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Clinica Chimica Acta; International... Jun 2022Myofibrillar myopathy (MFM) is characterized by phenotypic heterogeneity; decreased function of the myosin-directed chaperone, UNC-45B protein, leads to MFM II, which is...
Myofibrillar myopathy (MFM) is characterized by phenotypic heterogeneity; decreased function of the myosin-directed chaperone, UNC-45B protein, leads to MFM II, which is characterized by slow progressive proximal myasthenia. Currently, only two studies have reported 11 cases worldwide. This study aimed to conduct genetic research and etiological analysis of a neonatal case of perinatal myasthenia who eventually died due to autonomic dyspnea. The case involved a newborn female admitted for weak cries and groaning. Physical examination revealed shallow and irregular spontaneous breathing, difficulty feeding, hip flexion and knee flexion in both lower limbs, hypotonia (level 1), less translation action, and inability to resist gravity. The child died at 23 days after birth. Gene testing, mutation analysis, and crystal structure analysis were conducted. Cell culture and plasmid construction were conducted, followed by western blot analysis. Pathological changes, including Z-line breakage, were observed in the muscle biopsies of different tissues. Gene testing showed that UNC-45B had a novel compound heterozygous mutation (c.2357T>A/p.Met786Lys, c.2591A>C/p.His864Pro), and in vitro functional experiments showed that the variants could lead to a decrease in protein expression. This study expands the UNC-45B mutation and phenotype spectrum by reporting an MFM II case in a Chinese patient for the first time.
Topics: Female; Humans; Muscle Weakness; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital; Phenotype
PubMed: 35292251
DOI: 10.1016/j.cca.2022.03.002 -
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 -
Chinese Medical Sciences Journal =... Dec 2021Objective -related myopathy is a rare condition so far reported in twenty patients worldwide. The purpose of this study was to draw attention to this rare disease and to... (Review)
Review
Objective -related myopathy is a rare condition so far reported in twenty patients worldwide. The purpose of this study was to draw attention to this rare disease and to the fact that -related myopathy should be considered as a rare differential diagnosis of hypercapnia. Methods We report a sporadic case of a 14-year-old Chinese girl with a p.Pro209Leu mutation in and reviewed the literatures for reported cases related to this mutation. Results We described a 14-year-old Chinese girl who presented with gradually appearing symptoms of hypercapnia that required assisted ventilation. The muscle biopsy and the blood whole-exome sequencing results confirmed the diagnosis of myofibrillar myopathy with a p.Pro209Leu mutation in . Totally twenty-one patients from twenty families with a confirmed diagnosis of -related myopathy were reported to date, including this patient and literature review. The male to female ratio was 11:10 and most showed initial symptoms in the first decade of life. Most patients presented toe/clumsy walking or running as the onset symptom, followed by muscle weakness or atrophy. Creatine kinase levels were elevated in fourteen patients and were normal in three. Eighteen patients developed respiratory insufficiency during the disease course and thirteen (one could not tolerate non-invasive assisted ventilation) required non-invasive assisted ventilation for treatment. Except for one not reported, heart involvement was found in seventeen patients during the disease course and seven underwent heart transplantation. Z-disk streaming and aggregation could be observed in most of the patients' muscle histology. In the long-term follow-up, five patients died of cardiac or respiratory failure. Conclusion -associated myopathy is a rare type of myofibrillar myopathy. It should be considered as a rare differential diagnosis of hypercapnia.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Apoptosis Regulatory Proteins; Female; Humans; Hypercapnia; Male; Mutation; Myopathies, Structural, Congenital
PubMed: 34986963
DOI: 10.24920/003883 -
Brain and Behavior Feb 2022Mutations in the GFPT1 gene are associated with a particular subtype of congenital myasthenia syndrome (CMS) called limb-girdle myasthenia with tubular aggregates....
INTRODUCTION
Mutations in the GFPT1 gene are associated with a particular subtype of congenital myasthenia syndrome (CMS) called limb-girdle myasthenia with tubular aggregates. However, not all patients show tubular aggregates in muscle biopsy, suggesting the diversity of myopathology should be further investigated.
METHODS
In this study, we reported two unrelated patients clinically characterized by easy fatigability, limb-girdle muscle weakness, positive decrements of repetitive stimulation, and response to pyridostigmine. The routine examinations of myopathology were conducted. The causative gene was explored by whole-exome screening. In addition, we summarized all GFPT1-related CMS patients with muscle biopsy in the literature.
RESULTS
Pathogenic biallelic GFPT1 mutations were identified in the two patients. In patient one, muscle biopsy indicated vacuolar myopathic changes and atypical pathological changes of myofibrillar myopathy characterized by desmin deposits, Z-disc disorganization, and electronic dense granulofilamentous aggregation. In patient two, muscle biopsy showed typical myopathy with tubular aggregates. Among the 51 reported GFPT1-related CMS patients with muscle biopsy, most of them showed tubular aggregates myopathy, while rimmed vacuolar myopathy, autophagic vacuolar myopathy, mitochondria-like myopathy, neurogenic myopathy, and unspecific myopathic changes were also observed in some patients. These extra-synaptic pathological changes might be associated with GFPT1-deficiency hypoglycosylation and altered function of muscle-specific glycoproteins, as well as partly responsible for the permanent muscle weakness and resistance to acetylcholinesterase inhibitor therapy.
CONCLUSIONS
Most patients with GFPT1-related CMS had tubular aggregates in the muscle biopsy, but some patients could show great diversities of the pathological change. The myopathological findings might be a biomarker to predict the prognosis of the disease.
Topics: Acetylcholinesterase; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); Humans; Muscle Weakness; Muscle, Skeletal; Mutation; Myasthenic Syndromes, Congenital; Myopathies, Structural, Congenital
PubMed: 34978387
DOI: 10.1002/brb3.2469 -
Molecular Therapy. Nucleic Acids Mar 2022FilaminC (Flnc) is a member of the actin binding protein family, which is preferentially expressed in the cardiac and skeletal muscle tissues. Although it is known to...
FilaminC (Flnc) is a member of the actin binding protein family, which is preferentially expressed in the cardiac and skeletal muscle tissues. Although it is known to interact with proteins associated with myofibrillar myopathy, its unique role in skeletal muscle remains largely unknown. In this study, we identify the biological functions of Flnc and using chicken primary myoblast cells and animal models, respectively. From the results, we observe that the growth rate and mass of the skeletal muscle of fast-growing chickens (broilers) were significantly higher than those in slow-growing chickens (layers). Furthermore, we find that the expression of Flnc in the skeletal muscle of broilers was higher than that in the layers. Our results indicated that Flnc was highly expressed in the skeletal muscle, especially in the skeletal muscle of broilers than in layers. This suggests that Flnc plays a positive regulatory role in myoblast development. Flnc knockdown resulted in muscle atrophy, whereas the overexpression of Flnc promotes muscle hypertrophy in an animal model. We also found that Flnc interacted with dishevelled-2 (Dvl2), activated the wnt/β-catenin signaling pathway, and controlled skeletal muscle development. Flnc also antagonized the LC3-mediated autophagy system by decreasing Dvl2 ubiquitination. Moreover, Flnc knockdown activated and significantly increased mitophagy. In summary, these results indicate that the absence of Flnc induces autophagy or mitophagy and regulates muscle atrophy.
PubMed: 34976434
DOI: 10.1016/j.omtn.2021.11.022 -
Neuromuscular Disorders : NMD Dec 2021We report a case of a patient presenting with arrhythmogenic cardiomyopathy, myofibrillar myopathy, and multiorgan tumors. A 41-year-old woman with a history of...
We report a case of a patient presenting with arrhythmogenic cardiomyopathy, myofibrillar myopathy, and multiorgan tumors. A 41-year-old woman with a history of hypertrophic cardiomyopathy, diagnosed at 6 years of age, developed scoliosis after puberty. Following spinal surgery to address the scoliosis, she developed recurrent severe arrhythmia and heart failure. She developed hypoventilation at age 29 years. Proximal dominant weakness and mild elevation of serum creatine kinase indicated possible myopathy. Myofibrillar myopathy was diagnosed by muscle biopsy at age 30 year. Acute abdomen was repeatedly reported from age 33 years, eventually leading to a diagnosis of gastric polyp and erosive ulcer. A urinary bladder tumor was found at age 35 years, and breast cancer was diagnosed at age 40 years. Whole exome sequencing detected a heterozygous missense mutation in Filamin C. Recent evidences suggest that filamins are associated with tumors, and this case further highlights the clinical spectrum of filaminopathy.
Topics: Adult; Breast Neoplasms; Cardiomyopathy, Hypertrophic; Female; Humans; Muscular Dystrophies; Myopathies, Structural, Congenital; Urinary Bladder Neoplasms
PubMed: 34857437
DOI: 10.1016/j.nmd.2021.10.002 -
PloS One 2021αB-crystallin (heat shock protein β5/HSPB5) is a member of the family of small heat shock proteins that is expressed in various organs of the human body including eye...
αB-crystallin (heat shock protein β5/HSPB5) is a member of the family of small heat shock proteins that is expressed in various organs of the human body including eye lenses and muscles. Therefore, mutations in the gene of this protein (CRYAB) might have many pathological consequences. A new mutation has recently been discovered in the α-crystallin domain of this chaperone protein which replaces aspartate 109 with alanine (D109A). This mutation can cause myofibrillar myopathy (MFM), cataracts, and cardiomyopathy. In the current study, several spectroscopic and microscopic analyses, as well as gel electrophoresis assessment were applied to elucidate the pathogenic contribution of human αB-crystallin bearing D109A mutation in development of eye lens cataract and myopathies. The protein oligomerization, chaperone-like activity and chemical/thermal stabilities of the mutant and wild-type protein were also investigated in the comparative assessments. Our results suggested that the D109A mutation has a significant impact on the important features of human αB-crystallin, including its structure, size of the protein oligomers, tendency to form amyloid fibrils, stability, and chaperone-like activity. Given the importance of aspartate 109 in maintaining the proper structure of the α-crystallin domain, its role in the dimerization and chaperone-like activity, as well as preserving protein stability through the formation of salt bridges; mutation at this important site might have critical consequences and can explain the genesis of myopathy and cataract disorders. Also, the formation of large light-scattering aggregates and disruption of the chaperone-like activity by D109A mutation might be considered as important contributing factors in development of the eye lens opacity.
Topics: Cardiomyopathies; Cataract; Humans; Models, Molecular; Point Mutation; Protein Conformation; Protein Folding; Protein Multimerization; Protein Stability; alpha-Crystallin B Chain
PubMed: 34843556
DOI: 10.1371/journal.pone.0260306 -
Neurological Sciences : Official... May 2022Hereditary myopathy with early respiratory failure (HMERF) is a subtype of myofibrillar myopathy. Mutations located on exon 344 of the titin-A band, the 119th...
Hereditary myopathy with early respiratory failure (HMERF) is a subtype of myofibrillar myopathy. Mutations located on exon 344 of the titin-A band, the 119th fibronectin-3 domain (FN 119), are responsible for HMERF. In this article, we retrospectively analyzed the clinical features, findings of muscle imaging, muscle pathology, immunohistochemistry, and ultrastructural characteristics of seven patients diagnosed with HMERF at a single center in China. Muscle MRI showed the involvement of semitendinosus in four patients. The common pathological features were variability in fiber diameter, increased internal nuclei, endomysial fibrosis, and cytoplasmic bodies. On immunohistochemical examination, the cytoplasmic bodies stained positive for calpain-3, p53, and programmed death-ligand 1. Electron microscopy showed cytoplasmic bodies, distorted sarcomere architecture, glycogen pool, and subsarcolemmal accumulation of mitochondria and lysosomes. We retrospectively reviewed four reported HMERF patients in China. Among the 11 patients, the median age at onset was 34 years (range 14-54). Allelic frequency of mutation c.95195C > T was 36.36%. This study characterizes the phenotype and genotype spectrum of HMERF in China.
Topics: Genetic Diseases, Inborn; Humans; Molecular Biology; Muscle, Skeletal; Muscular Diseases; Mutation; Respiratory Insufficiency; Retrospective Studies
PubMed: 34839411
DOI: 10.1007/s10072-021-05783-1