Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia

Romero, Norma B.; Monnier, Nicole; Viollet, Louis; Cortey, A.; Chevallay, M.; Leroy, J P; Lunardi, Joël; Fardeau, Michel

doi:10.1093/brain/awg244

Cited by 149 publications

(123 citation statements)

References 24 publications

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“…Findings such as decreased fetal movement, polyhydramnios, hypotonia, arthrogryposis, respiratory insufficiency, and feeding difficulties were seen in nearly all patients in this series, and are consistent with previously reported cases of the severe neonatal phenotype. 9,16 Patient 10 with a de novo dominant mutation had clinically impressive spinal rigidity of neonatal onset. In addition, early-onset kyphoscoliosis as well as a rapid and early progression of scoliosis was seen in 4 patients, 1 of whom demonstrated paraspinal muscle involvement on muscle ultrasound.…”

Section: Pathologymentioning

confidence: 99%

Severe congenital RYR1 -associated myopathy

et al. 2013

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Objective: To report a series of 11 patients on the severe end of the spectrum of ryanodine receptor 1 (RYR1) gene-related myopathy, in order to expand the clinical, histologic, and genetic heterogeneity associated with this group of patients.Methods: Eleven patients evaluated in the neonatal period with severe neonatal-onset RYR1-associated myopathy confirmed by genetic testing were ascertained. Clinical features, molecular testing results, muscle imaging, and muscle histology are reviewed.Results: Clinical features associated with the severe neonatal presentation of RYR1-associated myopathy included decreased fetal movement, hypotonia, poor feeding, respiratory involvement, arthrogryposis, and ophthalmoplegia in 3 patients, and femur fractures or hip dislocation at birth. Four patients had dominant RYR1 mutations, and 7 had recessive RYR1 mutations. One patient had a cleft palate, and another a congenital rigid spine phenotype-findings not previously described in the literature in patients with early-onset RYR1 mutations. Six patients who underwent muscle ultrasound showed relative sparing of the rectus femoris muscle. Histologically, all patients with dominant mutations had classic central cores on muscle biopsy. Patients with recessive mutations showed great histologic heterogeneity, including fibrosis, variation in fiber size, skewed fiber typing, very small fibers, and nuclear internalization with or without ill-defined cores. Conclusions: This series confirms and expands the clinical and histologic variability associated withsevere congenital RYR1-associated myopathy. Both dominant and recessive mutations of the RYR1 gene can result in a severe neonatal-onset phenotype, but more clinical and histologic heterogeneity has been seen in those with recessive RYR1 gene mutations. Central cores are not obligatory histologic features in recessive RYR1 mutations. Sparing of the rectus femoris muscle on imaging should prompt evaluation for RYR1-associated myopathy in the appropriate clinical context. Central core disease (CCD) is a form of congenital myopathy due mostly to dominant, and occasionally to recessive, mutations in the skeletal muscle ryanodine receptor 1 (RYR1) gene, characterized clinically by a static to slowly progressive course beginning with congenital hypotonia. 1-3 RYR1 is a 106 exon gene that encodes the skeletal muscle ryanodine receptor, an intracellular calcium-release channel that is crucial to excitation-contraction coupling in muscle.

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Section: Pathologymentioning

confidence: 99%

Severe congenital RYR1 -associated myopathy

et al. 2013

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“…1). The two mutations were linked to CCD in several unrelated families (3,16,30). Homozygous expression of CCD mutations RyR1-G4898E and ϪG4898R in myotubes lacking RyR1 resulted in minimal caffeine-induced Ca 2ϩ release, which suggested that the two mutants did not release significant amounts of Ca 2ϩ from SR (31).…”

Section: Discussionmentioning

confidence: 99%

Single Channel Properties of Heterotetrameric Mutant RyR1 Ion Channels Linked to Core Myopathies

Wang

Yamaguchi

et al. 2008

Journal of Biological Chemistry

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“…Arthrogryposis also occurs in infants with inherited mutations in genes that encode skeletal muscle acetylcholine receptor proteins, or proteins associated with these receptors (e.g., rapsyn [RAPSN]) [53][54][55] . Congenital myopathies that are sometimes associated with arthrogryposis can be caused by mutations of genes that encode fetal skeletal-muscle myosin heavy chains 32,56 , skeletal-muscle thin filament proteins 57,58 , and the ryanodine receptor protein [59][60][61] . Congenital myotonic dystrophy causes arthrogryposis 62 because of the toxicity of RNA encoded by a triplet repeat expansion in the 3-prime untranslated region of the dystrophia myotonica protein kinase (DMPK) gene 63 .…”

Section: Neuromuscular Causes Of Arthrogryposismentioning

confidence: 99%