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Respiratory Medicine Case Reports 2023Myofibrillar myopathies (MFM) are a group of heterogenic muscular disorders characterized by histological disorders with accumulation of myofibrillar degradation...
Myofibrillar myopathies (MFM) are a group of heterogenic muscular disorders characterized by histological disorders with accumulation of myofibrillar degradation products and providing disorganization of the myofibril network. Respiratory muscles may be involved in this disease. Ultrasound is used to assess not only the diaphragm but also the parasternal intercostal muscle. Parasternal intercostal muscle thickening may be used as an index of respiratory effort particularly in patients with diaphragm failure. We report the case of high parasternal intercostal muscle thickening associated with diaphragm dysfunction in a patient with MFM.
PubMed: 36479323
DOI: 10.1016/j.rmcr.2022.101788 -
Acta Neuropathologica Jan 2023DNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding. We performed exome sequencing on patients...
DNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding. We performed exome sequencing on patients with a presumed hereditary muscle disease and no genetic diagnosis. This identified four individuals from three unrelated families carrying an unreported homozygous stop gain (c.856A > T; p.Lys286Ter), or homozygous missense variants (c.74G > A; p.Arg25Gln and c.785 T > C; p.Leu262Ser) in DNAJB4. Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life. Selective involvement of the semitendinosus and biceps femoris muscles was seen on MRI scans of the thigh. On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles. DNAJB4 normally localizes to the Z-disc and was absent from muscle and fibroblasts of affected patients supporting a loss of function. Functional studies confirmed that the p.Lys286Ter and p.Leu262Ser mutant proteins are rapidly degraded in cells. In contrast, the p.Arg25Gln mutant protein is stable but failed to complement for DNAJB function in yeast, disaggregate client proteins or protect from heat shock-induced cell death consistent with its loss of function. DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis. DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones. These data demonstrate a novel chaperonopathy associated with DNAJB4 causing a myopathy with early respiratory failure. DNAJB4 loss of function variants may lead to the accumulation of DNAJB4 client proteins resulting in muscle dysfunction and degeneration.
Topics: Animals; Mice; Mutation; Muscular Diseases; Molecular Chaperones; Mutation, Missense; Respiratory Insufficiency; Muscle, Skeletal
PubMed: 36264506
DOI: 10.1007/s00401-022-02510-8 -
European Journal of Human Genetics :... Jan 2023Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and...
Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.
Topics: Infant; Mice; Animals; Humans; Child; Female; Cardiomyopathy, Dilated; Stroke Volume; Adaptor Proteins, Signal Transducing; LIM Domain Proteins; Ventricular Function, Left; Cardiomyopathies
PubMed: 36253531
DOI: 10.1038/s41431-022-01204-9 -
ELife Aug 2022Dystonin (), which encodes cytoskeletal linker proteins, expresses three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. mutations cause...
Dystonin (), which encodes cytoskeletal linker proteins, expresses three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. mutations cause different disorders, including hereditary sensory and autonomic neuropathy 6 (HSAN-VI) and epidermolysis bullosa simplex; however, etiology of the muscle phenotype in -related diseases has been unclear. Because contains all of the -encoding exons, known HSAN-VI mutations could affect both DST-a and DST-b isoforms. To investigate the specific function of DST-b in striated muscles, we generated a -specific mutant mouse model harboring a nonsense mutation. mutant mice exhibited late-onset protein aggregate myopathy and cardiomyopathy without neuropathy. We observed desmin aggregation, focal myofibrillar dissolution, and mitochondrial accumulation in striated muscles, which are common characteristics of myofibrillar myopathy. We also found nuclear inclusions containing p62, ubiquitin, and SUMO proteins with nuclear envelope invaginations as a unique pathological hallmark in mutation-induced cardiomyopathy. RNA-sequencing analysis revealed changes in expression of genes responsible for cardiovascular functions. In silico analysis identified alleles with nonsense mutations in populations worldwide, suggesting that some unidentified hereditary myopathy and cardiomyopathy are caused by mutations. Here, we demonstrate that the Dst-b isoform is essential for long-term maintenance of striated muscles.
Topics: Animals; Cardiomyopathies; Dystonin; Hereditary Sensory and Autonomic Neuropathies; Mice; Muscular Diseases; Mutation; Protein Aggregates; Protein Isoforms
PubMed: 35942699
DOI: 10.7554/eLife.78419 -
Neuromuscular Disorders : NMD Aug 2022The diagnosis of adult-onset genetic muscle diseases is challenging because of the diversity of clinical phenotypes, findings on muscle biopsy that may be nonspecific,...
The diagnosis of adult-onset genetic muscle diseases is challenging because of the diversity of clinical phenotypes, findings on muscle biopsy that may be nonspecific, and the large number of genetic causes. Even with thorough investigation, the diagnostic yield for genetic testing in these populations is very low, and the distinction from acquired conditions such as sporadic inclusion body myositis [sIBM] can also prove difficult. In this study, we analysed whole transcriptome data generated from RNA isolated from muscle biopsy tissues, from a cohort of 16 participants with sIBM and other histologic diagnoses. Our objective was to identify candidate RNA biomarkers that could be an adjunctive tool in differentiating these conditions. Principal component analysis was able to delineate the groups based on their histologic diagnoses. Gene ontology and pathway analyses demonstrated dysregulation of immune pathways in sIBM. In mitochondrial myopathy we observed upregulation of FGF21, GDF15, ASNS and TRIB3, which are known candidate biomarkers for mitochondrial myopathy. Novel findings included the identification of transcripts of unknown function that were dysregulated in myofibrillar myopathy [JPX], dystrophic changes [MEG3], and mitochondrial myopathy [GAS5]. We suggest future investigations with larger cohorts of participants to confirm the findings of this study, with further directed experiments to determine the role of novel transcripts in disease pathogenesis.
Topics: Biomarkers; Biopsy; Gene Expression Profiling; Humans; Muscle, Skeletal; Myositis, Inclusion Body; RNA
PubMed: 35850946
DOI: 10.1016/j.nmd.2022.04.009 -
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 -
Equine Veterinary Journal Mar 2023Genetic tests for variants in MYOT (P2; rs1138656462), FLNC (P3a; rs1139799323 or P3b; rs1142918816) and MYOZ3 (P4; rs1142544043) genes are offered commercially to...
Absence of myofibrillar myopathy in Quarter Horses with a histopathological diagnosis of type 2 polysaccharide storage myopathy and lack of association with commercial genetic tests.
BACKGROUND
Genetic tests for variants in MYOT (P2; rs1138656462), FLNC (P3a; rs1139799323 or P3b; rs1142918816) and MYOZ3 (P4; rs1142544043) genes are offered commercially to diagnose myofibrillar myopathy (MFM) and type 2 polysaccharide storage myopathy (PSSM2) in Quarter Horses (QH).
OBJECTIVES
To determine if PSSM2-QH has histopathological features of MFM. To compare genotype and allele frequencies of variants P2, P3, P4 between control-QH and PSSM2-QH diagnosed by histopathology.
STUDY DESIGN
Retrospective cross-sectional.
METHODS
The study includes a total of 229 healthy control-QH, 163 PSSM2-QH GYS1 mutation negative. Desmin stains of gluteal/semimembranosus muscle were evaluated. Purported disease alleles P2, P3a, P3b, P4 were genotyped by pyrosequencing. Genotype, allele frequency and total number of variant alleles or loci were compared between phenotypes using additive/genotypic and dominant models and quantitative effects evaluated by multivariable logistic regression.
RESULTS
Histopathological features of MFM were absent in all QH. A P variant allele at any locus was not associated (P > .05) with a histopathological diagnosis of PSSM2 and one or more P variants were common in control-QH (57%) and PSSM2-QH (61%). Allele frequencies (control/PSSM2) were: 0.24/0.21 (P2), 0.07/0.12 (P3a), 0.07/0.11 (P3b) and 0.06/0.08 (P4). P3a and P3b loci were not independent (r = 0.894); and not associated with PSSM2 histopathology comparing the haplotype of both P3a and P3b variants to other haplotypes. A receiver operator curve did not accurately predict the PSSM2 phenotype (AUC = 0.67, 95% CI 0.62-0.72), and there was no difference in the total number of variant loci or total variant allele count between control-QH and PSSM2-QH.
MAIN LIMITATIONS
P3a and P3b were not in complete linkage disequilibrium.
CONCLUSIONS
The P2, P3 and P4 variants in genes associated with human MFM were not associated with PSSM2 in 392 QH. Their use would improperly diagnose PSSM2/MFM in 57% of healthy QH and fail to diagnose PSSM2 in 40% of QH with histopathological evidence of PSSM2.
Topics: Humans; Horses; Animals; Retrospective Studies; Cross-Sectional Studies; Muscle, Skeletal; Myopathies, Structural, Congenital; Polysaccharides; Horse Diseases
PubMed: 35288976
DOI: 10.1111/evj.13574 -
Acta Myologica : Myopathies and... Dec 2021Myofibrillar myopathies are a heterogeneous group of neuromuscular disorders characterized by degeneration of Z-disk, causing the disintegration of myofibrils. They may...
Myofibrillar myopathies are a heterogeneous group of neuromuscular disorders characterized by degeneration of Z-disk, causing the disintegration of myofibrils. They may be caused by mutations in different genes, among these, the BAG3 gene (Bcl-2 associed-athanogene-3) encodes a multidomain protein that plays an important role in many cellular processes. We report the case of a 16-year-old male who at 4 years of age presented with a hypertrophic obstructive cardiomyopathy, then developed axonal sensory motor polyneuropathy, muscle weakness, rigid spine, severe kyphoscoliosis and respiratory failure. Muscle biopsy showed the typical hallmark of myofibrillar myopathy with abnormal cytoplasmic expression of multiple proteins. Ade novo heterozygous common mutation in the BAG3 gene with a c.626C > T (p.Pro209Leu) was discovered on NGS genetic analysis. Mutations in the BAG3 gene are causes of a severe and progressive condition and natural history data are important to be collected. An early diagnosis is critical for prognostic implications in cardiomyopathy and respiratory failure treatment.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Apoptosis Regulatory Proteins; Cardiomyopathies; Child; Humans; Male; Mutation; Myopathies, Structural, Congenital
PubMed: 35047758
DOI: 10.36185/2532-1900-061 -
Medicine Jan 2022Mutations in Bcl-2-associated athanogene-3 (BAG-3) can cause a rare subtype of myofibrillar myopathies (MFMs), characterized by progressive muscle weakness,...
RATIONALE
Mutations in Bcl-2-associated athanogene-3 (BAG-3) can cause a rare subtype of myofibrillar myopathies (MFMs), characterized by progressive muscle weakness, cardiomyopathy, and severe respiratory insufficiency in childhood. Little is known about diaphragmatic function in BAG-3 MFM. To our knowledge, this is the first case report of detailed evaluation of diaphragmatic function with ultrasound in BAG-3 MFM.
PATIENT CONCERN
We describe the case of a 15-year-old girl who complained of fever and shortness of breath. Diaphragmatic sonography revealed bilateral diaphragmatic paralysis. Shortness of breath progressed to respiratory failure approximately 3 months later.
DIAGNOSIS
A neurologist was consulted and genetic sequencing identified a p.Pro209Leu mutation in BAG-3, yielding diagnosis of BAG-3 MFM leading to bilateral diaphragmatic paralysis.
INTERVENTIONS
Respiratory muscle training and long-term mechanical ventilation.
OUTCOMES
It is quite unfortunate for this patient to have a poor prognosis due to the lack of effective treatment for this genetic disorder.
LESSONS
This case provides more clinical information for this rare disease which may cause severe diaphragm pathological damage leading to respiratory failure in BAG3 MFM and a future study with a systematic evaluation of a greater number of patients will be necessary to characterize this population.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Apoptosis Regulatory Proteins; Diaphragm; Dyspnea; Female; Humans; Muscle Weakness; Myopathies, Structural, Congenital; Respiratory Paralysis; Transcription Factors
PubMed: 35029900
DOI: 10.1097/MD.0000000000028484