Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures

2018 ◽  
Vol 56 (9) ◽  
pp. 617-621 ◽  
Author(s):  
Johann Böhm ◽  
Edoardo Malfatti ◽  
Emily Oates ◽  
Kristi Jones ◽  
Guy Brochier ◽  
...  
Keyword(s):  
Muscle Weakness ◽  
Bone Fractures ◽  
Bone Development ◽  
Homozygous Mutation ◽  
Transcriptional Coactivator ◽  
Related Disorder ◽  
Physiological Importance ◽  
Muscle Histology ◽  
Muscle Biopsies ◽  
Fetal Muscle

BackgroundThe activating signal cointegrator 1 (ASC-1) complex acts as a transcriptional coactivator for a variety of transcription factors and consists of four subunits: ASCC1, ASCC2, ASCC3 and TRIP4. A single homozygous mutation in ASCC1 has recently been reported in two families with a severe muscle and bone disorder.ObjectiveWe aim to contribute to a better understanding of the ASCC1-related disorder.MethodsHere, we provide a clinical, histological and genetic description of three additional ASCC1 families.ResultsAll patients presented with severe prenatal-onset muscle weakness, neonatal hypotonia and arthrogryposis, and congenital bone fractures. The muscle biopsies from the affected infants revealed intense oxidative rims beneath the sarcolemma and scattered remnants of sarcomeres with enlarged Z-bands, potentially representing a histopathological hallmark of the disorder. Sequencing identified recessive nonsense or frameshift mutations in ASCC1, including two novel mutations.ConclusionOverall, this work expands the ASCC1 mutation spectrum, sheds light on the muscle histology of the disorder and emphasises the physiological importance of the ASC-1 complex in fetal muscle and bone development.

scholarly journals Ostm1 from Mouse to Human: Insights into Osteoclast Maturation

2020 ◽  
Vol 21 (16) ◽  
pp. 5600 ◽  
Author(s):  
Jean Vacher ◽  
Michael Bruccoleri ◽  
Monica Pata
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Bone Fractures ◽  
Bone Development ◽  
Bone Matrix ◽  
Adult Life ◽  
Cell Types ◽  
Severe Form ◽  
Isolation And Characterization

The maintenance of bone mass is a dynamic process that requires a strict balance between bone formation and resorption. Bone formation is controlled by osteoblasts, while osteoclasts are responsible for resorption of the bone matrix. The opposite functions of these cell types have to be tightly regulated not only during normal bone development, but also during adult life, to maintain serum calcium homeostasis and sustain bone integrity to prevent bone fractures. Disruption of the control of bone synthesis or resorption can lead to an over accumulation of bone tissue in osteopetrosis or conversely to a net depletion of the bone mass in osteoporosis. Moreover, high levels of bone resorption with focal bone formation can cause Paget’s disease. Here, we summarize the steps toward isolation and characterization of the osteopetrosis associated trans-membrane protein 1 (Ostm1) gene and protein, essential for proper osteoclast maturation, and responsible when mutated for the most severe form of osteopetrosis in mice and humans.

scholarly journals Four Individuals with a Homozygous Mutation in Exon 1f of the PLEC Gene and Associated Myasthenic Features

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 716
Author(s):  
Magdalena Mroczek ◽  
Hacer Durmus ◽  
Ana Töpf ◽  
Yesim Parman ◽  
Volker Straub
Keyword(s):  
Homozygous Mutation ◽  
Resonance Imaging ◽  
Facial Weakness ◽  
Repetitive Nerve Stimulation ◽  
Turkish Origin ◽  
Mri Features ◽  
Muscle Magnetic Resonance Imaging ◽  
Magnetic Resonance Imaging Mri ◽  
Muscle Biopsies

We identified the known c.1_9del mutation in the PLEC gene in four unrelated females from consanguineous families of Turkish origin. All individuals presented with slowly progressive limb-girdle weakness without any dermatological findings, and dystrophic changes observed in their muscle biopsies. Additionally, the neurological examination revealed ptosis, facial weakness, fatigability, and muscle cramps in all four cases. In two patients, repetitive nerve stimulation showed a borderline decrement and a high jitter was detected in all patients by single-fiber electromyography. Clinical improvement was observed after treatment with pyridostigmine and salbutamol was started. We further characterize the phenotype of patients with limb-girdle muscular dystrophy R17 clinically, by muscle magnetic resonance imaging (MRI) features and by describing a common 3.8 Mb haplotype in three individuals from the same geographical region. In addition, we review the neuromuscular symptoms associated with PLEC mutations and the role of plectin in the neuromuscular junction.

Severe muscle damage with myofiber necrosis and macrophage infiltrates characterize anti-Mi2 positive dermatomyositis

Rheumatology ◽  
2020 ◽  
Author(s):  
Marco Fornaro ◽  
Francesco Girolamo ◽  
Lorenzo Cavagna ◽  
Franco Franceschini ◽  
Margherita Giannini ◽  
...  
Keyword(s):  
Muscle Damage ◽  
Medical Records ◽  
Pulmonary Involvement ◽  
Control Group ◽  
Histopathological Study ◽  
Diagnostic Purpose ◽  
Muscle Enzymes ◽  
Immune Mediated ◽  
Muscle Histology ◽  
Muscle Biopsies

Abstract Objective The aim of our study was to investigate clinical and histopathological findings in adult DM patients positive for anti-Mi2 (anti-Mi2+) antibodies compared with DM patients negative for anti-Mi2 (anti-Mi2–). Methods Clinical data of adult DM patients, who fulfilled EULAR/ACR 2017 classification criteria, were gathered from electronic medical records of three tertiary Rheumatology Units. Histopathological study was carried out on 12 anti-Mi2+ and 14 anti-Mi2– muscle biopsies performed for diagnostic purpose. Nine biopsies from immune mediated necrotizing myopathy (IMNM) patients were used as control group. Results Twenty-two anti-Mi2+ DM [90.9% female, mean age 56.5 (15.7) years] were compared with 69 anti-Mi2– DM patients [71% female, mean age 52.4 (17) years]. Anti-Mi2+ patients presented higher levels of serum muscle enzymes than anti-Mi2– patients [median (IQR) creatine-kinase fold increment: 16 (7–37)vs 3.5 (1–9.9), P <0.001] before treatment initiation. Moreover, a trend towards less pulmonary involvement was detected in anti-Mi2+ DM (9.1% vs 30.4%, P =0.05), without any case of rapidly progressive interstitial lung disease. At muscle histology, anti-Mi2+ patients showed more necrotic/degenerative fibres than anti-Mi2– patients [mean 5.3% (5) vs 0.8% (1), P <0.01], but similar to IMNM [5.9% (6), P >0.05]. In addition, the endomysial macrophage score was similar between anti-Mi2+ and IMNM patients [mean 1.2 (0.9) vs 1.3 (0.5), P >0.05], whereas lower macrophage infiltration was found in anti-Mi2– DM [mean 0.4 (0.5), <0.01]. Conclusions Anti-Mi2+ patients represent a specific DM subset with high muscle damage. Histological hallmarks were a higher prevalence of myofiber necrosis, endomysial involvement and macrophage infiltrates at muscle biopsy.

scholarly journals NXP-2 Positive Dermatomyositis: A Unique Clinical Presentation

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Zeeshan Butt ◽  
Leeza Patel ◽  
Manash K. Das ◽  
Christopher A. Mecoli ◽  
Alim Ramji
Keyword(s):  
Muscle Weakness ◽  
African American Male ◽  
Matrix Protein ◽  
Clinical Presentation ◽  
Tertiary Care ◽  
High Dose ◽  
Care Hospital ◽  
Nuclear Matrix Protein ◽  
Muscle Biopsies ◽  
Periorbital Swelling

Dermatomyositis (DM), a myopathy associated with inflammation and muscle weakness, has historically been difficult to diagnose. Recently, nuclear matrix protein (NXP-2) antibodies have been described as a myositis-specific antibody that may aid in the diagnostic evaluation. We present the case of a 21-year-old, previously healthy, African American male with DM. He presented to our outpatient clinic with periorbital swelling and a rash, for which he was started on prednisone by an ophthalmologist. Towards the end of the prednisone taper, he began to experience muscle weakness, a worsening rash, and dysphagia to solids with a resultant loss of 60 pounds within a month. He was transferred to a tertiary care hospital where he was further evaluated and ultimately diagnosed with dermatomyositis, supported by skin and muscle biopsies, and was found to be positive for NXP-2. He was given intravenous immunoglobulin (IVIG) and high-dose steroids with improvement.

scholarly journals Piezo1/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-ß-catenin

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Taifeng Zhou ◽  
Bo Gao ◽  
Yi Fan ◽  
Yuchen Liu ◽  
Shuhao Feng ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Fluid Shear Stress ◽  
Bone Fractures ◽  
Bone Development ◽  
Molecular Regulation ◽  
Matrix Stiffness ◽  
Fluid Shear ◽  
Newborn Mice ◽  
Cell Behaviors ◽  
Extracellular Matrix Stiffness

Mechanical forces are fundamental regulators of cell behaviors. However, molecular regulation of mechanotransduction remain poorly understood. Here, we identified the mechanosensitive channels Piezo1 and Piezo2 as key force sensors required for bone development and osteoblast differentiation. Loss of Piezo1, or more severely Piezo1/2, in mesenchymal or osteoblast progenitor cells, led to multiple spontaneous bone fractures in newborn mice due to inhibition of osteoblast differentiation and increased bone resorption. In addition, loss of Piezo1/2 rendered resistant to further bone loss caused by unloading in both bone development and homeostasis. Mechanistically, Piezo1/2 relayed fluid shear stress and extracellular matrix stiffness signals to activate Ca2+ influx to stimulate Calcineurin, which promotes concerted activation of NFATc1, YAP1 and ß-catenin transcription factors by inducing their dephosphorylation as well as NFAT/YAP1/ß-catenin complex formation. Yap1 and ß-catenin activities were reduced in the Piezo1 and Piezo1/2 mutant bones and such defects were partially rescued by enhanced ß-catenin activities.

scholarly journals Autosomal Dominant ANO5-Related Disorder Associated With Myopathy and Gnathodiaphyseal Dysplasia

2021 ◽  
Vol 7 (4) ◽  
pp. e612
Author(s):  
Aziz Shaibani ◽  
Shaida Khan ◽  
Marwan Shinawi
Keyword(s):  
Bone Fractures ◽  
Molecular Genetic ◽  
In Silico Analysis ◽  
Missense Variant ◽  
Neuromuscular Disorder ◽  
Muscle Disease ◽  
Molecular Testing ◽  
Loss Of Function ◽  
Related Disorder ◽  
Functional Studies

ObjectiveTo investigate the molecular basis of muscle disease and gnathodiaphyseal dysplasia (GDD) in a large kindred with 11 (6 women and 5 men) affected family members.MethodsWe performed clinical assessment of 3 patients and collected detailed clinical and family history data on 8 additional patients. We conducted molecular genetic analyses on 5 patients using comprehensive neuromuscular disorder panels, exome sequencing (ES), and targeted testing for specific genetic variants. We analyzed the segregation of the muscle and bone phenotypes with the underlying molecular cause.ResultsThe unique clinical presentation of recurrent episodes of rhabdomyolysis associated with muscle cramps, hyperCKemia, muscle hypertrophy, with absent or mild muscle weakness, as well as cemento-osseous lesions of the mandible, with or without bone fractures and other skeletal abnormalities, prompted us to look for the underlying molecular cause of the disorder in this kindred. Molecular testing revealed a missense variant in anoctamin 5 (ANO5) designated as c.1538C>T; p.Thr513Ile, which was previously described in a large kindred with GDD. In silico analysis, searching publicly available databases, segregation analysis, as well as functional studies performed by another group provide strong evidence for pathogenicity of the variant. ES data in the proband excluded the contribution of additional genetic factors.ConclusionsThis report described the coexistence of muscle and bone phenotypes in the same patients with ANO5-related disorder. Our data challenge recent results that suggested complete dichotomy of these phenotypes and the proposed loss-of-function and gain-of-function mechanisms for the skeletal and muscle phenotypes, respectively.

scholarly journals IL-1 receptor–associated kinase M is a central regulator of osteoclast differentiation and activation

2005 ◽  
Vol 201 (7) ◽  
pp. 1169-1177 ◽  
Author(s):  
Hongmei Li ◽  
Esteban Cuartas ◽  
Weiguo Cui ◽  
Yongwon Choi ◽  
Todd D. Crawford ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Fractures ◽  
Bone Development ◽  
Osteoclast Differentiation ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Downstream Signaling ◽  
Signaling Complex ◽  
Mitogen Activated Protein ◽  
Protein Kinase Signaling

Osteoporosis is a serious problem worldwide; it is characterized by bone fractures in response to relatively mild trauma. Osteoclasts originate from the fusion of macrophages and they play a central role in bone development and remodeling via the resorption of bone. Therefore, osteoclasts are important mediators of bone loss that leads, for example, to osteoporosis. Interleukin (IL)-1 receptor (IL-1R)–associated kinase M (IRAK-M) is only expressed in cells of the myeloid lineage and it inhibits signaling downstream of IL-1R and Toll-like receptors (TLRs). However, it lacks a functional catalytic site and, thus, cannot function as a kinase. IRAK-M associates with, and prevents the dissociation of, IRAK–IRAK-4–TNF receptor–associated factor 6 from the TLR signaling complex, with resultant disruption of downstream signaling. Thus, IRAK-M acts as a dominant negative IRAK. We show here that mice that lack IRAK-M develop severe osteoporosis, which is associated with the accelerated differentiation of osteoclasts, an increase in the half-life of osteoclasts, and their activation. Ligation of IL-1R or TLRs results in hyperactivation of NF-κB and mitogen-activated protein kinase signaling pathways, which are essential for osteoclast differentiation. Thus, IRAK-M is a key regulator of the bone loss that is due to osteoclastic resorption of bone.

scholarly journals Le Cerveau Influence-t-il le Développement Musculaire du Foetus Humain?

1985 ◽  
Vol 12 (2) ◽  
pp. 111-120 ◽  
Author(s):  
Harvey B. Sarnat
Keyword(s):  
Muscle Development ◽  
Corticospinal Tract ◽  
Fetal Brain ◽  
Muscle Fibres ◽  
Type I ◽  
Normal Muscle ◽  
Motor Tracts ◽  
Human Fetal Muscle ◽  
Muscle Biopsies ◽  
Fetal Muscle

ABSTRACT:Does the human fetal brain influence muscle development? The importance of suprasegmental cerebral influence on developing human fetal muscle is less well understood than the control of histochemical differentiation of muscle by the motor neuron. Muscle biopsies of 21 hypotonic infants and children with nonprogressive congenital lesions of the cerebellum and/or brainstem were studied by histochemical methods. Two neonates who died with severely dysplastic brains and no descending motor tracts had normal muscle. The others, particularly those with cerebellar hypoplasia, had delayed muscle maturation, selective predominance of type I or II muscle fibres or disproportion in fibre sizes. It is concluded that the motor unit is capable of developing normally without suprasegmental influence, but that an abnormal balance of descending impulses may alter histochemical differentiation of fetal muscle. The small ‘subcorticospinal’ pathways arising in the brainstem probably are more influential than the larger corticospinal tract because of later myelination in the latter. The muscle biopsy thus serves to provide evidence of suprasegmental disease in infantile hypotonia.

Selective screening of late-onset Pompe disease (LOPD) in patients with non-diagnostic muscle biopsies

2019 ◽  
Vol 72 (7) ◽  
pp. 468-472
Author(s):  
Marija Meznaric ◽  
Ksenija Fumic ◽  
Lea Leonardis
Keyword(s):  
Muscle Weakness ◽  
Pompe Disease ◽  
Late Onset ◽  
Tissue Bank ◽  
Study Results ◽  
French Speaking ◽  
Ventilatory Insufficiency ◽  
Low Prevalence ◽  
The University ◽  
Muscle Biopsies

AimsAs of 2016, there were five patients with Pompe in Slovenia (two infantile, one childhood and two adult onset) with a prevalence of 1:400 000; however, the prevalence of late-onset Pompe disease (LOPD) in some other countries means this ratio could be an underestimate. Since an LOPD muscle biopsy could be unspecific or even normal, the purpose of this study is to assess the prevalence of LOPD in patients with non-diagnostic muscle biopsies.MethodsSix hundred biopsies were recorded at the Neuromuscular Tissue Bank of the University of Ljubljana for the period 2004–2014. All adult patients with non-diagnostic muscle biopsies were invited to the National Slovenian Neuromuscular Centre for dried blood spot testing for LOPD.ResultsA total of 90 patients (56% of those invited) responded. No patient with LOPD was found. A total of 49 patients (54%) had fixed muscle weakness, 31 (34%) had mild symptoms and no weakness and 10 (11%) had asymptomatic hyperCKemia. Ventilatory insufficiency associated with proximal muscle weakness was found in two patients (2%). No patients exhibited vacuolar myopathy, globular accumulations of glycogen or regions of increased acid phosphatase activity within the sarcoplasm.ConclusionsThe study results do not support the hypothesis that LOPD is underestimated in Slovenian patients with non-diagnostic muscle biopsies; this could be consistent with the fact that LOPD is of low prevalence in Slovenia, as is the case in the populations of Finland, French-speaking Belgium, west Sweden and west Denmark.

Abnormal actin binding of aberrant β-tropomyosins is a molecular cause of muscle weakness in TPM2-related nemaline and cap myopathy

2012 ◽  
Vol 442 (1) ◽  
pp. 231-239 ◽  
Author(s):  
Minttu Marttila ◽  
Elina Lemola ◽  
William Wallefeld ◽  
Massimiliano Memo ◽  
Kati Donner ◽  
...  
Keyword(s):  
Muscle Weakness ◽  
Nemaline Myopathy ◽  
Actin Binding ◽  
Muscle Fibres ◽  
Gene Encoding ◽  
Related Disorder ◽  
Structural Abnormalities ◽  
Muscle Disorder ◽  
Myosin Interaction ◽  
Nemaline Bodies

NM (nemaline myopathy) is a rare genetic muscle disorder defined on the basis of muscle weakness and the presence of structural abnormalities in the muscle fibres, i.e. nemaline bodies. The related disorder cap myopathy is defined by cap-like structures located peripherally in the muscle fibres. Both disorders may be caused by mutations in the TPM2 gene encoding β-Tm (tropomyosin). Tm controls muscle contraction by inhibiting actin–myosin interaction in a calcium-sensitive manner. In the present study, we have investigated the pathogenetic mechanisms underlying five disease-causing mutations in Tm. We show that four of the mutations cause changes in affinity for actin, which may cause muscle weakness in these patients, whereas two show defective Ca2+ activation of contractility. We have also mapped the amino acids altered by the mutation to regions important for actin binding and note that two of the mutations cause altered protein conformation, which could account for impaired actin affinity.

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