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Frontiers in Neurology 2022The gene encodes desmin, a key intermediate filament of skeletal, cardiac and smooth muscle. Pathogenic variants produce a range of skeletal and cardiac muscle...
The gene encodes desmin, a key intermediate filament of skeletal, cardiac and smooth muscle. Pathogenic variants produce a range of skeletal and cardiac muscle disorders collectively known as the desminopathies. We report three desminopathy cases which highlight the phenotypic heterogeneity of this disorder and discuss various factors that may contribute to the clinical differences seen between patients with different desmin variants and also between family members with the same variant.
PubMed: 36726751
DOI: 10.3389/fneur.2022.1110934 -
International Journal of Molecular... Dec 2022Mutations in the human desmin gene (DES) may cause both autosomal dominant and recessive cardiomyopathies leading to heart failure, arrhythmias and atrio-ventricular...
Mutations in the human desmin gene (DES) may cause both autosomal dominant and recessive cardiomyopathies leading to heart failure, arrhythmias and atrio-ventricular blocks, or progressive myopathies. Cardiac conduction disorders, arrhythmias and cardiomyopathies usually associated with progressive myopathy are the main manifestations of autosomal dominant desminopathies, due to mono-allelic pathogenic variants. The recessive forms, due to bi-allelic variants, are very rare and exhibit variable phenotypes in which premature sudden cardiac death could also occur in the first or second decade of life. We describe a further case of autosomal recessive desminopathy in an Italian boy born of consanguineous parents, who developed progressive myopathy at age 12, and dilated cardiomyopathy four years later and died of intractable heart failure at age 17. Next Generation Sequencing (NGS) analysis identified the homozygous loss-of-function variant c.634C>T; p.Arg212*, which was likely inherited from both parents. Furthermore, we performed a comparison of clinical and genetic results observed in our patient with those of cases so far reported in the literature.
Topics: Male; Humans; Child; Adolescent; Desmin; Muscle, Skeletal; Cardiomyopathies; Myopathies, Structural, Congenital; Mutation; Arrhythmias, Cardiac; Heart Failure; Pedigree
PubMed: 36555543
DOI: 10.3390/ijms232415906 -
Human Molecular Genetics Jul 2020Cofilin-2 is an actin-binding protein that is predominantly expressed in skeletal and cardiac muscles and belongs to the AC group of proteins, which includes cofilin-1...
Cofilin-2 is an actin-binding protein that is predominantly expressed in skeletal and cardiac muscles and belongs to the AC group of proteins, which includes cofilin-1 and destrin. In humans, cofilin-2 (CFL2) mutations have been associated with congenital myopathies that include nemaline and myofibrillar myopathy. To understand the pathogenicity of the human CFL2 mutation, p.A35T, that first linked cofilin-2 with the human disease, we created a knock-in mouse model. The Cfl2A35T/A35T (KI) mice were indistinguishable from their wild-type littermates at birth, but they rapidly worsened and died by postnatal day 9. The phenotypic, histopathologic and molecular findings mimicked the constitutive Cfl2-knockout (KO) mice described previously, including sarcomeric disruption and actin accumulations in skeletal muscles and negligible amounts of cofilin-2 protein. In addition, KI mice demonstrated a marked reduction in Cfl2 mRNA levels in various tissues including skeletal muscles. Further investigation revealed evidence of alternative splicing with the presence of two alternate transcripts of smaller size. These alternate transcripts were expressed at very low levels in the wild-type mice and were significantly upregulated in the mutant mice, indicating that pre-translational splicing defects may be a critical component of the disease mechanism associated with the mutation. Evidence of reduced expression of the full-length CFL2 transcript was also observed in the muscle biopsy sample of the patient with p.A35T mutation.
Topics: Actins; Animals; Cofilin 2; Disease Models, Animal; Gene Knock-In Techniques; Genetic Predisposition to Disease; Humans; Mice; Mice, Knockout; Microfilament Proteins; Muscle, Skeletal; Muscular Diseases; Mutation; Phenotype; RNA, Messenger
PubMed: 32160286
DOI: 10.1093/hmg/ddaa035 -
European Journal of Medical Genetics Nov 2020Mutations in the gene kyphoscoliosis peptidase (KY) are known to cause myofibrillar myopathy-7 and hereditary spastic paraplegia. We investigated the genetic cause of a...
Mutations in the gene kyphoscoliosis peptidase (KY) are known to cause myofibrillar myopathy-7 and hereditary spastic paraplegia. We investigated the genetic cause of a complex neurological phenotype in a consanguineous Pakistani family with four affected members, manifesting lower limb spasticity and weakness, toe walking, pes equinovarus, and a speech disorder. Genome-wide linkage analysis with microsatellite markers delineated chromosome 3q22.2-q24 harboring the disease gene. Whole exome sequencing was performed for two subjects, identifying a homozygous 14-bp frameshift deletion NM_178554.6:c.842_855del; p(Val281GlyfsTer18) in KY. The variant segregated with the phenotype and was absent from public databases and 100 ethnically matched controls. We confirm a novel homozygous KY variant causing a complex neurological phenotype in this family. A review of previously reported KY variants suggests that variants in this gene can cause a spectrum of neurological phenotypes.
Topics: Child; Female; Frameshift Mutation; Gait; Homozygote; Humans; Male; Myopathies, Structural, Congenital; Pedigree; Peptide Hydrolases; Phenotype; Spastic Paraplegia, Hereditary; Speech
PubMed: 32818658
DOI: 10.1016/j.ejmg.2020.104031 -
European Journal of Human Genetics :... Aug 2019We establish autosomal recessive DES variants p.(Leu190Pro) and a deep intronic splice variant causing inclusion of a frameshift-inducing artificial exon/intronic...
We establish autosomal recessive DES variants p.(Leu190Pro) and a deep intronic splice variant causing inclusion of a frameshift-inducing artificial exon/intronic fragment, as the likely cause of myopathy with cardiac involvement in female siblings. Both sisters presented in their twenties with slowly progressive limb girdle weakness, severe systolic dysfunction, and progressive, severe respiratory weakness. Desmin is an intermediate filament protein typically associated with autosomal dominant myofibrillar myopathy with cardiac involvement. However a few rare cases of autosomal recessive desminopathy are reported. In this family, a paternal missense p.(Leu190Pro) variant was viewed unlikely to be causative of autosomal dominant desminopathy, as the father and brothers carrying this variant were clinically unaffected. Clinical fit with a DES-related myopathy encouraged closer scrutiny of all DES variants, identifying a maternal deep intronic variant within intron-7, predicted to create a cryptic splice site, which segregated with disease. RNA sequencing and studies of muscle cDNA confirmed the deep intronic variant caused aberrant splicing of an artificial exon/intronic fragment into maternal DES mRNA transcripts, encoding a premature termination codon, and potently activating nonsense-mediate decay (92% paternal DES transcripts, 8% maternal). Western blot showed 60-75% reduction in desmin levels, likely comprised only of missense p.(Leu190Pro) desmin. Biopsy showed fibre size variation with increased central nuclei. Electron microscopy showed extensive myofibrillar disarray, duplication of the basal lamina, but no inclusions or aggregates. This study expands the phenotypic spectrum of recessive DES cardio/myopathy, and emphasizes the continuing importance of muscle biopsy for functional genomics pursuit of 'tricky' variants in neuromuscular conditions.
Topics: Adult; Base Sequence; Cardiomyopathies; Desmin; Exons; Family Health; Female; Genes, Recessive; Genetic Predisposition to Disease; Humans; Introns; Male; Muscular Dystrophies; Mutation, Missense; Myopathies, Structural, Congenital; Pedigree; RNA Splicing; Siblings
PubMed: 31024060
DOI: 10.1038/s41431-019-0393-6 -
Journal of Integrative Neuroscience Mar 2021Infantile hypertonic myofibrillar myopathy is characterized by the rapid development of rigid muscles and respiratory insufficiency soon after birth, with very high...
Infantile hypertonic myofibrillar myopathy is characterized by the rapid development of rigid muscles and respiratory insufficiency soon after birth, with very high mortality. It is extremely rare, and only a few cases having been reported until now. Here we report four Chinese infants with fatal neuromuscular disorders characterized by abdominal and trunk skeletal muscle stiffness and rapid respiratory insufficiency progression. Electromyograms showed increased insertion activities and profuse fibrillation potentials with complex repetitive discharges. Immunohistochemistry staining of muscle biopsies showed accumulations of desmin in the myocytes. Powdery Z-bands with dense granules across sarcomeres were observed in muscle fibers using electron microscopy. All patients carry a homozygous c.3G>A mutation in the gene, which resulted in the loss of the initiating methionine and the absence of protein. This study's findings help further understand the disease and highlight a founder mutation in the Chinese population.
Topics: China; Electromyography; Fatal Outcome; Humans; Infant; Magnetic Resonance Imaging; Male; Muscle, Skeletal; Myopathies, Structural, Congenital; alpha-Crystallin B Chain
PubMed: 33834702
DOI: 10.31083/j.jin.2021.01.267 -
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 -
Molecular Genetics and Metabolism... Mar 2024gene encodes for Filamin-C (FLNC) protein, a sacromeric protein with important structural and signaling functions in the myocyte. Pathogenic dominant variants in were...
gene encodes for Filamin-C (FLNC) protein, a sacromeric protein with important structural and signaling functions in the myocyte. Pathogenic dominant variants in were initially linked to myofibrillar myopathy and over time, evidence showed association of this gene with different forms of autosomal dominant cardiomyopathy including hypertrophic, dilated and restrictive forms. Recently, two cases of recessive mutations have been reported by Reinstein et al. and Kölbel et al., one with only cardiomyopathy and other with only myopathy. In this report, we describe a third case, a boy who was diagnosed at 10 years of age with shortness of breath and dilated cardiomyopathy who on sequencing was found to have a novel homozygous splice site variant (NM_001458.4 c.2122-1G>C) in . This case suggests that the phenotype associated with variants in FLNC is very heterogenous and can be inherited in dominant or recessive forms, with later being more severe and of earlier onset.
PubMed: 38077956
DOI: 10.1016/j.ymgmr.2023.101027 -
Clinical Medicine (London, England) Nov 2020Breathlessness is a subjective symptom that may stem from a number of pathological and functional aetiologies. Consequently, clinicians are often faced with the...
Breathlessness is a subjective symptom that may stem from a number of pathological and functional aetiologies. Consequently, clinicians are often faced with the challenge of navigating between the tensions of Occam's razor (parsimonious aetiology) or Hickam's dictum (multiple diagnoses). We report a case of a 36-year-old woman with a lifelong history of episodic breathlessness caused at various times by dysfunctions of lung parenchyma (emphysema) and airway smooth muscle (asthma), skeletal muscle (filamin-C fibrillary myopathy) and cardiac muscle (cardiomyopathy). We illustrate the utility of the modern diagnostic toolbox in the assessment, understanding and management of complex dyspnoea (including the use of inflammometry, inhaled-gas magnetic resonance imaging-guided bronchial thermoplasty, and genetic testing), and also demonstrate the importance of interdisciplinary data interpretation in establishing accurate aetiologic diagnoses.
Topics: Adult; Asthma; Dyspnea; Female; Genomics; Humans; Lung; Lung Neoplasms
PubMed: 33199334
DOI: 10.7861/clinmed.2020-0661 -
Heliyon Feb 2024Myofibrillar myopathies (MFM) are a group of sporadic and inherited progressive skeletal muscle disorders that can lead to physical disability and premature death. To...
OBJECTIVE
Myofibrillar myopathies (MFM) are a group of sporadic and inherited progressive skeletal muscle disorders that can lead to physical disability and premature death. To date, pathogenic variants in different genes are associated with MFM. MFM induced by variants in the Desmin () gene is the most common subtype of MFM.
CASE PRESENTATION
A 15-year-old boy with MFM was described, whose symptoms first presented as cardiac symptoms. Enlarged right and left atria, thickened ventricular septal (IVS) and mild mitral (MR) and tricuspid regurgitation (TR) in the echocardiography were found. Atrial fibrillation, intermittent atrioventricular (AV) block, ST-T changes in the dynamic electrocardiogram (ECG) were shown. Mild myopathic changes in the electromyographic exam were detected. Ultrastructural analysis found slight Z-line changes and a few small myolysis lesions, but no abnormal inclusion bodies. Genetic testing detected a heterozygous missense variant (c.1216C > T) of DES, and 2 rare variants: (c.1102C > G) and (c.3074G > A). The patient's parents didn't show skeletal and cardiac muscle disorders. DNA sequencing analysis showed no variant of was carried by them. Thus, we detected a case of MFM caused by de novo variant c.1216C > T/p.Arg406Trp with predominantly myocardial alterations.
PubMed: 38314304
DOI: 10.1016/j.heliyon.2024.e25009