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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 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 -
Neurology. Genetics Jun 2021
PubMed: 34084941
DOI: 10.1212/NXG.0000000000000587 -
Case Reports in Neurology 2020A 76-year-old man with a 5-year history of gait difficulties was suspected to have length-dependent sensorimotor polyneuropathy. Electrodiagnostic results pointed to a...
A 76-year-old man with a 5-year history of gait difficulties was suspected to have length-dependent sensorimotor polyneuropathy. Electrodiagnostic results pointed to a foot drop of neurogenic etiology, except for the prominence of myotonic discharges on needle EMG. Tests for acquired and genetic causes of polyneuropathy were unrevealing. The patient's first-degree cousin, with a much different clinical phenotype had been diagnosed with myofibrillar myopathy. Our patient was eventually found to carry the same myotilin c.179C>T p.Ser60Phe mutation. Muscle MRI was helpful in delineating clinically unsuspected involvement of paraspinal and pelvi-femoral muscles, as well as showing marked myopathic fatty infiltration of distal leg muscles. The association of neuropathy and myopathy is a recognized feature of myofibrillar myopathy. In some patients with unexplained foot drop, whole-body muscle MRI and a dedicated genetic mutation testing strategy may help reveal a diagnosis of genetic myopathy.
PubMed: 32647524
DOI: 10.1159/000506193 -
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 -
Clinical Medicine Insights. Cardiology 2016Arrhythmogenic right ventricular dysplasia (ARVD) is a rare, genetic disorder predominantly affecting the right ventricle. There is increasing evidence that in some... (Review)
Review
OBJECTIVES
Arrhythmogenic right ventricular dysplasia (ARVD) is a rare, genetic disorder predominantly affecting the right ventricle. There is increasing evidence that in some cases, ARVD is due to mutations in genes, which have also been implicated in primary myopathies. This review gives an overview about myopathy-associated ARVD and how these patients can be managed.
METHODS
A literature review was done using appropriate search terms.
RESULTS
The myopathy, which is most frequently associated with ARVD, is the myofibrillar myopathy due to desmin mutations. Only in a single patient, ARVD was described in myotonic dystrophy type 1. However, there are a number of genes causing either myopathy or ARVD. These genes include lamin A/C, ZASP/cypher, transmembrane protein-43, titin, and the ryanodine receptor-2 gene. Diagnosis and treatment are identical for myopathy-associated ARVD and nonmyopathy-associated ARVD.
CONCLUSIONS
Patients with primary myopathy due to mutations in the desmin, dystrophia myotonica protein kinase, lamin A/C, ZASP/cypher, transmembrane protein-43, titin, or the ryanodine receptor-2 gene should be screened for ARVD. Patients carrying a pathogenic variant in any of these genes should undergo annual cardiological investigations for cardiac function and arrhythmias.
PubMed: 27790050
DOI: 10.4137/CMC.S38446 -
Brain : a Journal of Neurology Oct 2023Filamin-A-interacting protein 1 (FILIP1) is a structural protein that is involved in neuronal and muscle function and integrity and interacts with FLNa and FLNc....
Filamin-A-interacting protein 1 (FILIP1) is a structural protein that is involved in neuronal and muscle function and integrity and interacts with FLNa and FLNc. Pathogenic variants in filamin-encoding genes have been linked to neurological disorders (FLNA) and muscle diseases characterized by myofibrillar perturbations (FLNC), but human diseases associated with FILIP1 variants have not yet been described. Here, we report on five patients from four unrelated consanguineous families with homozygous FILIP1 variants (two nonsense and two missense). Functional studies indicated altered stability of the FILIP1 protein carrying the p.[Pro1133Leu] variant. Patients exhibit a broad spectrum of neurological symptoms including brain malformations, neurodevelopmental delay, muscle weakness and pathology and dysmorphic features. Electron and immunofluorescence microscopy on the muscle biopsy derived from the patient harbouring the homozygous p.[Pro1133Leu] missense variant revealed core-like zones of myofibrillar disintegration, autophagic vacuoles and accumulation of FLNc. Proteomic studies on the fibroblasts derived from the same patient showed dysregulation of a variety of proteins including FLNc and alpha-B-crystallin, a finding (confirmed by immunofluorescence) which is in line with the manifestation of symptoms associated with the syndromic phenotype of FILIP1opathy. The combined findings of this study show that the loss of functional FILIP1 leads to a recessive disorder characterized by neurological and muscular manifestations as well as dysmorphic features accompanied by perturbed proteostasis and myopathology.
Topics: Humans; Filamins; Proteomics; Mutation; Muscular Diseases; Muscle Weakness; Carrier Proteins; Cytoskeletal Proteins
PubMed: 37163662
DOI: 10.1093/brain/awad152