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Acta Myologica : Myopathies and... Dec 2020Distal myopathies are genetic primary muscle disorders with a prominent weakness at onset in hands and/or feet. The age of onset (from early childhood to adulthood), the... (Review)
Review
Distal myopathies are genetic primary muscle disorders with a prominent weakness at onset in hands and/or feet. The age of onset (from early childhood to adulthood), the distribution of muscle weakness (upper versus lower limbs) and the histological findings (ranging from nonspecific myopathic changes to myofibrillar disarrays and rimmed vacuoles) are extremely variable. However, despite being characterized by a wide clinical and genetic heterogeneity, the distal myopathies are a category of muscular dystrophies: genetic diseases with progressive loss of muscle fibers. Myopathic congenital arthrogryposis is also a form of distal myopathy usually caused by focal amyoplasia. Massive parallel sequencing has further expanded the long list of genes associated with a distal myopathy, and contributed identifying as distal myopathy-causative rare variants in genes more often related with other skeletal or cardiac muscle diseases. Currently, almost 20 genes (ACTN2, CAV3, CRYAB, DNAJB6, DNM2, FLNC, HNRNPA1, HSPB8, KHLH9, LDB3, MATR3, MB, MYOT, PLIN4, TIA1, VCP, NOTCH2NLC, LRP12, GIPS1) have been associated with an autosomal dominant form of distal myopathy. Pathogenic changes in four genes (ADSSL, ANO5, DYSF, GNE) cause an autosomal recessive form; and disease-causing variants in five genes (DES, MYH7, NEB, RYR1 and TTN) result either in a dominant or in a recessive distal myopathy. Finally, a digenic mechanism, underlying a Welander-like form of distal myopathy, has been recently elucidated. Rare pathogenic mutations in SQSTM1, previously identified with a bone disease (Paget disease), unexpectedly cause a distal myopathy when combined with a common polymorphism in TIA1. The present review aims at describing the genetic basis of distal myopathy and at summarizing the clinical features of the different forms described so far.
Topics: Age of Onset; Distal Myopathies; Humans
PubMed: 33458580
DOI: 10.36185/2532-1900-028 -
Human Mutation Jun 2020Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later,... (Review)
Review
Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype-phenotype correlations based on available evidence.
Topics: Animals; Arrhythmias, Cardiac; Cardiomyopathies; Cardiomyopathy, Dilated; Disease Models, Animal; Filamins; Genetic Association Studies; Humans; Muscular Diseases; Mutation; Myopathies, Structural, Congenital
PubMed: 32112656
DOI: 10.1002/humu.24004 -
Neurologic Clinics Aug 2020The distal myopathies are a rare and heterogeneous group of neuromuscular disorders. Patients present with weakness of the hands, distal lower extremities, or both. Age... (Review)
Review
The distal myopathies are a rare and heterogeneous group of neuromuscular disorders. Patients present with weakness of the hands, distal lower extremities, or both. Age of onset varies from early childhood to late adulthood. Most of the disorders causing distal myopathic weakness are genetically based. The list of genetic disorders associated with distal-onset weakness is ever-expanding and complicated by pronounced genetic heterogeneity, phenotypic variability, and complex multisystem involvement. There are no known effective disease-modifying treatments for the distal myopathies. Evaluation, symptomatic management, and periodic monitoring of patients in a multidisciplinary neuromuscular center are the mainstays of care.
Topics: Adult; Aged; Distal Myopathies; Female; Humans; Male; Mass Screening; Middle Aged; Young Adult
PubMed: 32703474
DOI: 10.1016/j.ncl.2020.03.007 -
Neurologic Clinics Aug 2014In this article, distal myopathy syndromes are discussed. A discussion of the more traditional distal myopathies is followed by discussion of the myofibrillar... (Review)
Review
In this article, distal myopathy syndromes are discussed. A discussion of the more traditional distal myopathies is followed by discussion of the myofibrillar myopathies. Other clinically and genetically distinctive distal myopathy syndromes usually based on single or smaller family cohorts are reviewed. Other neuromuscular disorders that are important to recognize are also considered, because they show prominent distal limb weakness.
Topics: Age of Onset; Disease Progression; Distal Myopathies; Humans; Muscle Proteins; Muscle, Skeletal; Mutation
PubMed: 25037092
DOI: 10.1016/j.ncl.2014.04.004 -
European Journal of Translational... Mar 2022Neuromuscular disorders are a heterogeneous group of acquired or hereditary conditions that affect striated muscle function. The resulting decrease in muscle strength...
Neuromuscular disorders are a heterogeneous group of acquired or hereditary conditions that affect striated muscle function. The resulting decrease in muscle strength and motility irreversibly impacts quality of life. In addition to directly affecting skeletal muscle, pathogenesis can also arise from dysfunctional crosstalk between nerves and muscles, and may include cardiac impairment. Muscular weakness is often progressive and paralleled by continuous decline in the ability of skeletal muscle to functionally adapt and regenerate. Normally, the skeletal muscle resident stem cells, named satellite cells, ensure tissue homeostasis by providing myoblasts for growth, maintenance, repair and regeneration. We recently defined 'Satellite Cell-opathies' as those inherited neuromuscular conditions presenting satellite cell dysfunction in muscular dystrophies and myopathies (doi:10.1016/j.yexcr.2021.112906). Here, we expand the portfolio of Satellite Cell-opathies by evaluating the potential impairment of satellite cell function across all 16 categories of neuromuscular disorders, including those with mainly neurogenic and cardiac involvement. We explore the expression dynamics of myopathogenes, genes whose mutation leads to skeletal muscle pathogenesis, using transcriptomic analysis. This revealed that 45% of myopathogenes are differentially expressed during early satellite cell activation (0 - 5 hours). Of these 271 myopathogenes, 83 respond to Pax7, a master regulator of satellite cells. Our analysis suggests possible perturbation of satellite cell function in many neuromuscular disorders across all categories, including those where skeletal muscle pathology is not predominant. This characterisation further aids understanding of pathomechanisms and informs on development of prognostic and diagnostic tools, and ultimately, new therapeutics.
PubMed: 35302338
DOI: 10.4081/ejtm.2022.10064 -
Revue Neurologique Oct 2016Distal myopathies and myofibrillar myopathies are both rare subcategories of muscle diseases. Myofibrillar myopathies are genetically heterogeneous group of diseases... (Review)
Review
Distal myopathies and myofibrillar myopathies are both rare subcategories of muscle diseases. Myofibrillar myopathies are genetically heterogeneous group of diseases characterized by distinctive histopathology of abnormal protein aggregations and myofibrillar disintegration. All genes causing myofibrillar myopathy encode proteins that either reside in or associate with the Z-disc. Distal myopathies are also genetically heterogeneous muscular dystrophies in which muscle weakness presents distally in the feet and/or hands. A subgroup of distal myopathies, desminopathy, distal myotilinopathy, ZASPopathy and alpha-B crystallin-mutated distal myopathy, belong to myofibrillar myopathies and show similar pathological changes in muscle biopsies. Common features of these diseases are dominant inheritance and adult-onset of symptoms starting in the feet and slowly progressing to encompass other muscle groups. Cardiomyopathy is not a common feature in distal MFM myopathies.
Topics: Distal Myopathies; Humans; Myofibrils
PubMed: 27638134
DOI: 10.1016/j.neurol.2016.07.019 -
Neurology. Genetics Jun 2021
PubMed: 34084941
DOI: 10.1212/NXG.0000000000000587 -
The Veterinary Clinics of North... Aug 2018Optimal function of skeletal muscle is essential for successful athletic performance. Even minor derangements in locomotor muscle function will impact power output,... (Review)
Review
Optimal function of skeletal muscle is essential for successful athletic performance. Even minor derangements in locomotor muscle function will impact power output, coordination, stamina, and desire to work during exercise. In this review, the presenting clinical signs, differential diagnoses, approach to diagnostic testing and treatment of muscle atrophy and weakness, focal muscle strain, and exertional myopathies are discussed. Exertional myopathies include polysaccharide storage myopathies, recurrent exertional rhabdomyolysis, malignant hyperthermia, and myofibrillar myopathy.
Topics: Animals; Genetic Predisposition to Disease; Horse Diseases; Horses; Muscular Diseases; Physical Exertion
PubMed: 29853158
DOI: 10.1016/j.cveq.2018.04.004 -
Annual Review of Pathology Jan 2020Autophagy is an evolutionarily conserved catabolic process that targets different types of cytoplasmic cargo (such as bulk cytoplasm, damaged cellular organelles, and... (Review)
Review
Autophagy is an evolutionarily conserved catabolic process that targets different types of cytoplasmic cargo (such as bulk cytoplasm, damaged cellular organelles, and misfolded protein aggregates) for lysosomal degradation. Autophagy is activated in response to biological stress and also plays a critical role in the maintenance of normal cellular homeostasis; the latter function is particularly important for the integrity of postmitotic, metabolically active tissues, such as skeletal muscle. Through impairment of muscle homeostasis, autophagy dysfunction contributes to the pathogenesis of many different skeletal myopathies; the observed autophagy defects differ from disease to disease but have been shown to involve all steps of the autophagic cascade (from induction to lysosomal cargo degradation) and to impair both bulk and selective autophagy. To highlight the molecular and cellular mechanisms that are shared among different myopathies with deficient autophagy, these disorders are discussed based on the nature of the underlying autophagic defect rather than etiology or clinical presentation.
Topics: Animals; Autophagy; Humans; Lysosomes; Muscle, Skeletal; Muscular Diseases; Protein Aggregation, Pathological
PubMed: 31594457
DOI: 10.1146/annurev-pathmechdis-012419-032618 -
Human Molecular Genetics Aug 2023The ZAK gene encodes two functionally distinct kinases, ZAKα and ZAKβ. Homozygous loss of function mutations affecting both isoforms causes a congenital muscle...
The ZAK gene encodes two functionally distinct kinases, ZAKα and ZAKβ. Homozygous loss of function mutations affecting both isoforms causes a congenital muscle disease. ZAKβ is the only isoform expressed in skeletal muscle and is activated by muscle contraction and cellular compression. The ZAKβ substrates in skeletal muscle or the mechanism whereby ZAKβ senses mechanical stress remains to be determined. To gain insights into the pathogenic mechanism, we exploited ZAK-deficient cell lines, zebrafish, mice and a human biopsy. ZAK-deficient mice and zebrafish show a mild phenotype. In mice, comparative histopathology data from regeneration, overloading, ageing and sex conditions indicate that while age and activity are drivers of the pathology, ZAKβ appears to have a marginal role in myoblast fusion in vitro or muscle regeneration in vivo. The presence of SYNPO2, BAG3 and Filamin C (FLNC) in a phosphoproteomics assay and extended analyses suggested a role for ZAKβ in the turnover of FLNC. Immunofluorescence analysis of muscle sections from mice and a human biopsy showed evidence of FLNC and BAG3 accumulations as well as other myofibrillar myopathy markers. Moreover, endogenous overloading of skeletal muscle exacerbated the presence of fibres with FLNC accumulations in mice, indicating that ZAKβ signalling is necessary for an adaptive turnover of FLNC that allows for the normal physiological response to sustained mechanical stress. We suggest that accumulation of mislocalized FLNC and BAG3 in highly immunoreactive fibres contributes to the pathogenic mechanism of ZAK deficiency.
Topics: Animals; Humans; Mice; Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Filamins; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital; Protein Isoforms; Zebrafish; Zebrafish Proteins
PubMed: 37427997
DOI: 10.1093/hmg/ddad113