RYR1 causing distal myopathy

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. We describe a patient with distal myopathy and jaw contractures due to RYR1 variants. Our findings suggest that RYR1 gene analysis should be included in the list of genes causative of distal myopathies.
Source: Molecular Genetics & Genomic Medicine - Category: Genetics & Stem Cells Authors: Tags: Clinical Report Source Type: research

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Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by the morphological feature of centrally located nuclei in a large number of muscle fibers. CNM is related to several causative genes: dynamin 2 (DNM2), myotubularin (MTM1), amphiphysin 2 (BIN1), and ryanodine receptor 1 (RYR1) [1]. DNM2-related CNM (DNM2-CNM) is an autosomal-dominant inherited disease that accounts for about 50% of CNM cases [1]. Although DNM2-CNM has shown a variety of clinical manifestations, from severe neonatal onset to mild adult onset, most patients present with slowly progressive muscle weakness in the distal or sometimes pro...
Source: Journal of the Neurological Sciences - Category: Neurology Authors: Tags: Letters to the Editor Source Type: research
ActiMyo ® is a device developed to evaluate the physical condition of patients suffering with movement disorders. It contains three-axis accelerometer, gyroscope, and magnetometer which allow recording daily life movements of patients in their usual environment using a wearable device. ActiMyo® has been t ested as an outcome measure in several trials involving ambulant and non-ambulant patients with neuromuscular disease as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), or facio scapulohumeral dystrophy (FSHD).
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin, a protein that connects the extracellular matrix to the cytoskeleton in muscle fibres. DMD boys develop progressive muscle wasting, leading to cardiac and respiratory failure and premature death. X-linked myotubular (centronuclear) myopathy (XLMTM) is a very severe myopathy characterized by generalized hypotonia from birth and death of most patients before the age of 2. Our recent preclinical data in mice demonstrated that tamoxifen (a drug used against breast cancer) may be helpful for boys with DMD and XLMTM.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Mutations in DNM2, encoding dynamin 2, an ubiquitously expressed GTPase, cause the autosomal dominant centronuclear myopathy (AD-CNM). Most of the AD-CNM mutations in DNM2 (such as S619L) are gain-of-function mutations leading to an increased GTPase activity. So far, DNM2 AD-CNM mutations have only been modelled transiently in zebrafish through the injection of mutated mRNA. mRNA injected larvae disclosed a severe phenotype with structural and functional abnormalities of the triad (Gibbs et al 2013).
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterized by the presence of hypotrophic myofibers with centrally placed nuclei on muscle biopsies. CNM exists in 3 forms: i) X-linked recessive caused by mutations in the MTM gene encoding for the myotubularin protein (OMIM 310400), ii) autosomal dominant caused by mutations in the DNM2 gene encoding for the dynamin 2 protein (OMIM 160150) and iii) autosomal recessive form due to mutations in the BIN1 gene encoding for the amphyphysin 2 protein (OMIM 255200).
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy due to mutations in MTM1 encoding a 3-phosphoinositides phosphatase myotubularin. XLMTM patients display severe generalized hypotonia at birth accompanied by respiratory insufficiency and pathologically show small-size fibers with peripheral halo, centrally located nuclei, disorganized perinuclear organelles in the muscle. Among 78 patients with pathologically diagnosed as XLMTM in our cohort, causative mutations were not identified in 20 cases by targeted re-sequencing panel for congenital myopathy, MTM1 Sanger sequencing nor Whole-exome sequencing.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
XLMTM is a rare disease caused by mutations in the MTM1 gene, leading to profound muscle weakness, respiratory failure and early death. INCEPTUS (NCT02704273) is a prospective, non-interventional study in patients (pts) ≤4 years old to characterize the course and natural history of XLMTM using neuromuscular and respiratory assessments and to identify adverse events (AEs). INCEPTUS will generate within-pt control data to support a Phase 1/2 gene therapy clinical trial (ASPIRO). As of 22MAR19, 32 male pts (0.3-4.6 years of age) have been enrolled and assessed every 3 months for up to 24 months.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Centronuclear myopathies (CNM) are a group of severe muscle diseases for which no effective therapy is currently available. The most severe and neonatal X-linked form is known as myotubular myopathy and caused by loss-of-function mutations in Myotubularin (MTM1), while the main autosomal dominant form is due to mutations in Dynamin 2 (DNM2). We previously showed that genetic reduction of DNM2 expression in Mtm1 knockout (Mtm1KO) mice prevents development of muscle pathology. We are now investigating skeletal muscle targeting of Dnm2 reduction in mice.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are spectra of the same disease affecting muscle, platelets, spleen, and skin. TAM and STRMK arise from gain-of-function mutations in STIM1 or ORAI1, both encoding key regulators of Ca2+ homeostasis, and mutations in either gene results in excessive Ca2+ entry. To elucidate the physiological consequences of STIM1 over-activation, we generated a murine model harboring the most common TAM/STRMK mutation and characterized the phenotype at the histological, ultrastructural, metabolic, physiological, and functional level.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Mutations in RYR1 are often associated with central core disease, and are also the most common cause of other congenital myopathies (CMs) such as multi-minicore disease, CFTD (congenital fiber type disproportion) and centronuclear myopathy (CNM). There is an increasing interest in the clinical variability and pathologic overlap among these CMs due to RYR1 mutations. In addition, it has been reported that the compound heterozygous RYR1 mutations can cause more severe phenotype compared to the autosomal dominant cases.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
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