Publications by authors named "Thomas E Lloyd"

80 Publications

Loss of TDP-43 function and rimmed vacuoles persist after T cell depletion in a xenograft model of sporadic inclusion body myositis.

Sci Transl Med 2022 Jan 19;14(628):eabi9196. Epub 2022 Jan 19.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over age 50, yet it remains unclear whether the disease is primarily driven by T cell-mediated autoimmunity. IBM muscle biopsies display nuclear clearance and cytoplasmic aggregation of TDP-43 in muscle cells, a pathologic finding observed initially in neurodegenerative diseases, where nuclear loss of TDP-43 in neurons causes aberrant RNA splicing. Here, we show that loss of TDP-43-mediated splicing repression, as determined by inclusion of cryptic exons, occurs in skeletal muscle of subjects with IBM. Of 119 muscle biopsies tested, RT-PCR-mediated detection of cryptic exon inclusion was able to diagnose IBM with 84% sensitivity and 99% specificity. To determine the role of T cells in pathogenesis, we generated a xenograft model by transplanting human IBM muscle into the hindlimb of immunodeficient mice. Xenografts from subjects with IBM displayed robust regeneration of human myofibers and recapitulated both inflammatory and degenerative features of the disease. Myofibers in IBM xenografts showed invasion by human, oligoclonal CD8 T cells and exhibited MHC-I up-regulation, rimmed vacuoles, mitochondrial pathology, p62-positive inclusions, and nuclear clearance and cytoplasmic aggregation of TDP-43, associated with cryptic exon inclusion. Reduction of human T cells within IBM xenografts by treating mice intraperitoneally with anti-CD3 (OKT3) suppressed MHC-I up-regulation. However, rimmed vacuoles and loss of TDP-43 function persisted. These data suggest that T cell depletion does not alter muscle degenerative pathology in IBM.
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http://dx.doi.org/10.1126/scitranslmed.abi9196DOI Listing
January 2022

Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS.

Nat Neurosci 2021 12 15;24(12):1673-1685. Epub 2021 Nov 15.

Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Amyotrophic lateral sclerosis (ALS) is a devastating disorder in which motor neurons degenerate, the causes of which remain unclear. In particular, the basis for selective vulnerability of spinal motor neurons (sMNs) and resistance of ocular motor neurons to degeneration in ALS has yet to be elucidated. Here, we applied comparative multi-omics analysis of human induced pluripotent stem cell-derived sMNs and ocular motor neurons to identify shared metabolic perturbations in inherited and sporadic ALS sMNs, revealing dysregulation in lipid metabolism and its related genes. Targeted metabolomics studies confirmed such findings in sMNs of 17 ALS (SOD1, C9ORF72, TDP43 (TARDBP) and sporadic) human induced pluripotent stem cell lines, identifying elevated levels of arachidonic acid. Pharmacological reduction of arachidonic acid levels was sufficient to reverse ALS-related phenotypes in both human sMNs and in vivo in Drosophila and SOD1 mouse models. Collectively, these findings pinpoint a catalytic step of lipid metabolism as a potential therapeutic target for ALS.
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http://dx.doi.org/10.1038/s41593-021-00944-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639773PMC
December 2021

An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients.

iScience 2021 Nov 12;24(11):103221. Epub 2021 Oct 12.

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in . Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.
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http://dx.doi.org/10.1016/j.isci.2021.103221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554488PMC
November 2021

Performance of the 2017 EULAR/ACR classification criteria for inflammatory myopathies in patients with myositis-specific autoantibodies.

Arthritis Rheumatol 2021 Sep 4. Epub 2021 Sep 4.

Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Background: The objectives of the study were to (1) determine the sensitivity of EULAR/ACR criteria to properly classify myositis-specific autoantibody (MSA) positive myositis patients, (2) describe the phenotype and muscle involvement over time in different MSA-positive patients, and (3) compare MSAs with the EULAR/ACR subgroups to predict clinical phenotypes.

Methods: The study included 524 MSA-positive myositis patients from the Johns Hopkins Myositis Center. Each patient was classified using the EULAR/ACR classification criteria. Patient phenotypes were summarized using factor analysis of mixed data (FAMD). We compared the ability of MSAs with the EULAR/ACR subgroups to predict the phenotype of patients by applying the Akaike information criterion (AIC) and the Bayesian information criteria (BIC) to the linear regression models.

Results: Overall, 91% of MSA-positive patients met EULAR/ACR criteria to be classified as myositis. However, 20% of anti-HMGCR and 50% of anti-PL7 patients were incorrectly classified as not myositis. Furthermore, ~10% of anti-SRP and anti-HMGCR patients were misclassified as having inclusion body myositis. FAMD demonstrated that patients within each MSA-defined group had similar phenotypes. Application of both the AIC and BIC to the linear regression models revealed that MSAs better predict myositis phenotypes than the subgroups defined by the EULAR/ACR criteria.

Conclusions: Although the EULAR/ACR criteria successfully classified 91% of MSA-positive myositis patients, certain MSA-defined subgroups, including those with autoantibodies against HMGCR, SRP, and PL7, are frequently misclassified. In myositis patients with MSAs, autoantibodies outperform the EULAR/ACR-defined subgroups to predict clinical phenotypes. These findings underscore the need to include MSAs in a revised myositis classification scheme.
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http://dx.doi.org/10.1002/art.41964DOI Listing
September 2021

Anti-Cortactin Autoantibodies Are Associated With Key Clinical Features in Adult Myositis but Are Rarely Present in Juvenile Myositis.

Arthritis Rheumatol 2021 Jul 27. Epub 2021 Jul 27.

National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, and Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: To define the prevalence and clinical phenotype of anti-cortactin autoantibodies in adult and juvenile myositis.

Methods: In this longitudinal cohort study, anti-cortactin autoantibody titers were assessed by enzyme-linked immunosorbent assay in 670 adult myositis patients and 343 juvenile myositis patients as well as in 202 adult healthy controls and 90 juvenile healthy controls. The prevalence of anti-cortactin autoantibodies was compared among groups. Clinical features of patients with and those without anti-cortactin autoantibodies were also compared.

Results: Anti-cortactin autoantibodies were more common in adult dermatomyositis (DM) patients (15%; P = 0.005), particularly those with coexisting anti-Mi-2 autoantibodies (24%; P = 0.03) or anti-NXP-2 autoantibodies (23%; P = 0.04). In adult myositis, anti-cortactin was associated with DM skin involvement (62% of patients with anti-cortactin versus 38% of patients without anti-cortactin; P = 0.03), dysphagia (36% versus 17%; P = 0.02) and coexisting anti-Ro 52 autoantibodies (47% versus 26%; P = 0.001) or anti-NT5c1a autoantibodies (59% versus 33%; P = 0.001). Moreover, the titers of anti-cortactin antibodies were higher in patients with interstitial lung disease (0.15 versus 0.12 arbitrary units; P = 0.03). The prevalence of anti-cortactin autoantibodies was not different in juvenile myositis patients (2%) or in any juvenile myositis subgroup compared to juvenile healthy controls (4%). Nonetheless, juvenile myositis patients with these autoantibodies had a higher prevalence of "mechanic's hands" (25% versus 7%; P = 0.03), a higher number of hospitalizations (2.9 versus 1.3; P = 0.04), and lower peak creatine kinase values (368 versus 818 IU/liter; P = 0.02) than those without anti-cortactin.

Conclusion: The prevalence of anti-cortactin autoantibodies is increased in adult DM patients with coexisting anti-Mi-2 or anti-NXP-2 autoantibodies. In adults, anti-cortactin autoantibodies are associated with dysphagia and interstitial lung disease.
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http://dx.doi.org/10.1002/art.41931DOI Listing
July 2021

Prevalence of avascular necrosis in idiopathic inflammatory myositis: a single center experience.

Rheumatology (Oxford) 2021 Jun 27. Epub 2021 Jun 27.

Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objectives: To assess the prevalence of avascular necrosis (AVN) in a large cohort of patients with idiopathic inflammatory myopathies (IIM) and define the major associated risk factors.

Methods: We retrospectively reviewed the electronic medical records of all patients with a definitive diagnosis of IIM enrolled in our registry between 2003-2017 and followed until 2020. Pertinent demographic, clinical, serologic and imaging data were collected. A matched group of patients without AVN was then selected for comparison.

Results: 1680 patients were diagnosed with IIM. Fifty-one patients developed AVN, with an overall prevalence of 3%. Musculoskeletal magnetic resonance imaging (MSK MRI) was available for 1085 patients and AVN was present in 46 patients (43 lower extremities and 3 upper extremities MRI studies), with a relative prevalence of 4.2%. Most patients with AVN were Caucasian females (57%) with a mean age at diagnosis of 44.5 ± 12.4 years. 61% had dermatomyositis (DM) and 29% had polymyositis (PM). The median time from onset of IIM to diagnosis of AVN was 46 months. The hip joint was most commonly involved in 76% of cases, followed by the knee joint in 15% and shoulder joint in 9%. 81% of patients were asymptomatic. Established risk factors for AVN were not found to be associated with the development of AVN in IIM patients.

Conclusion: Although mostly asymptomatic and incidental, the overall prevalence of AVN in IIM was 3% and the prevalence by MRI was 4.2%. None of the established risk factors were found to be associated with AVN development.
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http://dx.doi.org/10.1093/rheumatology/keab493DOI Listing
June 2021

The phenotype of myositis patients with anti-Ku autoantibodies.

Semin Arthritis Rheum 2021 08 28;51(4):728-734. Epub 2021 Apr 28.

Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD USA; Johns Hopkins University School of Medicine, Baltimore, Maryland USA. Electronic address:

Objectives: To define the clinical features of anti-Ku-positive myositis patients and to determine the reliability of the Euroline assay to detect anti-Ku autoantibodies.

Methods: Serum samples were screened for anti-Ku autoantibodies by Euroline and positive samples were confirmed by ELISA. The prevalence and severity of clinical features at onset and during follow-up in patients with anti-Ku-positive myositis were compared to those with dermatomyositis, immune-mediated necrotizing myopathy (IMNM), the antisynthetase syndrome (AS), inclusion body myositis (IBM), anti-U1-RNP-positive myositis, and anti-PM/Scl-positive myositis.

Results: 72 (2.9%) of 2475 samples were anti-Ku positive by Euroline using the manufacturer's recommended cutoff of >15. Just 17 (23.6%) of these were confirmed by ELISA and considered anti-Ku-positive for the analysis. Comparators included 169 IMNM, 168 AS, 387 IBM, 20 anti-U1-RNP-positive, and 47 anti-PM/Scl-positive patients. Muscle weakness was a presenting feature in 38% of anti-Ku-positive patients; 81% developed weakness during follow-up. Anti-Ku-positive patients had increased distal weakness compared to the non-IBM comparators. Interstitial lung disease (ILD) was present in 19% of anti-Ku-positive patients at the first visit and eventually developed in 56% of them. Throughout the course of disease, Gottron's papules and/or heliotrope rashes were less common in anti-Ku-positive patients (19%) compared to those with dermatomyositis (94%) or anti-PM/Scl-positive myositis (89%). Anti-Ku-positive patients never developed calcinosis.

Conclusions: The phenotype of anti-Ku positive myositis is distinguished by distal weakness, frequent ILD, infrequent rash, and no calcinosis. When used according to the current manufacturer's instructions, the Euroline assay has a high false-positive rate for anti-Ku autoantibodies.
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http://dx.doi.org/10.1016/j.semarthrit.2021.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384675PMC
August 2021

Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases.

J Neurol Neurosurg Psychiatry 2021 11 8;92(11):1186-1196. Epub 2021 Jun 8.

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA

Background: We used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres.

Methods: WES was performed on 66 individuals with neurogenetic diseases using candidate gene filters and stringent algorithms for assessing sequence variants. Pathogenic or likely pathogenic missense variants were interpreted using in silico prediction tools, family segregation analysis, previous publications of disease association and relevant biological assays.

Results: Molecular diagnosis was achieved in 39% (n=26) including 59% of childhood-onset cases and 27% of late-onset cases. Overall, 37% (10/27) of myopathy, 41% (9/22) of neuropathy, 22% (2/9) of MND and 63% (5/8) of complex phenotypes were given genetic diagnosis. Twenty-seven disease-associated variants were identified including ten novel variants in and . Single-nucleotide variants (n=10) affected conserved residues within functional domains and previously identified mutation hot-spots. Established pathogenic variants (n=16) presented with atypical features, such as optic neuropathy in adult polyglucosan body disease, facial dysmorphism and skeletal anomalies in cerebrotendinous xanthomatosis, steroid-responsive weakness in congenital myasthenia syndrome 10. Potentially treatable rare diseases were diagnosed, improving the quality of life in some patients.

Conclusions: Integrating deep phenotyping, gene filter algorithms and biological assays increased diagnostic yield of exome sequencing, identified novel pathogenic variants and extended phenotypes of difficult to diagnose rare neurogenetic disorders in an outpatient clinic setting.
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http://dx.doi.org/10.1136/jnnp-2020-325437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522445PMC
November 2021

Risk Factors For Infection And Health Impacts Of The Covid-19 Pandemic In People With Autoimmune Diseases.

Clin Infect Dis 2021 May 6. Epub 2021 May 6.

Department of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences.

Methods: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health.

Results: 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (OR: 1.43; 95%CI: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95%CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95%CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95%CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income.

Conclusions: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.
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http://dx.doi.org/10.1093/cid/ciab407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135997PMC
May 2021

UPF1 reduces C9orf72 HRE-induced neurotoxicity in the absence of nonsense-mediated decay dysfunction.

Cell Rep 2021 03;34(13):108925

Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Multiple cellular pathways have been suggested to be altered by the C9orf72 GGGGCC (GC) hexanucleotide repeat expansion (HRE), including aspects of RNA regulation such as nonsense-mediated decay (NMD). Here, we investigate the role that overexpression of UPF1, a protein involved in NMD, plays in mitigating neurotoxicity in multiple models of C9orf72 ALS/FTD. First, we show that NMD is not altered in our endogenous induced pluripotent stem cell (iPSC)-derived spinal neuron (iPSN) model of C9orf72 ALS (C9-ALS) or postmortem motor cortex tissue from C9-ALS patients. Unexpectedly, we find that UPF1 overexpression significantly reduces the severity of known neurodegenerative phenotypes without altering NMD function itself. UPF1 overexpression reduces poly(GP) abundance without altering the amount of repeat RNA, providing a potential mechanism by which UPF1 reduces dipeptide repeat (DPR) protein-mediated toxicity. Together, these findings indicate that UPF1 is neuroprotective in the context of C9-ALS, albeit independent of known UPF1-mediated NMD pathways.
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http://dx.doi.org/10.1016/j.celrep.2021.108925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063722PMC
March 2021

Neuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension.

Nat Commun 2021 03 4;12(1):1444. Epub 2021 Mar 4.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

TRPV4 is a cell surface-expressed calcium-permeable cation channel that mediates cell-specific effects on cellular morphology and function. Dominant missense mutations of TRPV4 cause distinct, tissue-specific diseases, but the pathogenic mechanisms are unknown. Mutations causing peripheral neuropathy localize to the intracellular N-terminal domain whereas skeletal dysplasia mutations are in multiple domains. Using an unbiased screen, we identified the cytoskeletal remodeling GTPase RhoA as a TRPV4 interactor. TRPV4-RhoA binding occurs via the TRPV4 N-terminal domain, resulting in suppression of TRPV4 channel activity, inhibition of RhoA activation, and extension of neurites in vitro. Neuropathy but not skeletal dysplasia mutations disrupt TRPV4-RhoA binding and cytoskeletal outgrowth. However, inhibition of RhoA restores neurite length in vitro and in a fly model of TRPV4 neuropathy. Together these results identify RhoA as a critical mediator of TRPV4-induced cell structure changes and suggest that disruption of TRPV4-RhoA binding may contribute to tissue-specific toxicity of TRPV4 neuropathy mutations.
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http://dx.doi.org/10.1038/s41467-021-21699-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933254PMC
March 2021

Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

Neurology 2021 03 17;96(12):e1595-e1607. Epub 2021 Feb 17.

From the Department of Neurology (A.A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Medical Research Council Centre for Neuromuscular Diseases (M.G.H., P.M.M.) and Institute of Neurology, Department of Neuromuscular Diseases & Centre for Rheumatology (P.M.M.), University College London; Department of Rheumatology & Queen Square Centre for Neuromuscular Diseases (P.M.M.), University College London Hospitals NHS Foundation Trust; Department of Rheumatology (P.M.M.), Northwick Park Hospital, London North West University Healthcare NHS Trust, UK; Department of Neurology (U.A.B.), Leiden University Medical Center, Netherlands; National Institute for Health Research Manchester Biomedical Research Centre (H.C.), Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, The University of Manchester, UK; Department of Internal Medicine and Clinical Immunology (O.B.), Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France; Novartis Healthcare Pvt. Ltd. (K.A.K), Hyderabad, India; Novartis Pharmaceuticals (M.W., D.A.P.), East Hanover, NJ; Novartis Pharma AG (L.B.T., A.A.S-T.), Basel, Switzerland; Department of Neurology (T.E.L.), The Johns Hopkins University School of Medicine, Baltimore, MD; Institute for Immunology & Infectious Diseases (M.N.), Fiona Stanley Hospital, Murdoch University and Notre Dame University, Perth; Department of Neurology (C.L.), Royal North Shore Hospital, New South Wales; Calvary Health Care Bethlehem (K.A.R.), Caulfield South, Australia; Department of Neurology (M.d.V), Amsterdam University Medical Centre, the Netherlands; Department of Medicine (D.P.A.), University of Miami, FL; Department of Neurology (R.J.B., M.M.D.), University of Kansas Medical Center, Kansas City; Department of Neurology (J.A.L.M.), Newcastle upon Tyne Hospitals NHS Foundation Trust, UK; Department of Neurology (J.T.K.), The Ohio State University Wexner Medical Center, Columbus; Neuromuscular Research Center (B.O., N.C.J.), UC Davis School of Medicine, Sacramento, CA; Department of Neurology (P.V.d.B.), University Hospital Saint-Luc, University of Louvain, Brussels; Neuromuscular Reference Centre, Department of Neurology (J.B.), Antwerp University Hospital; Institute Born-Bunge (J.B.), University of Antwerp; Department of Neurology (J.L.d.B.), Ghent University Hospital, Belgium; Department of Neurology (C.K.), Oregon Health & Science University, Portland; Department of Neurology (W.S.D.), Massachusetts General Hospital, Neuromuscular Diagnostic Center and Electromyography Laboratory, Boston; Department of Neurology (M.M.), Fondazione Policlinico Universitario Agostino Gemelli IRCCS; Università Cattolica del Sacro Cuore (M.M.), Rome, Italy; Department of Neurology (S.P.N.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (H.H.J.), University Hospital and University of Zurich, Switzerland; Department of Neurosciences (E.P.), University of Padova School of Medicine; Fondazione IRCCS Istituto Neurologico Carlo Besta (L.M.), Milan; Unit of Neurology and Neuromuscular Disorders (C.R.), Azienda Ospedaliera Universitaria Policlinico G Martino, University of Messina; Center for Neuromuscular Diseases (M.F.), Unit of Neurology, ASST Spedali Civili and University of Brescia, Italy; Nerve and Muscle Center of Texas (A.I.S.), Houston; Neuromuscular Research Center (K.S.), Phoenix, AZ; Department of Neurology (N.A.G.), ALS & Neuromuscular Center, University of California Irvine, Orange; Department of Neurology (M.M.-Y.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Neurology (S.Y.), Kumamoto University Hospital; Department of Neurology (N.S.), Tohoku University Hospital, Miyagi; Department of Neurology (M.A.), Tohoku University School of Medicine, Sendai; Department of Neurology (M.K.), Nagoya University Hospital, Aichi; Department of Neurology (H.M.), Osaka City General Hospital; Wakayama Medical University Hospital (K.M.); Tokushima University Hospital (H.N.); Department of Neuromuscular Research (I.N.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; RTI Health Solutions (C.D.R., V.S.L.W.), Research Triangle Park, NC; Copenhagen Neuromuscular Center (J.V.), Rigshospitalet, University of Copenhagen, Denmark; and UCB (L.Z.A.), Bulle, Switzerland. H.N. is currently affiliated with the Department of Neurology, Kanazawa Medical University, Ishikawa, Japan. B.O. is currently affiliated with the Department of Neurology, Mayo Clinic, Jacksonville, FL.

Objective: To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM).

Methods: Participants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety.

Results: Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively).

Conclusion: Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.

Clinical Trial Registration: Clinicaltrials.gov identifier NCT02573467.

Classification Of Evidence: This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.
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http://dx.doi.org/10.1212/WNL.0000000000011626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032371PMC
March 2021

RISK FACTORS FOR INFECTION AND HEALTH IMPACTS OF THE COVID-19 PANDEMIC IN PEOPLE WITH AUTOIMMUNE DISEASES.

medRxiv 2021 Feb 5. Epub 2021 Feb 5.

Department of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: People with autoimmune or inflammatory conditions who take immunomodulatory/suppressive medications may have a higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences.

Objective: Assess whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterize pandemic-associated changes to care.

Design: Longitudinal registry study.

Participants: 4666 individuals with autoimmune or inflammatory conditions followed by specialists in neurology, rheumatology, cardiology, pulmonology or gastroenterology at Johns Hopkins.

Measurements: Periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare.

Results: A total of 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medication exposure) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in multivariable models incorporating behavior and other potential confounders (OR: 1.43; 95%CI: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95%CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95%CI: 1.24, 2.28), and chronic kidney disease (OR: 1.76; 95%CI: 1.04, 2.97) were each associated with higher odds of COVID-19. Pandemic-related disruption to care was common. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions. Individuals experiencing changes to employment or income were at highest odds of care disruption.

Limitations: Results may not be generalizable to all patients with autoimmune or inflammatory conditions. Information was self-reported.

Conclusions: Exposure to glucocorticoids may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.
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http://dx.doi.org/10.1101/2021.02.03.21251069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872366PMC
February 2021

p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR).

Cell 2021 02 21;184(3):689-708.e20. Epub 2021 Jan 21.

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.
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http://dx.doi.org/10.1016/j.cell.2020.12.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886018PMC
February 2021

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study.

Brain 2020 12;143(12):3589-3602

Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.
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http://dx.doi.org/10.1093/brain/awaa323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805791PMC
December 2020

TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS.

Elife 2020 12 10;9. Epub 2020 Dec 10.

Cellular and Molecular Medicine Program, School of Medicine, Johns Hopkins University, Baltimore, United States.

Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which disrupted NCT causes neurodegeneration remain unclear. In a screen, we identified , a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy of tissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the -HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD.
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http://dx.doi.org/10.7554/eLife.59419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758070PMC
December 2020

Secondary Causes of Myositis.

Curr Treat Options Neurol 2020 6;22(11):38. Epub 2020 Oct 6.

Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD USA.

Purpose Of Review: The purpose of this paper is to comprehensively evaluate secondary causes of inflammatory myopathies (myositis) and to review treatment options.

Recent Findings: This review highlights recent advancements in our understanding of known causes of myositis, including newer drugs that may cause myositis such as checkpoint inhibitors and viruses such as influenza, HIV, and SARS-CoV2. We also discuss treatment for malignancy-associated myositis and overlap myositis, thought to be a separate entity from other rheumatologic diseases.

Summary: Infections, drugs, rheumatologic diseases, and malignancies are important causes of myositis and are important to diagnose as they may have specific therapies beyond immunomodulatory therapy.
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http://dx.doi.org/10.1007/s11940-020-00646-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538050PMC
October 2020

Accumulation of autophagosome cargo protein p62 is common in idiopathic inflammatory myopathies.

Clin Exp Rheumatol 2021 Mar-Apr;39(2):351-356. Epub 2020 Sep 1.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objectives: The subsarcolemmal accumulation of p62 aggregates in myofibres has been proposed to be characteristic of sporadic inclusion body myositis (sIBM). The objective of this study was to analyse the patterns and prevalence of p62 immunostaining and to quantitate p62 gene expression in muscle biopsies from a large number of patients with different types of myopathic and neurogenic disorders.

Methods: For the p62 immunostaining analysis, all patients with a muscle biopsy immunostained for p62 at the Johns Hopkins Neuromuscular Pathology Laboratory from 2013 to 2017 were included (n=303). The prevalence and pattern of p62 immunostaining were compared between patients with histologically normal muscle (n=29), inflammatory myopathies (n=136), non-inflammatory myopathies (n=53), and neurogenic disorders (n=85). p62 expression levels were analysed using an existing RNAseq dataset including data from dermatomyositis (DM; n=39), immune-mediated necrotising myopathy (IMNM; n=49), antisynthetase syndrome (AS; n=18), and sIBM (n=23) patients as well as 20 histologically normal muscle biopsies.

Results: p62 staining was absent in normal biopsies, but present in biopsies from those with polymyositis (29%), non-inflammatory myopathies (all <31%), neurogenic disorders (31%), dermatomyositis (57%), sIBM (92%) and IMNM (87%). In all diseases studied, p62 accumulation was more prevalent in biopsies with more severe muscle damage. sIBM biopsies had decreased p62 expression levels compared to the other groups (corrected p<0.04).

Conclusions: p62 accumulation is a general response to muscle injury and not a specific marker for sIBM. Also, in sIBM, p62 RNA levels are decreased, suggesting that, in this disease, p62 aggregation is not due to overexpression.
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April 2021

Ultra-efficient sequencing of T Cell receptor repertoires reveals shared responses in muscle from patients with Myositis.

EBioMedicine 2020 Sep 3;59:102972. Epub 2020 Sep 3.

Division of Immunology, Pathology Department, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Myositis, or idiopathic inflammatory myopathy (IIM), is a group disorders of unknown etiology characterized by the inflammation of skeletal muscle. The role of T cells and their antigenic targets in IIM initiation and progression is poorly understood. T cell receptor (TCR) repertoire sequencing is a powerful approach for characterizing complex T cell responses. However, current TCR sequencing methodologies are complex, expensive, or both, greatly limiting the scale of feasible studies.

Methods: Here we present Framework Region 3 AmplifiKation sequencing ("FR3AK-seq"), a simplified multiplex PCR-based approach for the ultra-efficient and quantitative analysis of TCR complementarity determining region 3 (CDR3) repertoires. By using minimal primer sets targeting a conserved region immediately upstream of CDR3, undistorted amplicons are analyzed via short read, single-end sequencing. We also introduce the novel algorithm Inferring Sequences via Efficiency Projection and Primer Incorporation ("ISEPPI") for linking CDR3s to their associated variable genes.

Findings: We find that FR3AK-seq is sensitive and quantitative, performing comparably to two different industry standards. FR3AK-seq and ISEPPI were used to efficiently and inexpensively characterize the T cell infiltrates of surgical muscle biopsies obtained from 145 patients with IIM and controls. A cluster of closely related TCRs was identified in samples from patients with sporadic inclusion body myositis (IBM).

Interpretation: The ease and minimal cost of FR3AK-seq removes critical barriers to routine, large-scale TCR CDR3 repertoire analyses, thereby democratizing the quantitative assessment of human TCR repertoires in disease-relevant target tissues. Importantly, discovery of closely related TCRs in muscle from patients with IBM provides evidence for a shared antigen-driven T cell response in this disease of unknown pathogenesis.

Funding: This work was supported by NIH grant U24AI118633 and a Prostate Cancer Foundation Young Investigator Award.
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http://dx.doi.org/10.1016/j.ebiom.2020.102972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484536PMC
September 2020

Assessing non-Mendelian inheritance in inherited axonopathies.

Genet Med 2020 12 3;22(12):2114-2119. Epub 2020 Aug 3.

Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Purpose: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot-Marie-Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance.

Methods: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis.

Results: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA.

Conclusion: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders.
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http://dx.doi.org/10.1038/s41436-020-0924-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710562PMC
December 2020

Machine learning algorithms reveal unique gene expression profiles in muscle biopsies from patients with different types of myositis.

Ann Rheum Dis 2020 09 16;79(9):1234-1242. Epub 2020 Jun 16.

Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Insititutes of Health, Bethesda, Maryland, USA

Objectives: Myositis is a heterogeneous family of diseases that includes dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), polymyositis and overlap myositis. Additional subtypes of myositis can be defined by the presence of myositis-specific autoantibodies (MSAs). The purpose of this study was to define unique gene expression profiles in muscle biopsies from patients with MSA-positive DM, AS and IMNM as well as IBM.

Methods: RNA-seq was performed on muscle biopsies from 119 myositis patients with IBM or defined MSAs and 20 controls. Machine learning algorithms were trained on transcriptomic data and recursive feature elimination was used to determine which genes were most useful for classifying muscle biopsies into each type and MSA-defined subtype of myositis.

Results: The support vector machine learning algorithm classified the muscle biopsies with >90% accuracy. Recursive feature elimination identified genes that are most useful to the machine learning algorithm and that are only overexpressed in one type of myositis. For example, CAMK1G (calcium/calmodulin-dependent protein kinase IG), EGR4 (early growth response protein 4) and CXCL8 (interleukin 8) are highly expressed in AS but not in DM or other types of myositis. Using the same computational approach, we also identified genes that are uniquely overexpressed in different MSA-defined subtypes. These included apolipoprotein A4 (APOA4), which is only expressed in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) myopathy, and MADCAM1 (mucosal vascular addressin cell adhesion molecule 1), which is only expressed in anti-Mi2-positive DM.

Conclusions: Unique gene expression profiles in muscle biopsies from patients with MSA-defined subtypes of myositis and IBM suggest that different pathological mechanisms underly muscle damage in each of these diseases.
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http://dx.doi.org/10.1136/annrheumdis-2019-216599DOI Listing
September 2020

TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca.

Nat Commun 2020 05 29;11(1):2679. Epub 2020 May 29.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The cation channel transient receptor potential vanilloid 4 (TRPV4) is one of the few identified ion channels that can directly cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here, we show that in vivo expression of a neuropathy-causing TRPV4 mutant (TRPV4) causes dose-dependent neuronal dysfunction and axonal degeneration, which are rescued by genetic or pharmacological blockade of TRPV4 channel activity. TRPV4 triggers increased intracellular Ca through a Ca/calmodulin-dependent protein kinase II (CaMKII)-mediated mechanism, and CaMKII inhibition prevents both increased intracellular Ca and neurotoxicity in Drosophila and cultured primary mouse neurons. Importantly, TRPV4 activity impairs axonal mitochondrial transport, and TRPV4-mediated neurotoxicity is modulated by the Ca-binding mitochondrial GTPase Miro. Our data highlight an integral role for CaMKII in neuronal TRPV4-associated Ca responses, the importance of tightly regulated Ca dynamics for mitochondrial axonal transport, and the therapeutic promise of TRPV4 antagonists for patients with TRPV4-related neurodegenerative diseases.
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http://dx.doi.org/10.1038/s41467-020-16411-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260201PMC
May 2020

A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores.

Neurology 2020 03 11;94(9):e884-e896. Epub 2020 Feb 11.

From the Department of Neurology (V.F., S.S., S.A.K.), University of Colorado Denver, Aurora; Department of Neurology (G.A.), Connecticut Children's Medical Center, Hartford; Department of Neurology (C.B., S.F., T.G., L.G., R.R.S., J.W., M.E.S.), University of Iowa Hospitals and Clinics, Iowa City; Health Informatics Institute (K.D., C.A.K.), University of South Florida, Tampa; University of Sydney and The Children's Hospital at Westmead (J.B.), New South Wales, Australia; Department of Neurology (J.D., C.E.S.), Stanford University, CA; Department of Neurology (S.F., J.L., S.R., R.R.S. , M.E.S.), Wayne State University, Detroit, MI; Department of Neurology (R.S.F.), Nemours Children's Hospital, Orlando, FL; Department of Neurology (D.N.H.), University of Rochester, NY; MRC Centre for Neuromuscular Diseases (M.L., M.M.R.), UCL Queen Square Institute of Neurology, London, UK; Department of Neurology (R.A.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology (J.L.), Vanderbilt University, Nashville, TN; Departments of Neurology and Neuroscience (T.E.L., C.J.S.), John Hopkins University School of Medicine, Baltimore, MD; Department of Child Neurology (I.M., E.P.) and Department of Clinical Neurosciences (C.P., G.P.,* D.P.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Istituti Clinici Scientifici Maugeri (G.P.*), Neurorehabilitation Unit, Scientific Institute of Telese Terme (BN), Italy; Department of Neurology (F.M.), UCL Institute of Child Health and Great Ormond Street Hospital, London, UK; Department of Neurology (S.R.), University of Michigan, Ann Arbor; PRA Health Sciences (S.R.), Raleigh, NC; Department of Neurology (M.S.) and Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Department of Neurology (R.S.), Massachusetts General Hospital, Boston; Department of Neurology (D.W.), University of Minnesota, Minneapolis; Department of Neurology (S.W.Y., S.S.S.), Hospital of the University of Pennsylvania, Philadelphia; and Department of Neurology (S.W.Y.), Children's Hospital of Philadelphia, PA.

Objective: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A).

Methods: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models.

Results: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, < 0.0001, for baseline CMTES-R score 0-9).

Conclusion: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A.

Clinicaltrialsgov Identifier: NCT01193075.
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http://dx.doi.org/10.1212/WNL.0000000000009035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238948PMC
March 2020

Performing Human Skeletal Muscle Xenografts in Immunodeficient Mice.

J Vis Exp 2019 09 16(151). Epub 2019 Sep 16.

Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine; Department of Neurology, Johns Hopkins University School of Medicine; Department of Neuroscience, Johns Hopkins University School of Medicine;

Treatment effects observed in animal studies often fail to be recapitulated in clinical trials. While this problem is multifaceted, one reason for this failure is the use of inadequate laboratory models. It is challenging to model complex human diseases in traditional laboratory organisms, but this issue can be circumvented through the study of human xenografts. The surgical method we describe here allows for the creation of human skeletal muscle xenografts, which can be used to model muscle disease and to carry out preclinical therapeutic testing. Under an Institutional Review Board (IRB)-approved protocol, skeletal muscle specimens are acquired from patients and then transplanted into NOD-Rag1 IL2rγ (NRG) host mice. These mice are ideal hosts for transplantation studies due to their inability to make mature lymphocytes and are thus unable to develop cell-mediated and humoral adaptive immune responses. Host mice are anaesthetized with isoflurane, and the mouse tibialis anterior and extensor digitorum longus muscles are removed. A piece of human muscle is then placed in the empty tibial compartment and sutured to the proximal and distal tendons of the peroneus longus muscle. The xenografted muscle is spontaneously vascularized and innervated by the mouse host, resulting in robustly regenerated human muscle that can serve as a model for preclinical studies.
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http://dx.doi.org/10.3791/59966DOI Listing
September 2019

Identification of distinctive interferon gene signatures in different types of myositis.

Neurology 2019 09 21;93(12):e1193-e1204. Epub 2019 Aug 21.

From the National Institute of Arthritis and Musculoskeletal and Skin Diseases (I.P.-F, M.C.-D, A.D., K.P., P.P., F.W.M., A.L.M.), NIH, Bethesda; Johns Hopkins University School of Medicine (I.P.-F., M.C.-D., J.P., J.A., L.C.-S., T.E.L., A.M.C., A.L.M.), Baltimore, MD; Clinic Hospital and the University of Barcelona (J.C.M., J.M.G.-J.); Vall d'Hebron Hospital and Autonomous University of Barcelona (A.S.-O.); and Faculty of Health Sciences (I.P.-F.), Universitat Oberta de Catalunya, Barcelona, Spain.

Objective: Activation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies.

Methods: The expression of IFN1- and IFN2-inducible genes was compared between the different groups.

Results: The expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note, expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies.

Conclusions: IFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways.
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http://dx.doi.org/10.1212/WNL.0000000000008128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808530PMC
September 2019

Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial.

Lancet Neurol 2019 09;18(9):834-844

Center for Neuromuscular Diseases, Unit of Neurology, Azienda Socio Sanitaria Territoriale Spedali Civili and University of Brescia, Brescia, Italy.

Background: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis.

Methods: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis.

Findings: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab.

Interpretation: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months.

Funding: Novartis Pharma.
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http://dx.doi.org/10.1016/S1474-4422(19)30200-5DOI Listing
September 2019

How can an understanding of the C9orf72 gene translate into amyotrophic lateral sclerosis therapies?

Expert Rev Neurother 2019 10 3;19(10):895-897. Epub 2019 Jul 3.

Department of Neurology, School of Medicine, Johns Hopkins University , Baltimore , MD , USA.

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http://dx.doi.org/10.1080/14737175.2019.1635884DOI Listing
October 2019

Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.

J Neuromuscul Dis 2019 ;6(2):201-211

Department for Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability.

Objective: We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A.

Methods: We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study.

Results: The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P = 9.91×10-7, odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P = 2.08×10-7, odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P = 1.63×10-7, odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P = 1.14×10-7, beta = 3.014).

Conclusions: While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.
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http://dx.doi.org/10.3233/JND-190377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597974PMC
December 2019

Myositis Autoantigen Expression Correlates With Muscle Regeneration but Not Autoantibody Specificity.

Arthritis Rheumatol 2019 08 18;71(8):1371-1376. Epub 2019 Jun 18.

National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, and Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: Although more than a dozen myositis-specific autoantibodies (MSAs) have been identified, most patients with myositis are positive for a single MSA. The specific overexpression of a given myositis autoantigen in myositis muscle has been proposed as initiating and/or propagating autoimmunity against that particular autoantigen. The present study was undertaken to test this hypothesis.

Methods: In order to quantify autoantigen RNA expression, RNA sequencing was performed on muscle biopsy samples from control subjects, MSA-positive patients with myositis, regenerating mouse muscles, and cultured human muscle cells.

Results: Muscle biopsy samples were available from 20 control subjects and 106 patients with autoantibodies recognizing hydroxymethylglutaryl-coenzyme A reductase (n = 40), signal recognition particles (n = 9), Jo-1 (n = 18), nuclear matrix protein 2 (n = 12), Mi-2 (n = 11), transcription intermediary factor 1γ (n = 11), or melanoma differentiation-associated protein 5 (n = 5). The increased expression of a given autoantigen in myositis muscle was not associated with autoantibodies recognizing that autoantigen (all q > 0.05). In biopsy specimens from both myositis muscle and regenerating mouse muscles, autoantigen expression correlated directly with the expression of muscle regeneration markers and correlated inversely with the expression of genes encoding mature muscle proteins. Myositis autoantigens were also expressed at high levels in cultured human muscle cells.

Conclusion: Most myositis autoantigens are highly expressed during muscle regeneration, which may relate to the propagation of autoimmunity. However, factors other than overexpression of specific autoantigens are likely to govern the development of unique autoantibodies in individual patients with myositis.
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http://dx.doi.org/10.1002/art.40883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663619PMC
August 2019
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