 66: 389-396, 1987. [PubMed: 3626847]
Shy, G. M., Engel, W. K., Wanko, T. Central core disease: a myofibrillary and mitochondrial abnormality of muscle. Ann. Intern. Med. 56: 511-520, 1962.
Shy, G. M., Magee, K. R. A new congenital non-progressive myopathy. Brain 79: 610-621, 1956. [PubMed: 13396066] [Full Text: https://doi.org/10.1093/brain/79.4.610]
Tilgen, N., Zorzato, F., Halliger-Keller, B., Muntoni, F., Sewry, C., Palumucci, L. M., Schneider, C., Hauser, E., Lehmann-Horn, F., Muller, C. R., Treves, S. Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis. Hum. Molec. Genet. 10: 2879-2887, 2001. [PubMed: 11741831] [Full Text: https://doi.org/10.1093/hmg/10.25.2879]
Tojo, M., Ozawa, M., Nonaka, I. Central core disease and congenital neuromuscular disease with uniform type 1 fibers in one family. Brain Dev. 22: 262-264, 2000. [PubMed: 10838116] [Full Text: https://doi.org/10.1016/s0387-7604(00)00108-x]
Vanneste, J. A. L., Stam, F. C. Autosomal dominant multicore disease. J. Neurol. Neurosurg. Psychiat. 45: 360-365, 1982. [PubMed: 7077346] [Full Text: https://doi.org/10.1136/jnnp.45.4.360]
Wu, S., Ibarra M, C. A., Malicdan, M. C. V., Murayama, K., Ichihara, Y., Kikuchi, H., Nonaka, I., Noguchi, S., Hayashi, Y. K., Nishino, I. Central core disease is due to RYR1 mutations in more than 90% of patients. Brain 129: 1470-1480, 2006. [PubMed: 16621918] [Full Text: https://doi.org/10.1093/brain/awl077]
Zhang, Y., Chen, H. S., Khanna, V. K., De Leon, S., Phillips, M. S., Schappert, K., Britt, B. A., Brownell, A. K. W., MacLennan, D. H. A mutation in the human ryanodine receptor gene associated with central core disease. Nature Genet. 5: 46-50, 1993. [PubMed: 8220422] [Full Text: https://doi.org/10.1038/ng0993-46]
Zhou, H., Brockington, M., Jungbluth, H., Monk, D., Stanier, P., Sewry, C. A., Moore, G. E., Muntoni, F. Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies. Am. J. Hum. Genet. 79: 859-868, 2006. [PubMed: 17033962] [Full Text: https://doi.org/10.1086/508500]
Zorzato, F., Yamaguchi, N., Xu, L., Meissner, G., Muller, C. R., Pouliquin, P., Muntoni, F., Sewry, C., Girard, T., Treves, S. Clinical and functional effects of a deletion in a COOH-terminal lumenal loop of the skeletal muscle ryanodine receptor. Hum. Molec. Genet. 12: 379-388, 2003. [PubMed: 12566385] [Full Text: https://doi.org/10.1093/hmg/ddg032]