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Journal of Applied Genetics Nov 2018Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibril dissolution and abnormal accumulation of degradation products. The... (Review)
Review
Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibril dissolution and abnormal accumulation of degradation products. The diagnosis of muscular disorders based on clinical presentation is difficult due to phenotypic heterogeneity and overlapping symptoms. In addition, precise diagnosis does not always explain the disease etiopathology or the highly variable clinical course even among patients diagnosed with the same type of myopathy. The advent of high-throughput next-generation sequencing (NGS) has provided a successful and cost-effective strategy for identification of novel causative genes in myopathies, including MFM. So far, pathogenic mutations associated with MFM phenotype, including atypical MFM-like cases, have been identified in 17 genes: DES, CRYAB, MYOT, ZASP, FLNC, BAG3, FHL1, TTN, DNAJB6, PLEC, LMNA, ACTA1, HSPB8, KY, PYROXD1, and SQSTM + TIA1 (digenic). Most of these genes are also associated with other forms of muscle diseases. In addition, in many MFM patients, numerous genomic variants in muscle-related genes have been identified. The various myopathies and muscular dystrophies seem to form a single disease continuum; therefore, gene identification in one disease impacts the genetic etiology of the others. In this review, we describe the heterogeneity of the MFM genetic background focusing on the role of rare variants, the importance of whole genome sequencing in the identification of novel disease-associated mutations, and the emerging concept of variant load as the basis of the phenotypic heterogeneity.
Topics: DNA Mutational Analysis; Genomics; High-Throughput Nucleotide Sequencing; Humans; Inheritance Patterns; Muscle Proteins; Mutation; Myopathies, Structural, Congenital; Phenotype
PubMed: 30203143
DOI: 10.1007/s13353-018-0463-4 -
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 -
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 -
Neuropathology : Official Journal of... Apr 2020Here, we report about reducing body myopathy, associated with a mutation in the four and a half LIM domain 1 gene (FHL1), identified in a 40-year-old woman who was...
Here, we report about reducing body myopathy, associated with a mutation in the four and a half LIM domain 1 gene (FHL1), identified in a 40-year-old woman who was suffering from subtle muscle weakness since the age of six and a limping gait since the age of 22 years. In addition to her elevated muscle enzyme level and magnetic resonance imaging, myopathy was highly suspected considering progression of symptoms. Nerve conduction studies and electromyogram suggested myopathy. The muscle biopsy revealed severe dystrophic features with many reducing bodies on hematoxylin and eosin, nicotinomide adenine dinucleotide dehydrogenase-tetrazolium reductase (NADH-TR), and modified Gomori stains and ubiquitin immunohistochemistry. Whole-exome sequencing revealed Xq26.3 encoding FHL1 missense mutations (NM_001159704) in exon 4: p.C150R, c.T448C. FHL1-mutated "reducing body myopathy" is worth reporting based on its rarity and unique clinicopathologic features including ultrastructure. The confirmative diagnosis is still very difficult before gene analysis because clinical and pathological features of this disease overlap with other myofibrillar myopathies. We stress the importance of genotype-phenotype correlation to obtain a precise diagnosis.
Topics: Adult; Female; Genetic Diseases, X-Linked; Humans; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Muscle Proteins; Muscular Diseases; Mutation, Missense
PubMed: 31803991
DOI: 10.1111/neup.12619 -
Cells May 2023Myofibrillar myopathies (MFM) are a group of chronic muscle diseases pathophysiologically characterized by accumulation of protein aggregates and structural failure of...
Myofibrillar myopathies (MFM) are a group of chronic muscle diseases pathophysiologically characterized by accumulation of protein aggregates and structural failure of muscle fibers. A subtype of MFM is caused by heterozygous mutations in the filamin C () gene, exhibiting progressive muscle weakness, muscle structural alterations and intracellular protein accumulations. Here, we characterize in depth the pathogenicity of two novel truncating FLNc variants (p.Q1662X and p.Y2704X) and assess their distinct effect on FLNc stability and distribution as well as their impact on protein quality system (PQS) pathways. Both variants cause a slowly progressive myopathy with disease onset in adulthood, chronic myopathic alterations in muscle biopsy including the presence of intracellular protein aggregates. Our analyses revealed that p.Q1662X results in FLNc haploinsufficiency and p.Y2704X in a dominant-negative FLNc accumulation. Moreover, both protein-truncating variants cause different PQS alterations: p.Q1662X leads to an increase in expression of several genes involved in the ubiquitin-proteasome system (UPS) and the chaperone-assisted selective autophagy (CASA) system, whereas p.Y2704X results in increased abundance of proteins involved in UPS activation and autophagic buildup. We conclude that truncating variants might have different pathogenetic consequences and impair PQS function by diverse mechanisms and to varying extents. Further studies on a larger number of patients are necessary to confirm our observations.
Topics: Humans; Filamins; Muscle Fibers, Skeletal; Myopathies, Structural, Congenital; Proteasome Endopeptidase Complex; Protein Aggregates; Ubiquitin
PubMed: 37174721
DOI: 10.3390/cells12091321 -
European Journal of Neurology Nov 2015Myofibrillar myopathies are a genetically diverse group of skeletal muscle disorders, with distinctive muscle histopathology. Causative mutations have been identified in... (Review)
Review
Myofibrillar myopathies are a genetically diverse group of skeletal muscle disorders, with distinctive muscle histopathology. Causative mutations have been identified in the genes MYOT, LDB3, DES, CRYAB, FLNC, BAG3, DNAJB6, FHL1, PLEC and TTN, which encode proteins which either reside in the Z-disc or associate with the Z-disc. Mitochondrial abnormalities have been described in muscle from patients with a myofibrillar myopathy. We reviewed the literature to determine the extent of mitochondrial dysfunction in each of the myofibrillar myopathy subtypes. Abnormal mitochondrial distribution is a frequent finding in each of the subtypes, but a high frequency of COX-negative or ragged red fibres, a characteristic finding in some of the conventional mitochondrial myopathies, is a rare finding. Few in vitro studies of mitochondrial function have been performed in affected patients.
Topics: Humans; Mitochondria; Myopathies, Structural, Congenital
PubMed: 26204918
DOI: 10.1111/ene.12814 -
Neurologic Clinics Aug 2016About 15% of myopathies present with distal weakness. Lack of sensory deficit, and preservation of sensory responses and deep tendon reflexes, favors a myopathic cause... (Review)
Review
About 15% of myopathies present with distal weakness. Lack of sensory deficit, and preservation of sensory responses and deep tendon reflexes, favors a myopathic cause for distal weakness. Electromyogram confirms this diagnosis. Profuse spontaneous discharges are common in inflammatory, metabolic, and myofibrillar myopathy (MFM). If the clinical picture indicates a specific disease such as facioscapulohumeral muscular dystrophy (FSHD), genetic testing provides the quickest diagnosis. Otherwise, muscle biopsy can distinguish specific features. The common causes of myopathic distal weakness are FSHD, myotonic dystrophy, and inclusion body myositis. Other causes include MFM, distal muscular dystrophies, metabolic myopathies, and congenital myopathies.
Topics: Adult; Aged; Distal Myopathies; Female; Humans; Male; Middle Aged
PubMed: 27445241
DOI: 10.1016/j.ncl.2016.04.014 -
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 -
Cell Biology International Apr 2015Myofibrillar myopathies (MFMs) are a group of sporadic and hereditary skeletal muscle diseases, which lead to severe physical disability and premature death. Most MFMs... (Review)
Review
Myofibrillar myopathies (MFMs) are a group of sporadic and hereditary skeletal muscle diseases, which lead to severe physical disability and premature death. Most MFMs are caused by mutations in genes encoding desmin, plectin, VCP, filamin C, BAG3, FHL-1, αB-crystallin, DNAJB6, myotilin, and ZASP. Biomechanical studies on primary human myoblasts carrying desmin and plectin mutations showed increased stiffness and reduced mechanical stress tolerance i.e., higher mechanical vulnerability compared to control cells. Higher stiffness of mutant cells may lead to higher intracellular stress at physiologic stretch and shear deformation, which in turn could trigger muscle fiber degeneration.
Topics: Desmin; Humans; Muscle Fibers, Skeletal; Myopathies, Structural, Congenital; Plectin
PubMed: 25264173
DOI: 10.1002/cbin.10384