Congenital neuromuscular disease with uniform type 1 fiber and
            <i>RYR1</i>
            mutation

Sato, Ikuya; Wu, Shiwen; Ibarra, M. C. A.; Hayashi, Yukiko; Fujita, Hiroshi; Tōjō, Megumu; Oh, Shin J.; Nonaka, Ikuya; Noguchi, S.; Nishino, Ichizo

doi:10.1212/01.wnl.0000269792.63927.86

Cited by 63 publications

(52 citation statements)

References 37 publications

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“…associated with RYR1 myopathies. 3,10 Noncore RYR1-related myopathies may be more frequent than initially thought and are probably underdiagnosed. Amburgey et al 4 stated that 49% of recessive cases in their study (n ¼ 106) were noncore myopathies.…”

Section: Discussionmentioning

confidence: 99%

Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

Rocha

Taipa

Pires

et al. 2014

Pediatric Neurology

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BACKGROUND: Mutations in ryanodine receptor 1 gene (RYR1) are frequent causes of myopathies. They classically present with central core disease; however, clinical variability and histopathologic overlap are being increasingly recognized. PATIENTS: Patient 1 is a 15-year-old girl with mild proximal, four-limb weakness from age 5, presenting with a progressive scoliosis starting at age 10. Patient 2 is an 18-year-old girl with progressively worsening muscle hypotrophy and mild proximal, four-limb weakness. She developed a rapidly progressive scoliosis from age 11 and needed surgical treatment at age 14 years. Patient 3 is an 11-year-old boy with moderate proximal limb weakness and progressive neck flexor weakness, first noticed at age 2. Muscle biopsies revealed type 1 fiber predominance (Patients 1 and 2) or abnormal type 1 fiber uniformity (Patient 3). Different RYR1 variants were identified in all patients. In Patients 1 and 3, these changes were validated as being pathogenic. CONCLUSIONS: These patients illustrate early-onset, progressive myopathies with predominant axial involvement. Histopathologic findings were abnormal but not specific for a diagnosis, particularly central core myopathy. Genetic testing helped broaden the range of phenotypes included in the RYR1-related myopathies. Our patients reinforce the need to recognize the broad histopathologic variability of RYR1-related myopathies and sometimes lack of pathognomonic findings that may reduce the diagnostic threshold of this disease. We suggest that the predominance of type 1 fibers and involvement of axial muscles may be an important element to consider the RYR1 gene as candidate.

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Section: Discussionmentioning

confidence: 99%

Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

Rocha

Taipa

Pires

et al. 2014

Pediatric Neurology

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“…117000) (11), MmD with external ophthalmoplegia (OMIM no. 255320) (12), congenital myopathy with cores and rods (6,7), central nuclear myopathy (13), and neuromuscular disease with uniform type 1 fibers (14). For all of these disorders, Ca 2ϩ dysregulation is a likely primary cause and a common etiology is possible.…”

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confidence: 99%

Ca ²⁺ dysregulation in Ryr1 ^I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

Zvaritch

Kraeva

Bombardier

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Ryr1 I4895T/wt (IT/؉) mice express a knockin mutation corresponding to the human I4898T EC-uncoupling mutation in the type 1 ryanodine receptor/Ca 2؉ release channel (RyR1), which causes a severe form of central core disease (CCD). IT/؉ mice exhibit a slowly progressive congenital myopathy, with neonatal respiratory stress, skeletal muscle weakness, impaired mobility, dorsal kyphosis, and hind limb paralysis. Lesions observed in myofibers from diseased mice undergo age-dependent transformation from minicores to cores and nemaline rods. Early ultrastructural abnormalities include sarcomeric misalignment, Z-line streaming, focal loss of cross-striations, and myofibrillar splitting and intermingling that may arise from defective myofibrillogenesis. However, manifestation of the disease phenotype is highly variable on a Sv129 genomic background. Quantitative RT-PCR shows an equimolar ratio of WT and mutant Ryr1 transcripts within IT/؉ myofibers and total RyR1 protein expression levels are normal. We propose a unifying theory in which the cause of core formation lies in functional heterogeneity among RyR1 tetramers. Random combinations of normal and either leaky or EC-uncoupled RyR subunits would lead to spatial differences in Ca 2؉ transients; the resulting heterogeneity of contraction among myofibrils would lead to focal, irreversible tearing and shearing, which would, over time, enlarge to form minicores, cores, and nemaline rods. The IT/؉ mouse line is proposed to be a valid model of RyR1-related congenital myopathy, offering high potential for elucidation of the pathogenesis of skeletal muscle disorders arising from impaired EC coupling.calcium ͉ central core disease ͉ multiminicore disease ͉ nemaline rod myopathy ͉ ryanodine receptor

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“…Central core disease may also be related to RYR1 mutation and is likely to be complicated with MH [26][27][28]. An RYR1 mutation has also been suggested to be involved in CNMDU1 [3]. Therefore, perioperative MH is a concern in patients with suspected CNMDU1, which is another reason that preoperative definite diagnosis by biopsy is essential.…”

Section: Discussionmentioning

confidence: 99%

“…In 1983, Oh and Danon described CNMDU1 as a distinct nonprogressive congenital neuromuscular disease with features of delayed motor development with early onset, mild proximal muscle weakness, hyporeflexia, normal levels of serum muscle enzymes, including creatine kinase (CK), uniform type 1 fibers, and nonprogression of the disease course [2]. The etiology is unknown, but mutation of the ryanodine receptor gene one (RYR1) may be involved in CNMDU1 [3].…”

Section: Introductionmentioning

confidence: 99%

Kyphoscoliosis associated with congenital neuromuscular disease with uniform type 1 fibers

et al. 2011

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Objective To report the first case of surgical treatment for severe kyphoscoliosis associated with respiratory disorder in a patient with congenital neuromuscular disease with uniform type 1 fibers (CNMDU1), including management of the possible onset of malignant hyperthermia (MH) in general anesthesia. Summary of background data CNMDU1 is rare among congenital neuromuscular diseases, and surgery for spinal deformity in CNMDU1 has not been described. Onset of MH in general anesthesia is a concern in this disease. Methods A 13-year-old female with motor retardation, suspected myopathy, and severe spinal deformity was followed at another pediatric hospital before referral to Meijo Hospital. Symptoms at the initial consultation were mild general muscular weakness and muscular atrophy. The rib hump was 60°and trunk balance was poor. The tendon reflex showed hyporeflexia, and blood tests were normal. Vital capacity was 0.69 L and forced expiratory volume percentage in 1 s was 75.5%, showing a restrictive and obstructive ventilatory defect. A plain radiograph showed severe kyphoscoliosis with thoracic scoliosis of 130°(T5-L1) and thoracic kyphosis of 110°(T2-T12) with almost no flexibility in bending or traction film.

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Congenital neuromuscular disease with uniform type 1 fiber and RYR1 mutation

Abstract: Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) in 40% of patients is associated with mutations in the C-terminal domain of RYR1, suggesting that CNMDU1 is allelic to central core disease at least in some patients.

Cited by 63 publications

References 37 publications

Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

Ca ²⁺ dysregulation in Ryr1 ^I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

Kyphoscoliosis associated with congenital neuromuscular disease with uniform type 1 fibers

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Congenital neuromuscular disease with uniform type 1 fiber and RYR1 mutation

Abstract: Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) in 40% of patients is associated with mutations in the C-terminal domain of RYR1, suggesting that CNMDU1 is allelic to central core disease at least in some patients.

Cited by 63 publications

References 37 publications

Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

Ca 2+ dysregulation in Ryr1 I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

Kyphoscoliosis associated with congenital neuromuscular disease with uniform type 1 fibers

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Ca ²⁺ dysregulation in Ryr1 ^I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods