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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 -
Neuromuscular Disorders : NMD Jan 2021Z-band alternatively spliced PDZ-motif protein (ZASP) is a sarcomeric component expressed both in cardiac and skeletal muscles. Mutations in the LDB3/ZASP gene cause...
Z-band alternatively spliced PDZ-motif protein (ZASP) is a sarcomeric component expressed both in cardiac and skeletal muscles. Mutations in the LDB3/ZASP gene cause cardiomyopathy and myofibrillar myopathy. We describe a c.76C>T / p.[Pro26Ser] mutation in the PDZ motif of LDB3/ZASP in two siblings exhibiting late-onset myopathy with axial, proximal and distal muscles involvement and marked variability in clinical severity in the absence of a significant family history for neuromuscular disorders. Notably, we identified involvement of the psoas muscle on MRI and muscle CT, a feature not previously documented. Proband's muscle biopsy showed an increase of ZASP expression by western blotting. Muscle fibres morphological features included peculiar sarcolemmal invaginations, pathological aggregates positive to ZASP, ubiquitin, p62 and LC3 antibodies, and the accumulation of autophagic vacuoles, suggesting that protein aggregate formation and autophagy are involved in this additional case of zaspopathy.
Topics: Adaptor Proteins, Signal Transducing; Aged; Autophagy; Female; Humans; LIM Domain Proteins; Magnetic Resonance Imaging; Male; Muscle, Skeletal; Muscular Diseases; Mutation, Missense; Protein Aggregates; Sarcomeres
PubMed: 33308939
DOI: 10.1016/j.nmd.2020.11.008 -
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 -
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 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 -
Neuromuscular Disorders : NMD Mar 2021A 63 year old male presented with a 20 year history of facial weakness and several years of nasal regurgitation and dysphonia. Examination revealed bilateral facial...
A 63 year old male presented with a 20 year history of facial weakness and several years of nasal regurgitation and dysphonia. Examination revealed bilateral facial weakness with nasal speech. Serum creatine kinase was 918 U/L. Neurophysiological studies suggested a myopathy and biopsy of the left vastus lateralis showed serpentine basophilic inclusions in the sarcoplasm and strong oxidative enzyme activity suggesting mitochondria accumulation. The muscle MRI showed selective fatty replacement within semitendinosus, gastrocnemius and soleus indicative of a desminopathy. A heterozygous missense variant c.17C>G (p.Ser6Trp) was identified within DES, predicted to be pathogenic in silico and previously described in a family with distal limb weakness. There are no previous case reports of desminopathy presenting with facial weakness, to our knowledge. Diagnosis was suggested following myoimaging of clinically unaffected muscles. Our study highlights the importance of muscle MRI in the diagnostic evaluation of muscle disease and further expands the known phenotypic heterogeneity of desminopathies.
Topics: Cardiomyopathies; Facial Muscles; Heterozygote; Humans; Lower Extremity; Magnetic Resonance Imaging; Male; Middle Aged; Muscle Weakness; Muscular Dystrophies; Mutation, Missense
PubMed: 33546848
DOI: 10.1016/j.nmd.2020.12.013 -
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 -
Neuromuscular Disorders : NMD Mar 2020Mutations in heat shock protein B8 were initially identified in inherited neuropathies and were more recently found to cause a predominantly distal myopathy with...
Mutations in heat shock protein B8 were initially identified in inherited neuropathies and were more recently found to cause a predominantly distal myopathy with myofibrillar pathology and rimmed vacuoles. Rare patients also had proximal weakness. Only very few pathogenic variants have been identified in HSPB8. Disruption of the chaperone activity of heat shock protein B8 impairs chaperone-assisted selective autophagy and results in protein aggregation. We report a 23-year-old patient who presented with a 4-year history of predominantly proximal lower limb weakness due to a novel variant in HSPB8. The creatine kinase level was mildly elevated. Electrodiagnostic studies demonstrated a proximal-predominant myopathy without evidence of neuropathy, and muscle histopathology revealed rimmed vacuoles and myofibrillar protein aggregates. Whole exome sequencing identified a de novo frameshift variant in the C-terminal region of HSPB8 (c.577_580dupGTCA, p.Thr194Serfs*23). This case demonstrates that HSPB8-related disorders can present with early onset limb-girdle myopathy without associated neuropathy.
Topics: Adult; Heat-Shock Proteins; Humans; Lysosomal Storage Diseases; Male; Molecular Chaperones; Muscular Diseases; Muscular Dystrophies, Limb-Girdle; Myopathies, Structural, Congenital; Young Adult
PubMed: 32165108
DOI: 10.1016/j.nmd.2020.02.005 -
Journal of Neurology Apr 2020Bcl2-associated athanogene 3 (BAG3) gene mutations cause dilated cardiomyopathy and myofibrillar myopathy. Recently, a novel c.625C>T (p.Pro209Ser) mutation in BAG3 was...
Bcl2-associated athanogene 3 (BAG3) gene mutations cause dilated cardiomyopathy and myofibrillar myopathy. Recently, a novel c.625C>T (p.Pro209Ser) mutation in BAG3 was reported to cause axonal Charcot-Marie-Tooth (CMT) disease in three families. Here, we describe two patients with adult-onset and moderate CMT in a Chinese family. Nerve conduction velocity studies revealed an axonal sensorimotor neuropathy, which was supported by sural nerve biopsy. Lower limb magnetic resonance imaging (MRI) revealed fatty infiltration more severe in the soleus and deep posterior compartment muscles than in the medial gastrocnemius and anterior compartment muscles. Whole exome sequencing identified the same c.625C>T (p.Pro209Ser) mutation in BAG3, which co-segregated with the CMT disease in this family. This study further enforces the association between BAG3 gene and CMT disease, indicating that BAG3 should be considered in the genetic testing for CMT. The p.Pro209Ser mutation with different ethnic origins might be another hotspot mutation of BAG3. MRI is helpful to detect accurate extent of muscle involvement.
Topics: Adaptor Proteins, Signal Transducing; Adult; Apoptosis Regulatory Proteins; Charcot-Marie-Tooth Disease; China; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Pedigree
PubMed: 31853710
DOI: 10.1007/s00415-019-09680-8