Alternative titles; symbols
ICD10CM: G71.29; ORPHA: 598, 98905; DO: 0080991;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.2 | Congenital myopathy 1B, autosomal recessive | 255320 | Autosomal recessive | 3 | RYR1 | 180901 |
A number sign (#) is used with this entry because of evidence that autosomal recessive congenital myopathy-1B (CMYO1B) is caused by homozygous or compound heterozygous mutation in the RYR1 gene (180901) on chromosome 19q13.
Heterozygous mutation in the RYR1 gene causes autosomal dominant CMYO1A (117000), which shows clinical overlap with CMYO1B, but is less severe.
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).
Engel et al. (1971) first reported multiminicore myopathy in 2 affected sibs. The disorder was a congenital myopathy associated with multifocal degeneration of muscle fibers on pathologic examination.
Bethlem et al. (1978) noted external ophthalmoplegia in 2 sibs (family C, patients 7 and 8) in whom muscle biopsies showed both multicores and focal loss of cross-striations. The family was also reported by Van Wijngaarden et al. (1977).
Swash and Schwartz (1981) reported 2 brothers and a sister with a congenital myopathy characterized clinically by proximal weakness and external ophthalmoplegia and histologically by multicores and areas of focal loss of cross-striations in skeletal muscles. Both brothers showed highly arched palate. One brother, more severely affected than the other, developed respiratory failure in association with Mycoplasma pneumonia at age 14 years, and required mechanical ventilation for 3 days. Two other sisters and both parents were clinically normal. Swash and Schwartz (1981) noted the similarities to the phenotype described by Bethlem et al. (1978). Swash and Schwartz (1981) pointed out that previously reported patients in whom ophthalmoplegia was associated with core-like lesions all had focal loss of cross-striations as a prominent feature, with or without multicores (Engel et al., 1971; Van Wijngaarden et al., 1977; Bethlem et al., 1978), as in their patients. The authors regarded this disorder as a genetically distinct subtype of multicore disease.
Among 19 cases of minicore myopathy, Jungbluth et al. (2000) reported 2 with complete external ophthalmoplegia and a severe phenotype, including hypotonia and facial, axial, and proximal weakness.
Among 38 patients with histologically proven minicore myopathy, Ferreiro et al. (2000) reported 3 who had an antenatal-onset form with congenital generalized arthrogryposis, which the authors suggested was a distinct subtype of multiminicore disease. Other features included dolichocephaly, prominent nasal root, oblique palpebral fissures, high-arched palate, low-set ears, and short neck with mild pterygium colli. Two brothers also had a bell-shaped thorax, clinodactyly, bilateral cryptorchidism, and a single palmar crease. All 3 patients had moderate predominantly axial muscle weakness, early severe kyphosis or kyphoscoliosis, and reduced respiratory vital capacity.
Ferreiro et al. (2002) reported 3 affected members of a consanguineous Algerian family with CMYO1B manifest pathologically as central core disease transiently presenting as minicore myopathy. The 3 children presented in infancy with moderate weakness predominantly in axial muscles, pelvic girdle, and hands, joint hyperlaxity, and multiple minicores on skeletal muscle biopsy. Muscle biopsies from the 3 patients in adulthood demonstrated typical central core disease with rods; no cores were found in the healthy parents. Genetic analysis identified a homozygous mutation in the RYR1 gene (P3527S; 180901.0021). The family represented the first variant of central core disease with genetically proven recessive inheritance and transient presentation as minicore myopathy.
During an international workshop on multiminicore disease, Ferreiro and Fardeau (2002) reported 4 patients with external ophthalmoplegia of variable severity in addition to a generalized muscle involvement similar to the classic form of the disease. In this group, facial weakness, especially in the lower face, was severe.
Jungbluth et al. (2002) reported a 19-year-old girl, born of consanguineous parents, with CMYO1B manifest as central core disease on muscle biopsy. She presented at 4 years of age with moderate proximal weakness and mild scoliosis. She had weakness of the hip girdle, scoliosis, lumbar lordosis, and Achilles tendon contractures. Facial weakness was not noted. Skeletal muscle biopsy showed variability in fiber size, increased internal nuclei, a few rodlike structures, and multiple minicores and cores.
Monnier et al. (2003) reported a 17-year-old Tunisian boy, born of consanguineous parents, with CMYO1B with cores and multiminicores on skeletal muscle biopsy. He had neonatal hypotonia, delayed motor development with walking at age 3 years, generalized muscle weakness and amyotrophy with loss of ambulation at 12 years of age, respiratory insufficiency, scoliosis, facial dysmorphism, thorax deformity, and ocular paresis. Serum creatine kinase was normal.
Jungbluth et al. (2005) reported 11 individuals from 5 families with CMYO1B manifest as multiminicore disease and external ophthalmoplegia. One of the families (family 2) had previously been reported by Swash and Schwartz (1981). All patients showed a fairly homogeneous clinical phenotype with onset of marked generalized hypotonia and weakness in the neonatal period or early infancy associated with feeding and respiratory difficulties. Two patients from 1 family exhibited prenatal symptoms with reduced fetal movements, polyhydramnios, and hydrops. Most showed delayed motor development and difficulty running in childhood; some patients also reported limited walking distances. Patients showed muscle wasting of the neck and shoulder girdle muscles; weakness was most pronounced in the axial and proximal versus distal muscle groups. External ophthalmoplegia predominantly affected upward and lateral gaze. Weakness was exacerbated by cold in 6 patients. Other features included ligamentous laxity, moderate scoliosis, and moderately impaired respiratory function. Serum creatine kinase was normal. Skeletal muscle biopsies showed nonspecific myopathic changes with variability in fiber size and increased central nucleation. Both type 1 and 2 fibers showed multiple and single core lesions that extended the full fiber diameter but often did not run for the entire longitudinal axis. There was focal loss of cross-striations and disorganization of the normal myofibrillar pattern. Leg muscle MRI of 5 patients showed relative sparing of the gracilis and gastrocnemii compared to the sartorius and soleus, respectively.
Monnier et al. (2008) reported 9 unrelated nonconsanguineous families in which affected individuals had a severe recessive form of congenital myopathy resulting from biallelic mutations in the RYR1 gene. The clinical presentation was variable: 4 probands showed very severe neonatal hypotonia associated with major respiratory problems, whereas 5 other probands had a comparably intermediate or moderate phenotype. All documented patients had involvement of extraocular muscles, and other variable features included facial diplegia, amyotrophy, scoliosis, kyphosis, and joint contractures. Skeletal biopsies showed core lesions whose size and aspect ranged from small to large diffuse cores that extended various distances in the longitudinal axis. One of the affected males with neonatal onset showed mild intermittent 3-methylglutaconic aciduria, a nonspecific finding. All patients were found to have at least 1 null RYR1 allele in compound heterozygosity with another pathogenic mutation (see, e.g., 180901.0022 and 180901.0032), reflecting a critical functional decrease below 50% for the RYR1 protein. All heterozygous carriers were clinically unaffected.
Monnier et al. (2009) reported a newborn male with global hypotonia, total immobility of all 4 limbs, a frog position, and feeding difficulties. He had generalized muscle weakness affecting axial and facial muscles, resulting in amimia and difficulty in opening his eyes. There was mild distal arthrogryposis but no craniofacial abnormalities. He had progressive respiratory failure and died at age 2 months. Skeletal muscle biopsy showed fiber size variability, with internal nuclei in about 10% of fibers, and strong type 1 fiber predominance, corresponding to congenital fiber-type disproportion. Although no definite cores were present, focal, ill-defined lack of oxidative activity was observed, which could be interpreted as atypical cores. Electron microscopy showed focal loss of myofibrils and small foci of sarcomeric disorganization with Z-band streaming. The diagnosis was atypical multiminicore myopathy. Molecular analysis identified compound heterozygosity for 2 mutations in the RYR1 gene, 1 of which was a large genomic deletion. Each unaffected parent was heterozygous for 1 of the mutations.
Wilmshurst et al. (2010) reported 17 patients from unrelated nonconsanguineous families with CMYO1B and a clinicopathologic diagnosis of centronuclear myopathy associated with RYR1 mutations. Twelve were from South Africa and 5 from European countries. All except 1 had onset from birth of neonatal hypotonia and weakness, and most had feeding difficulties. Decreased fetal movements were often reported. Clinical features included delayed motor development, achievement of sitting or walking only, extraocular muscle involvement, proximal muscle weakness, and frequent respiratory infections. Eight achieved sitting only, 8 achieved walking only, and 1 achieved neither. Bulbar involvement was also common, and 3 required gastrostomy. Three patients had scoliosis. All patients had a similar appearance, with myopathic facies, inverted V-shaped mouth, and ptosis. Skeletal muscle biopsies showed about 10% fibers with central nuclei and type 1 fiber predominance. There was also type 2 hypertrophy with fiber-type disproportion. None had core-like structures on early biopsies, but 2 of 3 patients with follow-up developed mild central or minicores. In addition, most biopsies showed central accumulation of oxidative abnormalities. Electron microscopic studies showed Z-line streaming, and 5 had apparent core-like structures. Wilmshurst et al. (2010) noted the phenotypic overlap with the patients reported by Jungbluth et al. (2007) and Monnier et al. (2008).
Clarke et al. (2010) identified compound heterozygous RYR1 mutations in 5 affected members of 4 families with a congenital myopathy characterized by congenital fiber-type disproportion (CFTD) on muscle biopsy. All patients presented at birth or in early childhood with severe muscle weakness and variable but generalized features of myopathy, including myopathic facies, ophthalmoplegia, high-arched palate, and respiratory insufficiency. Patient 1 had generalized hypotonia from birth, delayed motor development, muscle wasting, ophthalmoplegia, and facial weakness. He required nocturnal CPAP and gastrostomy tube; he died of respiratory failure at 3 years of age. Patient 2 had severe hypotonia and respiratory insufficiency from birth, frog-leg posture, poor antigravity movements, external ophthalmoplegia, ptosis, and weak cry. He was intubated at 26 days of life, but died at age 1 month following extubation. Serum creatine kinase was normal. Patient 3 was a 29-year-old man with generalized hypotonia from birth, poor feeding, delayed walking, and inability to run. He was thin with generalized muscle wasting and showed a long thin face, ptosis, ophthalmoplegia, strabismus, facial weakness, high-arched palate, and reduced mouth opening. Other features included scoliosis, Achilles tendon contractures, hip flexion contractures, and decreased forced vital capacity. Serum creatine kinase was normal. Patients 4 and 5 were sibs, aged 18 and 12 years, who presented in infancy or early childhood with difficulty walking and running due to proximal muscle weakness of the lower limbs. Other variable features included generalized muscle hypotrophy, positive Gowers sign, mild facial weakness with ptosis, mild scapular winging, and mild scoliosis. Neither had ophthalmoplegia or contractures, and serum creatine kinase was normal. MRI from patient 4 at age 12 years showed involvement of the gluteus maximus, vastus lateralis, adductor magnus, and soleus muscles, with sparing of the rectus femoris, semitendinosus, gracilis, tibialis anterior, and gastrocnemius muscles. Skeletal muscle biopsy in all patients was consistent with a pathologic diagnosis of CFTD with type 1 fiber hypotrophy relative to type 2 fibers, and without core or rod structures. Additional pathologic features included internalized nuclei and myofibrillar disarray. All patients carried 1 null RYR1 mutation and 1 missense mutation. None of the parents were clinically unaffected, except for 1 mother who had unilateral ptosis. There was no family history of malignant hyperthermia in these individuals, although the authors noted that since heterozygous RYR1 missense mutations in particular may confer susceptibility, standard malignant hyperthermia precautions should be taken during anesthesia, and in vitro contractility tests conducted, in patients with autosomal recessive CFTD. Clarke et al. (2010) concluded that RYR1 mutations are a relatively common cause of congenital myopathy with CFTD.
Kondo et al. (2012) reported a Japanese male infant with severe congenital myopathy associated with compound heterozygous mutations in the RYR1 gene. The fetal period was complicated by nuchal translucency, fetal akinesia, and polyhydramnios. After birth, he showed generalized hypotonia, cyanosis, and bradycardia, necessitating intubation. He was noted to have a narrow face with facial muscle weakness, high-arched palate, ophthalmoplegia, and frog-leg posturing. Other features included micropenis, hypoplastic scrotum, and cryptorchidism. Although he had severe growth retardation in infancy, he later caught up to normal parameters. However, he had no ocular or swallowing movement. At age 1 year 9 months he showed an expressive face and some active limb movement, but he was mechanically ventilated and could not sit or speak. He showed some social development. Muscle biopsy showed cytoplasmic nemaline bodies and very small type 1 fibers, which were the predominant fiber type (71%). Central cores or minicores were not observed. The RYR1 mutations were identified by massively parallel sequencing and confirmed by Sanger sequencing; each unaffected parent was heterozygous for 1 of the mutations. Kondo et al. (2012) commented that RYR1 mutations are usually not associated with the pathologic finding of nemaline rods, but that congenital myopathies can be heterogeneous in presentation.
Klein et al. (2012) described 46 patients from 36 families with a congenital myopathy associated with biallelic RYR1 mutations, consistent with autosomal recessive inheritance. All patients with recessive mutations presented within the first 10 years of life, most at birth or prenatally. All had proximal weakness, some had distal weakness, and most had axial and facial weakness. More variable features included feeding difficulties and extraocular muscle involvement. Skeletal muscle biopsies tended to show type 1 fiber predominance or uniformity and core-like lesions; a few showed minicores. Klein et al. (2012) concluded that biallelic RYR1 mutations are at least as frequent as heterozygous mutations, and that there is marked variability in the clinical and pathologic features of RYR1-associated myopathies.
Bharucha-Goebel et al. (2013) reported 7 patients with severe CMYO1B due to recessive mutations in the RYR1 gene. Most had symptoms noted in utero, including decreased fetal movements, polyhydramnios, and intrauterine growth restriction. Variable features present at birth included hypotonia, feeding difficulties, arthrogryposis, hip dislocation, and respiratory insufficiency. Other variable features included kyphoscoliosis, cleft palate, rigid spine, and ophthalmoparesis. All patients had delayed motor milestones, but none showed evidence of intellectual impairment. Skeletal muscle biopsies were highly variable, showing fibrosis, small fibers, nonspecific myopathic changes, and a predominance of type 1 fibers, with or without ill-defined cores. Imaging tended to show sparing of the rectus femoris muscle. There were no genotype/phenotype correlations, and functional studies of the variants were not performed.
Lethal Fetal Akinesia Phenotype
McKie et al. (2014) reported 3 unrelated consanguineous families with recurrent fetal akinesia resulting in termination of pregnancy or lethality in utero. The families were of Dutch, Pakistani, and Palestinian descent, respectively. Prenatal ultrasounds showed fetal akinesia, joint contractures, and increased nuchal translucency. Postmortem examination showed arthrogryposis, lung hypoplasia, cystic hygroma, and often clubfoot. Some affected fetuses had pterygia and/or dysmorphic facial features, such as hypertelorism, downslanting palpebral fissures, low-set ears, and cleft palate. Intrauterine growth was not restricted. Skeletal muscle biopsies of 2 affected sibs showed fiber loss, increased fiber size variability, increased endomysial spacing with fibrosis, and tendency toward hypotrophy of type 1 fibers. Ultrastructural examination showed muscle fiber hypotrophy with myofibrillar disarray and Z-disc loss.
Clinical Variability
Matthews et al. (2018) reported 2 unrelated patients (cases 1 and 2) with periodic paralysis associated with compound heterozygous variants in the RYR1 gene. Case 1 was a 54-year-old man with a history of congenital myopathy since infancy who developed periodic paralysis at age 34 years. He had a waddling gait, long thin face, high-arched palate, lordosis, decreased reflexes, and ophthalmoplegia. Skeletal muscle biopsy showed some core-like structures. The McManis test for periodic paralysis was positive. Case 2 was a 42-year-old Swiss woman with a history of intermittent muscle weakness since age 23. She did not have features of a myopathy, EMG and muscle biopsy were normal, and the McManis test was negative.
The transmission pattern of CMYO1B in the family reported by Monnier et al. (2003) was consistent with autosomal recessive inheritance.
Cases of congenital myopathy with cores consistent with autosomal recessive inheritance have been reported (Manzur et al., 1998, Ferreiro et al., 2002, Jungbluth et al., 2002).
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.
Wilmshurst et al. (2010) identified 3 recurrent RYR1 mutations in patients with CMYO1B from South Africa (180901.0035-180901.0037). Haplotype analysis suggested founder effects.
Zhou et al. (2013) found that levels of mutant RYR1 transcripts and protein were decreased in skeletal muscle from patients with recessive RYR1 mutations. Although mRNA levels of CACNA1S (114208), the alpha subunit of the dihydropyridine receptor (DHPR) were normal, there were decreased protein levels of DHPR in patient muscle, as well as disruption of DHPR-RYR1 colocalization in skeletal muscle. Human myoblasts transfected with RYR1 siRNA confirmed that knockdown of RYR1 downregulates not only the DHPR, but also the expression of other proteins involved in excitation-contraction (EC) coupling. These changes were also paralleled by the upregulation of all 3 inositol-1,4,5-triphosphate receptors (ITPR1, 147265; ITPR2, 600144; ITPR3, 147267). However, upregulation of the ITPR calcium channels did not compensate for the lack of RYR1-mediated calcium release. The results suggested that RYR1 deficiency can cause EC uncoupling and alter the expression pattern of several proteins involved in calcium homeostasis, which may influence the manifestation of these diseases.
In affected members of a consanguineous Algerian family with CMYO1B, Ferreiro et al. (2002) identified a homozygous missense mutation in the RYR1 gene (P3527S; 180901.0021).
In a 19-year-old girl, born of consanguineous parents (family 1), with CMYO1B, Jungbluth et al. (2002) identified a homozygous missense mutation in the RYR1 gene (V4849I; 180901.0022). In a 9-year-old girl, born of consanguineous parents, with autosomal recessive CMYO1B and central core disease on muscle biopsy, Kossugue et al. (2007) identified a homozygous V4849I substitution in the RYR1 gene.
Monnier et al. (2003) and Jungbluth et al. (2005) identified biallelic mutations in the RYR1 gene (see, e.g., 180901.0025-180901.0029) in patients with CMYO1B manifest as minicore myopathy with external ophthalmoplegia.
Monnier et al. (2008) reported a 9-year-old Dutch boy with a severe autosomal recessive myopathy with ptosis and facial diplegia associated with compound heterozygous mutations in the RYR1 gene: V4849I and a 4-bp insertion (180901.0032). Monnier et al. (2008) postulated that since the patient had a hypomorphic frameshift RYR1 allele, the resultant phenotype was more severe compared to those patients with homozygous V4849I mutations.
In 17 unrelated patients with CMYO1B and a clinicopathologic diagnosis of centronuclear myopathy (CNM), Wilmshurst et al. (2010) identified mutations in the RYR1 gene (see, e.g., 180901.0035-180901.0037). Compound heterozygosity for a nonsense and missense mutation was found in all except 3 patients, in whom a second pathogenic allele could not be found. Twelve of the patients were from South Africa, and haplotype analysis suggested founder effects for some of the mutant alleles. The 17 patients were ascertained from a larger group of 24 patients with a diagnosis of CNM, indicating that RYR1 mutations can account for this subtype of myopathy.
In affected fetuses from 3 families with CMYO1B manifest as fetal akinesia deformation/lethal pterygium syndrome, McKie et al. (2014) identified 3 different homozygous nonsense or intragenic deletion mutations in the RYR1 gene (180901.0039-180901.0041). McKie et al. (2014) suggested that RYR1 mutation analysis should be performed in cases with severe early lethal fetal akinesia even in the absence of specific histopathologic indicators of RYR1-related disease. The patients were ascertained from a cohort of 36 families with the same phenotype; RYR1 mutations were found in 8.3%.
The involvement of RYR1 mutations in a congenital myopathy is supported by the findings of Takeshima et al. (1994). Mice homozygous for a targeted mutation in the skeletal muscle ryanodine receptor gene died perinatally with gross abnormalities of skeletal muscle. The contractile response to electrical stimulation under physiologic conditions was totally abolished in the mutant muscle, although ryanodine receptors other than the skeletal-muscle type seemed to exist because the response to caffeine was retained. Takeshima et al. (1994) interpreted the results as indicating that the skeletal muscle ryanodine receptor is essential for both muscular maturation and excitation-contraction (EC) coupling, and that the function of the skeletal muscle receptor during EC coupling cannot be substituted by other subtypes of the receptor.
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]
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]
Clarke, N. F., Waddell, L. B., Cooper, S. T., Perry, M., Smith, R. L. L., Kornberg, A. J., Muntoni, F., Lillis, S., Straub, V., Bushby, K., Guglieri, M., King, M. D., Farrell, M. A., Marty, I., Lunardi, J., Monnier, N., North, K. N. Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion. Hum. Mutat. 31: E1544-E1550, 2010. Note: Electronic Article. [PubMed: 20583297] [Full Text: https://doi.org/10.1002/humu.21278]
Engel, A. G., Gomez, M. R., Groover, R. V. Multicore disease: a recently recognized congenital myopathy associated with multifocal degeneration of muscle fibres. Mayo Clin. Proc. 46: 666-681, 1971. [PubMed: 5115748]
Ferreiro, A., Estournet, B., Chateau, D., Romero, N. B., Laroche, C., Odent, S., Toutain, A., Cabello, A., Fontan, D., dos Santos, H. G., Haenggeli, C.-A., Bertini, E., Urtizberea, J.-A., Guicheney, P., Fardeau, M. Multi-minicore disease-searching for boundaries: phenotype analysis of 38 cases. Ann. Neurol. 48: 745-757, 2000. [PubMed: 11079538]
Ferreiro, A., Fardeau, M. 80th ENMC International Workshop on Multi-minicore Disease: 1st International MmD Workshop 12-13th May, 2000, Soestduinen, The Netherlands. Neuromusc. Disord. 12: 60-68, 2002. [PubMed: 11731287] [Full Text: https://doi.org/10.1016/s0960-8966(01)00237-1]
Ferreiro, A., Monnier, N., Romero, N. B., Leroy, J.-P., Bonnemann, C., Haenggeli, C.-A., Straub, V., Voss, W. D., Nivoche, Y., Jungbluth, H., Lemainque, A., Voit, T., Lunardi, J., Fardeau, M., Guicheney, P. A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. Ann. Neurol. 51: 750-759, 2002. [PubMed: 12112081] [Full Text: https://doi.org/10.1002/ana.10231]
Jungbluth, H., Muller, C. R., Halliger-Keller, B., Brockington, M., Brown, S. C., Feng, L., Chattopadhyay, A., Mercuri, E., Manzur, A. Y., Ferreiro, A., Laing, N. G., Davis, M. R., Roper, H. P., Dubowitz, V., Bydder, G., Sewry, C. A., Muntoni, F. Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores. Neurology 59: 284-287, 2002. [PubMed: 12136074] [Full Text: https://doi.org/10.1212/wnl.59.2.284]
Jungbluth, H., Sewry, C., Brown, S. C., Manzur, A. Y., Mercuri, E., Bushby, K., Rowe, P., Johnson, M. A., Hughes, I., Kelsey, A., Dubowitz, V., Muntoni, F. Minicore myopathy in children: a clinical and histopathological study of 19 cases. Neuromusc. Disord. 10: 264-273, 2000. [PubMed: 10838253] [Full Text: https://doi.org/10.1016/s0960-8966(99)00125-x]
Jungbluth, H., Zhou, H., Hartley, L., Halliger-Keller, B., Messina, S., Longman, C., Brockington, M., Robb, S. A., Straub, V., Voit, T., Swash, M., Ferreiro, A., Bydder, G., Sewry, C. A., Muller, C., Muntoni, F. Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene. Neurology 65: 1930-1935, 2005. [PubMed: 16380615] [Full Text: https://doi.org/10.1212/01.wnl.0000188870.37076.f2]
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]
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: 1310, 2012. [PubMed: 22473935] [Full Text: https://doi.org/10.1002/humu.22056]
Kondo, E., Nishimura, T., Kosho, T., Inaba, Y., Mitsuhashi, S., Ishida, T., Baba, A., Koike, K., Nishino, I., Nonaka, I., Furukawa, T., Saito, K. Recessive RYR1 mutations in a patient with severe congenital nemaline myopathy with ophthalomoplegia (sic) identified through massively parallel sequencing. Am. J. Med. Genet. 158A: 772-778, 2012. [PubMed: 22407809] [Full Text: https://doi.org/10.1002/ajmg.a.35243]
Kossugue, P. M., Paim, J. F., Navarro, M. M., Silva, H. C., Pavanello, R. C. M., Gurgel-Giannetti, J., Zatz, M., Vainzof, M. Central core disease due to recessive mutations in RYR1 gene: is it more common than described? Muscle Nerve 35: 670-674, 2007. [PubMed: 17226826] [Full Text: https://doi.org/10.1002/mus.20715]
Manzur, A. Y., Sewry, C. A., Ziprin, J., Dubowitz, V., Muntoni, F. A severe clinical and pathological variant of central core disease with possible autosomal recessive inheritance. Neuromusc. Disord. 8: 467-473, 1998. [PubMed: 9829276] [Full Text: https://doi.org/10.1016/s0960-8966(98)00064-9]
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]
McKie, A. B., Alsaedi, A., Vogt, J., Stuurman, K. E., Weiss, M. M., Shakeel, H., Tee, L., Morgan, N. V., Nikkels, P. G. J., van Haaften, G., Park, S.-M., van der Smagt, J. J., Bugiani, M., Maher, E. R. Germline mutations in RYR1 are associated with foetal akinesia deformation sequence/lethal multiple pterygium syndrome. Acta Neuropath. Commun. 2: 148, 2014. Note: Electronic Article. [PubMed: 25476234] [Full Text: https://doi.org/10.1186/s40478-014-0148-0]
Monnier, N., Ferreiro, A., Marty, I., Labarre-Vila, A., Mezin, P., Lunardi, J. A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. Hum. Molec. Genet. 12: 1171-1178, 2003. [PubMed: 12719381] [Full Text: https://doi.org/10.1093/hmg/ddg121]
Monnier, N., Laquerriere, A., Marret, S., Goldenberg, A., Marty, I., Nivoche, Y., Lunardi, J. First genomic rearrangement of the RYR1 gene associated with an atypical presentation of lethal neonatal hypotonia. Neuromusc. Disord. 19: 680-684, 2009. [PubMed: 19734047] [Full Text: https://doi.org/10.1016/j.nmd.2009.07.007]
Monnier, N., Marty, I., Faure, J., Castiglioni, C., Desnuelle, C., Sacconi, S., Estournet, B., Ferreiro, A., Romero, N., Laquerriere, A., Lazaro, L., Martin, J.-J., Morava, E., Rossi, A., Van der Kooi, A., de Visser, M., Verschuuren, C., Lunardi, J. Null mutations causing depletion of the type 1 ryanodine receptor (RYR1) are commonly associated with recessive structural congenital myopathies with cores. Hum. Mutat. 29: 670-678, 2008. [PubMed: 18253926] [Full Text: https://doi.org/10.1002/humu.20696]
Swash, M., Schwartz, M. S. Familial multicore disease with focal loss of cross-striations and ophthalmoplegia. J. Neurol. Sci. 52: 1-10, 1981. [PubMed: 7299413] [Full Text: https://doi.org/10.1016/0022-510x(81)90129-5]
Takeshima, H., Iino, M., Takekura, H., Nishi, M., Kuno, J., Minowa, O., Takano, H., Noda, T. Excitation-contraction uncoupling and muscular degeneration in mice lacking functional skeletal muscle ryanodine-receptor gene. Nature 369: 556-559, 1994. [PubMed: 7515481] [Full Text: https://doi.org/10.1038/369556a0]
Van Wijngaarden, G. K., Bethlem, J., Dingemans, K. P., Coers, C., Telerman-Toppet, N., Gerard, J. M. Familial focal loss of cross striations. J. Neurol. 216: 163-172, 1977. [PubMed: 72134] [Full Text: https://doi.org/10.1007/BF00313617]
Wilmshurst, J. M., Lillis, S., Zhou, H., Pillay, K., Henderson, H., Kress, W., Muller, C. R., Ndondo, A., Cloke, V., Cullup, T., Bertini, E., Boennemann, C., and 10 others. RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann. Neurol. 68: 717-726, 2010. [PubMed: 20839240] [Full Text: https://doi.org/10.1002/ana.22119]
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]
Zhou, H., Rokach, O., Feng, L., Munteanu, I., Mamchaoui, K., Wilmshurst, J. M., Sewry, C., Manzur, A. Y., Pillay, K., Mouly, V., Duchen, M., Jungbluth, H., Treves, S., Muntoni, F. RyR1 deficiency in congenital myopathies disrupts excitation-contraction coupling. Hum. Mutat. 34: 986-996, 2013. [PubMed: 23553787] [Full Text: https://doi.org/10.1002/humu.22326]