217th ENMC International Workshop: RYR1-related myopathies, Naarden, The Netherlands, 29–31 January 2016

Jungbluth, Heinz; Dowling, James J.; Ferreiro, Ana; Muntoni, F.

doi:10.1016/j.nmd.2016.06.001

Cited by 36 publications

(30 citation statements)

References 52 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The morphological changes on muscle biopsy span from central cores to multi‐minicores, central nuclei, congenital fiber type disproportion, or may be absent (Jungbluth et al. ). In addition, RYR1 ‐related myopathies can be inherited also in an autosomal recessive manner, although more frequently with a dominant trait (Jungbluth et al.…”

Section: Introductionmentioning

confidence: 99%

RYR1 causing distal myopathy

Laughlin

Niu

Wieben

et al. 2017

Molec Gen & Gen Med

View full text Add to dashboard Cite

BackgroundCongenital myopathies due to ryanodine receptor (RYR1) mutations are increasingly identified and correlate with a wide range of phenotypes, most commonly that of malignant hyperthermia susceptibility and central cores on muscle biopsy with rare reports of distal muscle weakness, but in the setting of early onset global weakness.MethodsWe report a case of a patient presenting with childhood onset hand stiffness and adult onset progressive hand weakness and jaw contractures discovered to have two variants in the RYR1 gene.ResultsThe patient manifested with distal upper limb weakness which progressed to involve the distal lower limb, proximal upper limb, as well as the face in addition to limited jaw opening. Creatine kinase was mildly elevated with EMG findings supporting a myopathy. Muscle biopsy showed features consistent with centronuclear myopathy. Whole exome sequencing revealed a novel heterozygous pathogenic variant in RYR1 (c.12315_12328delAGAAATCCAGTTCC, p.Glu4106Alafs*8), and a heterozygous missense variant (c.10648C>T, p.Arg3550Trp) of unknown significance in compound heterozygous state.ConclusionWe expand the spectrum of RYR1‐related myopathy with the description of a novel phenotype in an adult patient presenting with hand weakness and suggest considering RYR1 analysis in the diagnosis of distal myopathies.

show abstract

Section: Introductionmentioning

confidence: 99%

RYR1 causing distal myopathy

Laughlin

Niu

Wieben

et al. 2017

Molec Gen & Gen Med

View full text Add to dashboard Cite

show abstract

“…These diagnostic guidelines based on expert opinion emphasize the need for future research, in particular aimed at the large-scale functional characterization of RYR1 variants implicated in RM, and the importance of international collaborative mutational databases to establish clinico-pathological genotype-phenotype correlations for RM and other RYR1 -related disorders in larger cohorts, ultimately reducing the need for invasive investigations such as a muscle biopsy [62]. …”

Section: Discussionmentioning

confidence: 99%

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations

et al. 2019

View full text Add to dashboard Cite

ObjectiveThe histopathological features of malignant hyperthermia (MH) and non-anaesthetic (mostly exertional) rhabdomyolysis (RM) due to RYR1 mutations have only been reported in a few cases.MethodsWe performed a retrospective multi-centre cohort study focussing on the histopathological features of patients with MH or RM due to RYR1 mutations (1987–2017). All muscle biopsies were reviewed by a neuromuscular pathologist. Additional morphometric and electron microscopic analysis were performed where possible.ResultsThrough the six participating centres we identified 50 patients from 46 families, including patients with MH (n = 31) and RM (n = 19). Overall, the biopsy of 90% of patients showed one or more myopathic features including: increased fibre size variability (n = 44), increase in the number of fibres with internal nuclei (n = 30), and type I fibre predominance (n = 13). Abnormalities on oxidative staining, generally considered to be more specifically associated with RYR1-related congenital myopathies, were observed in 52%, and included unevenness (n = 24), central cores (n = 7) and multi-minicores (n = 3). Apart from oxidative staining abnormalities more frequently observed in MH patients, the histopathological spectrum was similar between the two groups. There was no correlation between the presence of cores and the occurrence of clinically detectable weakness or presence of (likely) pathogenic variants.ConclusionsPatients with RYR1-related MH and RM exhibit a similar histopathological spectrum, ranging from mild myopathic changes to cores and other features typical of RYR1-related congenital myopathies. Suggestive histopathological features may support RYR1 involvement, also in cases where the in vitro contracture test is not informative.Electronic supplementary materialThe online version of this article (10.1007/s00415-019-09209-z) contains supplementary material, which is available to authorized users.

show abstract

“…The first 4000 amino acids make up the large cytoplasmic domain that contains binding sites for various modulators, while the last 1000 amino acids constitute the carboxy terminal pore-forming domain [21,22]. Dominant and recessive mutations in RYR1, the gene encoding the RyR1, are associated with a range of early-onset neuromuscular disorders including the core myopathies central core disease (CCD) and multi-minicore disease (MmD), congenital fiber type disproportion, (CFTD) centronuclear myopathy (CNM), exertional rhabdomyolysis/myalgia as well as the pharmacogenetic disorder malignant hyperthermia (MH) [23][24][25][26].…”

Section: Excitation-contraction Couplingmentioning

confidence: 99%

“…Since this initial discovery in the early 90s, more than 200 mutations have been identified in patients with a variety of inherited myopathies including MHS, exertional rhabdomyolysis/myalgia and a range of congenital myopathies including CCD, as well as subgroups of MmD, CNM and CFTD [23][24][25][26]. Because of the sheer size of the RYR1 gene which spans 106 exons and >15 kb DNA, initial mutation searches were confined to hotspot domains originally implicated in autosomal dominant MHS and CCD.…”

Section: Disorders Associated With Ryr1 Mutationsmentioning

confidence: 99%

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

Treves

Jungbluth

Voermans

et al. 2017

Seminars in Cell & Developmental Biology

Self Cite

View full text Add to dashboard Cite

a b s t r a c tThe physiological process by which Ca 2+ is released from the sarcoplasmic reticulum is called excitationcontraction coupling; it is initiated by an action potential which travels deep into the muscle fiber where it is sensed by the dihydropyridine receptor, a voltage sensing L-type Ca 2+ channel localized on the transverse tubules. Voltage-induced conformational changes in the dihydropyridine receptor activate the ryanodine receptor Ca 2+ release channel of the sarcoplasmic reticulum. The released Ca 2+ binds to troponin C, enabling contractile thick-thin filament interactions. The Ca 2+ is subsequently transported back into the sarcoplasmic reticulum by specialized Ca 2+ pumps (SERCA), preparing the muscle for a new cycle of contraction. Although other proteins are involved in excitation-contraction coupling, the mechanism described above emphasizes the unique role played by the two Ca 2+ channels (the dihydropyridine receptor and the ryanodine receptor), the SERCA Ca 2+ pumps and the exquisite spatial organization of the membrane compartments endowed with the proteins responsible for this mechanism to function rapidly and efficiently. Research over the past two decades has uncovered the fine details of excitation-contraction coupling under normal conditions while advances in genomics have helped to identify mutations in novel genes in patients with neuromuscular disorders. While it is now clear that many patients with congenital muscle diseases carry mutations in genes encoding proteins directly involved in Ca 2+ homeostasis, it has become apparent that mutations are also present in genes encoding for proteins not thought to be directly involved in Ca 2+ regulation. Ongoing research in the field now focuses on understanding the functional effect of individual mutations, as well as understanding the role of proteins not specifically located in the sarcoplasmic reticulum which nevertheless are involved in Ca 2+ regulation or excitation-contraction coupling. The principal challenge for the future is the identification of drug targets that can be pharmacologically manipulated by small molecules, with the ultimate aim to improve muscle function and quality of life of patients with congenital muscle disorders. The aim of this review is to give an overview of the most recent findings concerning Ca 2+ dysregulation and its impact on muscle function in patients with congenital muscle disorders due to mutations in proteins involved in excitation-contraction coupling and more broadly on Ca 2+ homeostasis.

show abstract

217th ENMC International Workshop: RYR1-related myopathies, Naarden, The Netherlands, 29–31 January 2016

Cited by 36 publications

References 52 publications

RYR1 causing distal myopathy

RYR1 causing distal myopathy

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

Contact Info

Product

Resources

About