Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization

Abstract

(2011) Neuropathology and Applied Neurobiology 37, 271-284 Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization Aims: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of congenital myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel (RYR1). Methods: Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. Results: Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor (RYR1) gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated 271Neuropathology and Applied Neurobiology (2011Neurobiology ( ), 37, 271-284 doi: 10.1111Neurobiology ( /j.1365Neurobiology ( -2990Neurobiology ( .2010 with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. Conclusion: Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity.A congenital myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related congenital myopathy.

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

“…During routine MTM1 gDNA sequencing in P2, no symmetrical PCR amplification was obtained for the majority of exons (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). This led us to suspect the presence of a large intragenic deletion, which was subsequently confirmed by MLPA (Supplementary Figure S5a).…”

“…1 Several genes are reported to be associated with CNM; these include MTM1 in the X-linked form, 3,4 DNM2 and MTMR14 in the autosomal dominant forms, [4][5][6] BIN1 and RYR1 associated with the autosomal recessive forms. 4,[7][8][9] X-linked myotubular myopathy (XLMTM; MIM 310400) has a prevalence of approximately 1/50 000 males and is characterized by severe hypotonia present at birth and inability to maintain sustained spontaneous respiration. 10 Different authors have proposed that patients be classified according to their phenotype, as: (i) severecharacteristic facial features, markedly delayed motor milestones and requiring prolonged ventilatory support (412 h); (ii) moderatemore rapid acquirement of motor milestones and independent respiration for 412 h per day; (iii) mild -motor milestones slightly delayed and independent spontaneous respiratory function achieved after the neonatal period.…”

Clinical utility gene card for: Centronuclear and myotubular myopathies

“…Indeed, at the ultrastructural level, there is a significant difference between the group of DNM2-, BIN1-and MTM1-CNM and RYR1-related myopathies, because despite of the ultrastructural particularities found in this first group of diseases, the sarcomeres appear preserved with a normal sequential structure, whereas in the RYR1-related myopathies, wide areas of sarcomeric disorganization with loss of the regular sarcomeric sequence are constantly observed. 4,34 The first suggestion of any primary muscle disease, including centronuclear myopathy, necessitates histological analysis of a muscle biopsy that is an invasive sampling. See 'management' part concerning the risk of MH for patients with RYR1 mutation and the precautions to be taken before anaesthesia.…”

“…2 RYR1 mutations have been mainly implicated in CNM2 associated with autosomal-recessive inheritance. 3,4 Implication of heterozygous RYR1 mutations in dominant CNM awaits confirmation.…”

“…[24][25][26] RYR1: To date, RYR1-related CNM has been mainly associated with compound heterozygosity for recessive RYR1 mutations, typically a missense mutation and a mutation predicted to reduce the amount of the functional RyR1 protein. 3,4 The mutational spectrum includes missense mutations, frame-shifting small insertions and deletions, and splice-altering mutations. Three recurrent RYR1 mutations associated with CNM have been reported in the South African population due to multiple founder effects.…”