• GENETICS
• MRI
• MYOPATHY
• NEUROPATHOLOGY

• Humans
• Myosin Heavy Chains/genetics
• Male
• Female
• Cardiac Myosins/genetics
• Middle Aged
• Adult
• Retrospective Studies
• Phenotype
• Magnetic Resonance Imaging
• Genotype
• Muscle, Skeletal/pathology
• Muscle, Skeletal/diagnostic imaging
• France
• Aged
• Muscular Diseases/genetics
• Muscular Diseases/pathology
• Muscular Diseases/diagnostic imaging
• Young Adult
• Adolescent
• Cohort Studies
• Child
• Mutation

• Distal dystrophy
• Distal myopathy
• Genetic diagnosis
• Neuromyopathy

• Humans
• Male
• Female
• Adult
• Middle Aged
• Distal Myopathies/genetics
• Distal Myopathies/diagnosis
• Distal Myopathies/epidemiology
• Distal Myopathies/physiopathology
• Mutation
• Cohort Studies
• Young Adult
• Aged
• Adolescent
• Electromyography
• Age of Onset
• Muscle, Skeletal/pathology
• Muscle, Skeletal/diagnostic imaging
• Muscle, Skeletal/physiopathology

• PI21/01532 Instituto de Salud Carlos III
• PROMETEO/2019/075 Generalitat Valenciana

• MYH7
• Neuromuscular scoliosis
• Skeletal myopathy
• Whole-exome sequencing

• Aging diseases
• Osteoporosis
• Osteosarcopenia
• Proteomics
• Sarcopenia
• Transcriptomics

• Humans
• Sarcopenia/metabolism
• Sarcopenia/genetics
• Osteoporosis/genetics
• Osteoporosis/metabolism
• Transcriptome
• Proteomics
• Aged
• Male
• Female
• Middle Aged
• Biomarkers/metabolism

• Humans
• Induced Pluripotent Stem Cells/metabolism
• Induced Pluripotent Stem Cells/pathology
• Myosin Heavy Chains/genetics
• Myosin Heavy Chains/metabolism
• Distal Myopathies/genetics
• Distal Myopathies/pathology
• Distal Myopathies/metabolism
• Cardiac Myosins/genetics
• Cardiac Myosins/metabolism
• Male
• Female
• Cell Line
• Cell Differentiation
• Adult

• Molecular pathology
• Mouse models
• Muscle
• Muscle biology

• Animals
• Mice
• Humans
• Proline/genetics
• Proline/metabolism
• Distal Myopathies/genetics
• Distal Myopathies/metabolism
• Distal Myopathies/pathology
• Amino Acid Substitution
• Mutation, Missense
• Cardiac Myosins/genetics
• Cardiac Myosins/metabolism
• Myosin Heavy Chains/genetics
• Myosin Heavy Chains/metabolism
• Myosin Heavy Chains/chemistry
• Female
• Male
• Mice, Transgenic
• Muscle Contraction/genetics
• Muscle, Skeletal/metabolism
• Muscle, Skeletal/pathology

• K12 HD057022 NICHD NIH HHS
• MR/S023593/1 Medical Research Council
• R01 GM029090 NIGMS NIH HHS
• National Institutes of Health
• Muscular Dystrophy UK

• Adult
• Humans
• Muscular Diseases/genetics
• Muscular Diseases/pathology
• Muscle, Skeletal/diagnostic imaging
• Muscle, Skeletal/pathology
• Actinin/genetics
• Phenotype
• Cardiomyopathies

• K22 NS104135 NINDS NIH HHS
• R01 HG009141 NHGRI NIH HHS

• Cardiomyopathy
• Genetic variant
• Hypertrophic cardiomyopathy
• MYH7
• Myosin myopathy

• Humans
• Myosin Heavy Chains/genetics
• Muscular Diseases/genetics
• Muscle, Skeletal
• Cardiomyopathies/genetics
• Heart
• Mutation
• Phenotype
• Cardiac Myosins/genetics

• Dilated cardiomyopathy
• In silico
• MYH7
• Myosin
• Myosin storage myopathy
• Whole-exome sequencing

• Child
• Humans
• Muscle, Skeletal
• Cardiomyopathy, Dilated/diagnostic imaging
• Cardiomyopathy, Dilated/genetics
• Iran
• Muscular Diseases
• Mutation
• Myosin Heavy Chains/genetics
• Pedigree
• Cardiac Myosins/genetics

• case report
• left ventricular noncompaction
• mosaicism mutation
• myosin heavy chain 7
• next-generation sequencing

• Concurrent neuromuscular diseases
• Double trouble
• Inherited myopathies
• Rare myopathies
• Rare neuromuscular disorders

• Female
• Humans
• Rare Diseases
• Muscular Diseases/diagnosis
• Muscular Diseases/genetics
• Muscular Diseases/pathology
• Myositis
• Phenotype
• Motor Neuron Disease
• Neuromuscular Diseases/diagnosis
• Neuromuscular Diseases/genetics

• Transcriptomic analysis
• biological information
• mechanism
• ovariectomized rat
• postmenopausal osteoporosis

• CMT
• HMSN
• MYH7 myopathy
• Neuropathy

• Actin-binding domain
• Exome-analysis
• MYH7
• Myopathy
• ß-cardiac myosin heavy chain

• Amino Acids/metabolism
• Cardiac Myosins/genetics
• Cardiac Myosins/metabolism
• Female
• Humans
• Muscle, Skeletal/metabolism
• Muscular Diseases/genetics
• Mutation
• Myosin Heavy Chains/genetics
• Myosin Heavy Chains/metabolism
• Polyhydramnios/metabolism
• Polyhydramnios/pathology
• Retrospective Studies

• I 4695 Austrian Science Fund FWF
• European Joint Programme on Rare Diseases and the EJPRD19-145 GENOMIT I4695-B project financed by the Austrian Science Funds, FWF
• Universitätsklinikum Tübingen (8868)

• MYH7
• RYR1
• TTN
• congenital myopathy
• histology

To describe a Filipino patient with adult-onset Sandhoff disease manifesting with an atypical asymmetric lower motor neuron syndrome due to a novel whole HEXB deletion in trans with a pathogenic missense variant and with a coexisting MYH7 pathogenic variant.

We performed clinical, laboratory, myopathologic, and genetic evaluation with next-generation sequencing in the proband and targeted mutational analysis in an asymptomatic sibling.

A 59-year-old Filipino woman presented with 15 years of slowly progressive, asymmetric, proximal-predominant, lower greater than upper extremity weakness, mildly elevated creatine kinase, and generalized cerebellar atrophy. Serum total β-hexosaminidase was significantly reduced, and hexosaminidase A percentage was increased. We identified a novel HEXB whole gene deletion in compound heterozygosity with a pathogenic missense variant (c.1513C>T, p.Arg505Trp) previously described in 1 patient with adult-onset Sandhoff disease. The patient, with a family history of cardiomyopathy, has a coexisting MYH7 pathogenic variant (c.3134G>A, p.Arg1045His), causative of cardiomyopathy but without cardiac involvement, likely due to variable penetrance. Myopathic features were absent from skeletal muscle biopsy.

This patient expands the genotypic, phenotypic, and ethnic spectrum of Sandhoff disease and highlights challenges generated by low-penetrant pathogenic variants, especially when considering a potentially polygenic phenotype.

Myosins are important eukaryotic motor proteins that bind actin and utilize the energy of ATP hydrolysis to perform a broad range of functions such as muscle contraction, cell migration, cytokinesis, and intracellular trafficking. However, the characterization and function of myosin is poorly studied in teleost fish. In this study, we identified 60 myosin family genes in a marine teleost, black rockfish (Sebastes schlegelii), and further characterized their expression patterns. myosin showed divergent expression patterns in adult tissues, indicating they are involved in different types and compositions of muscle fibers. Among 12 subfamilies, S. schlegelii myo2 subfamily was significantly expanded, which was driven by tandem duplication events. The up-regulation of five representative genes of myo2 in the skeletal muscle during fast-growth stages of juvenile and adult S. schlegelii revealed their active role in skeletal muscle fiber synthesis. Moreover, the expression regulation of myosin during the process of myoblast differentiation in vitro suggested that they contribute to skeletal muscle growth by involvement of both myoblast proliferation and differentiation. Taken together, our work characterized myosin genes systemically and demonstrated their diverse functions in a marine teleost species. This lays foundation for the further studies of muscle growth regulation and molecular mechanisms of indeterminate skeletal muscle growth of large teleost fishes.

• Sebastes schlegelii
• myo2
• myoblast differentiation
• myosin gene family
• skeletal muscle growth

• Clinical spectrum
• MYH7 gene
• MYH7-related diseases
• Novel variants

Congenital fiber-type disproportion (CFTD) is a form of congenital myopathy. CFTD is rare, especially when presenting in patients with critical illnesses. Here, we report a case of CFTD presenting with type II respiratory failure after delivery and provide a review of the literature on CFTD.

A 30-year-old woman was admitted to the obstetrics department of our hospital with premature rupture of the fetal membrane and with 7 h of regular contractions. After delivery, the patient experienced a refractory type II respiratory failure. Physical examination along with diagnostic procedures such as electromyography and biopsy confirmed CFTD. Use of invasive ventilator followed by intermittent use of noninvasive ventilator attenuated her symptoms. The patient recovered after ventilator-assisted respiration and was weaned off the noninvasive ventilator on the seventh day postpartum.

Congenital myopathy should be considered a differential diagnosis for type II respiratory failures that cannot be attributed to other diseases.

• Congenital fiber-type disproportion
• Congenital myopathy
• Type II respiratory failure
• Delivery
• Systematic review
• Case report

Laing distal myopathy is a rare autosomal dominant inherited distal myopathy caused by mutations of the MYH7 gene affecting mainly the rod region. We described the clinical features, muscle MRI and pathological changes as well as genetic mutations in a group of Chinese patients with Laing distal myopathy.

Six patients with the confirmed diagnoses of Laing distal myopathy were recruited. Ankle dorsiflexion and finger extension weakness, as well as neck flexion weakness were common in our patients. Myopathic as well as neurogenic lesions were suggested by electromyography in different patients. Respiratory abnormality of sleep apnea was detected in two of our patients stressing the necessity of close respiratory monitoring in this disease. Muscle MRIs showed similar features of concentric fatty infiltration of anterior thigh muscles together with early involvement of tibialis anterior and extensor hallucis longus. However, muscle pathological presentations were varied depending on the biopsied muscles and the severity of the disease. In-frame deletions of the MYH7 gene made up 3/4 of mutations in our patients, suggesting that these are common mutations of Laing distal myopathy.

Our study further expanded the phenotypes and genotypes of Laing distal myopathy. In-frame deletions of the MYH7 gene are common causes of Laing distal myopathy.

• Genotype
• Laing distal myopathy
• MYH7
• Pathology
• Phenotype

• MYH7
• distal myopathy
• heatmap
• laing distal myopathy
• muscle MRI

• Adult
• Aged
• Cardiac Myosins
• DNA Mutational Analysis
• Distal Myopathies/genetics
• Female
• Humans
• Male
• Middle Aged
• Muscle, Skeletal/pathology
• Mutation/genetics
• Myosin Heavy Chains/genetics
• Phenotype

• Arrhythmia
• Atrioventricular block
• Ion channels
• Whole exome sequencing

Congenital myopathies (CMs) constitute a group of heterogenous rare inherited muscle diseases with different incidences. They are traditionally grouped based on characteristic histopathological findings revealed on muscle biopsy. In recent decades, the ever-increasing application of modern genetic technologies has not just improved our understanding of their pathophysiology, but also expanded their phenotypic spectrum and contributed to a more genetically based approach for their classification. Later onset forms of CMs are increasingly recognised. They are often considered milder with slower progression, variable clinical presentations and different modes of inheritance. We reviewed the key features and genetic basis of late onset CMs with a special emphasis on those forms that may first manifest in adulthood.

• adult onset congenital myopathies
• inherited myopathies
• late onset myopathies

• Adult
• Female
• Humans
• Late Onset Disorders
• Male
• Myopathies, Structural, Congenital/classification
• Myopathies, Structural, Congenital/etiology
• Myopathies, Structural, Congenital/genetics
• Myopathies, Structural, Congenital/physiopathology

• Caenorhabditis elegans
• MYH7
• UNC-54
• mutation
• myosin
• overexpression

Myopathies caused by MYH7 gene mutations are clinically and pathologically heterogeneous and, until recently, difficult to diagnose. The availability of NGS panels for hereditary neuromuscular diseases changed our insight regarding their frequency and allowed a better perception of the different phenotypes and morphological abnormalities associated.

We present a male Portuguese patient with the classical phenotype of Laing early-onset distal myopathy (MPD1) beginning at 6 years of age, very slowly progressive, and with a mild to moderate impact on daily life by the age of 56. Muscle biopsy showed a myopathic pattern with hyaline bodies and cores. The NGS panel for structural myopathies identified a novel missense heterozygous variant, c.T4652C (p.Leu1551Pro), in the exon 34 of the MYH7 gene.

• MYH7 gene variant
• laing early-onset distal myopathy
• subsarcolemmal hyaline bodies

• smyhc1
• knockout
• sarcomere
• slow fibers
• zebrafish

• Animals
• Locomotion
• Mutation
• Myosin Heavy Chains/genetics
• Myosin Heavy Chains/metabolism
• Sarcomeres/genetics
• Sarcomeres/metabolism
• Zebrafish/genetics
• Zebrafish/growth & development
• Zebrafish Proteins/genetics
• Zebrafish Proteins/metabolism

• R01 AR072703 NIAMS NIH HHS
• S10 RR026870 NCRR NIH HHS

• Laing type
• MYH7 gene
• distal myopathy
• myofibrillar myopathy

• Case report
• MYH7
• Missense mutation
• Myosin storage myopathy
• Slow/cardiac beta-myosin heavy chain

TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.

• Autophagy
• E3 ubiquitin -ligase
• Muscle dystrophy
• Proliferation/differentiation
• TRIM32

• Congenital myopathy
• Dilated cardiomyopathy
• Dropped head syndrome
• Exon-skipping
• Floppy head syndrome
• MYH7
• MYH7-related myopathy
• Splicing

• MYH7
• Next-generation sequencing
• Restrictive cardiomyopathy
• Sarcomere
• Ventricular noncompaction

• Circular RNA
• biomarkers
• cardiology
• pathology
• therapy
• vascular

• MYH7
• MYH7-related disease
• cardiomyopathy
• skeletal myopathy

• Abba/Thin
• Drosophila
• Laing distal myopathy
• myosin
• myosin myopathy

Over 20 mutations in β-cardiac myosin heavy chain (β-MHC), expressed in cardiac and slow muscle fibers, cause Laing early-onset distal myopathy (MPD-1), a skeletal muscle myopathy. Most of these mutations are in the coiled-coil tail and commonly involve a mutation to a proline or a single-residue deletion, both of which are predicted to strongly affect the secondary structure of the coiled coil. To test this, we characterized the effects of two MPD-1 causing mutations: A1603P and K1617del in vitro and in cells. Both mutations affected secondary structure, decreasing the helical content of 15 heptad and light meromyosin constructs. Both mutations also severely disrupted the ability of glutathione S-transferase–light meromyosin fusion proteins to form minifilaments in vitro, as demonstrated by negative stain electron microscopy. Mutant eGFP-tagged β-MHC accumulated abnormally into the M-line of sarcomeres in cultured skeletal muscle myotubes. Incorporation of eGFP-tagged β-MHC into sarcomeres in adult rat cardiomyocytes was reduced. Molecular dynamics simulations using a composite structure of part of the coiled coil demonstrated that both mutations affected the structure, with the mutation to proline (A1603P) having a smaller effect compared to K1617del. Taken together, it seems likely that the MPD-1 mutations destabilize the coiled coil, resulting in aberrant myosin packing in thick filaments in muscle sarcomeres, providing a potential mechanism for the disease.

•

It is unclear how mutations in the coiled coil of β-myosin heavy chain cause distal myopathy.

• coiled coil
• muscle
• mutations
• myopathy
• myosin