The spectrum of pathology in central core disease

Sewry, Caroline A.; Müller, C. R.; Davis, Mark; Dwyer, J.S.M.; Dove, J.; Evans, Gwyn A.; Schröder, Rolf; Fürst, Dieter O.; Helliwell, Tim; Laing, Nigel G.; Quinlivan, R.

doi:10.1016/s0960-8966(02)00135-9

Cited by 134 publications

(108 citation statements)

References 27 publications

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“…1 C-G and Fig. S3), are diagnostic of core myopathy (1,2,9). In contrast to humans, type 1 fiber predominance is not a feature in the IT/ϩ mouse model, nor is it in the ␣-tropomyosin related nemaline myopathy mouse model (25).…”

Section: Discussionmentioning

confidence: 94%

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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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Section: Discussionmentioning

confidence: 94%

“…However, some cases of myopathy present with mixed histology so that cores are seen in combination with minicores or with nemaline rods (4)(5)(6)(7)(8). The etiology and pathogenesis of lesion formation is unclear and their presence does not always correlate with the severity of the clinical phenotype (5,9,10).…”

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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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“…The disturbance of desmin may be related to the ultrastructural appearance of misaligned myofibrils, because desmin links the myofibrils at the Z-line. 27,28 In our group of patients, five missense mutations were identified in the RYR1 gene. We could not find a clear clinical or histological distinction between patients with identified RYR1 mutations and patients with no causative changes in this gene.…”

Section: Discussionmentioning

confidence: 83%

Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptoms

et al. 2011

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Introduction:Ryanodine receptor gene (RYR1) mutations have been associated with central core disease (CCD), multiminicore/minicore/multicore disease (MmD), and susceptibility to malignant hyperthermia (MH).Methods:Patients with muscle symptoms in adulthood, who had features compatible with CCD/MmD, underwent clinical, histological, and genetic (RYR1 and SEPN1 genes) evaluations. Published cases of CCD and MmD with adult onset were also reviewed.Results:Eight patients fulfilled the criteria for further analysis. Five RYR1 mutations, 4 of them unreported, were detected in 3 patients. Compound heterozygosity was proven in 1 case.Conclusions:To our knowledge, this is the only report of adult onset associated with recessive RYR1 mutations and central core/multiminicores on muscle biopsy. Although adult patients with CCD, MmD, and minimally symptomatic MH with abnormal muscle biopsy findings usually have a mild clinical course, differential diagnosis and carrier screening is crucial for prevention of potentially life‐threatening reactions to general anesthesia. Muscle Nerve 44: 102–108, 2011

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“…Histopathological features: Typical RYR1-related CCD is characterised by well-defined, single or multiple, central or eccentric cores running a significant extent along the longitudinal muscle fibre axis on muscle biopsy. 14 In cases with suggestive clinical features but less specific histopathological findings such as type 1 predominance, uniformity, 15 or cores and rods, 16,17 muscle MRI may be more indicative of RYR1 involvement than muscle biopsy (see below). Muscle MR imaging: Muscle MR imaging in RYR1-related CCD shows a characteristic and consistent pattern of selective involvement, which may aid genetic testing and distinguish from core myopathies with different genetic backgrounds.…”

Section: Analytical Methods Selection Criteriamentioning

confidence: 99%

Clinical utility gene card for: Central core disease

et al. 2011

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The spectrum of pathology in central core disease

Cited by 134 publications

References 27 publications

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

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

Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptoms

Clinical utility gene card for: Central core disease

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The spectrum of pathology in central core disease

Cited by 134 publications

References 27 publications

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

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

Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptoms

Clinical utility gene card for: Central core disease

Contact Info

Product

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

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