Publications by authors named "Jan de Bleecker"

103 Publications

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

Neurology 2021 Feb 17. Epub 2021 Feb 17.

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

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

Methods: Participants (aged 36-85 years) who completed the core study (RESILIENT) were invited to join an extension study. Individuals continued on same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab, or matching placebo administered as intravenous 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) 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 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.

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.

Clinical Trial Registration: Registered at ClinicalTrials.gov: NCT02573467.
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http://dx.doi.org/10.1212/WNL.0000000000011626DOI Listing
February 2021

Diagnostic muscle biopsies in the era of genetics: the added value of myopathology in a selection of limb-girdle muscular dystrophy patients.

Acta Neurol Belg 2021 Jan 5. Epub 2021 Jan 5.

Department of Neurology, Laboratory for Neuropathology and Neuromuscular Reference Center, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Ghent, Belgium.

In the second most common dystrophy associated with predominant pelvic and shoulder girdle muscle weakness termed Limb-Girdle Muscular Dystrophy (LGMD), genetic complexity, large phenotypic variability, and clinical overlap can result in extensive diagnostic delays in certain individuals. In view of the large strides genetics has taken in this day and age, we address the question if muscle biopsies can still provide diagnostic evidence of substance for these patients. We reviewed and reanalyzed muscle biopsy characteristics in a cohort of LGMD patient pairs in which gene variants were picked up in CAPN3, FKRP, TTN, and ANO5, using histochemical-immunohistochemical-and immunofluorescent staining, and western blotting. We found that not the nature and severity of inflammatory changes, but the changed properties of the dystrophin complex were the most valuable assets to differentiate LGMD from myositis. Proteomic evaluation brought both primary and secondary deficiencies to light, which could be equally revealing for diagnosis. Though a muscle biopsy might, at present, not always be strictly necessary anymore, it still represents an irrefutable asset when the genetic diagnosis is complicated.
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http://dx.doi.org/10.1007/s13760-020-01559-0DOI Listing
January 2021

Description of a Novel Mechanism Possibly Explaining the Antiproliferative Properties of Glucocorticoids in Duchenne Muscular Dystrophy Fibroblasts Based on Glucocorticoid Receptor GR and NFAT5.

Int J Mol Sci 2020 Dec 3;21(23). Epub 2020 Dec 3.

Department of Neurology, Ghent University Hospital, Ghent University, C. Heymanslaan 10, 9000 Ghent, Belgium.

Glucocorticoids are drugs of choice in Duchenne muscular dystrophy (DMD), prolonging patients' ambulation. Their mode of action at the protein level is not completely understood. In DMD, muscle tissue is replaced by fibrotic tissue produced by fibroblasts, reducing mobility. Nuclear factor of activated T-cells 5 (NFAT5) is involved in fibroblast proliferation. By treating one DMD fibroblast cell culture and one of unaffected skeletal muscle fibroblasts with methylprednisolone (MP) or hydrocortisone (HC) for 24 h or 12 d, the antiproliferative properties of glucocorticoids could be unraveled. NFAT5 localization and expression was explored by immunocytochemistry (ICC), Western blotting (WB) and RT-qPCR. NFAT5 and glucocorticoid receptor (GR) colocalization was measured by ImageJ. GR siRNA was used, evaluating GR's influence on NFAT5 expression during MP and HC treatment. Cell proliferation was monitored by IncuCyte ZOOM. In DMD fibroblasts, treatment with MP for 24 h induced dots (ICC) positive for NFAT5 and colocalizing with GR. After 12 d of MP or HC in DMD fibroblasts, NFAT5 expression was decreased (RT-qPCR and WB) and growth arrest was observed (Incucyte ZOOM), whereas NFAT5 expression and cell growth remained unchanged in unaffected skeletal muscle fibroblasts. This study may help understand the antiproliferative properties of glucocorticoids in DMD fibroblasts.
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http://dx.doi.org/10.3390/ijms21239225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731298PMC
December 2020

Abnormal NFAT5 Physiology in Duchenne Muscular Dystrophy Fibroblasts as a Putative Explanation for the Permanent Fibrosis Formation in Duchenne Muscular Dystrophy.

Int J Mol Sci 2020 Oct 24;21(21). Epub 2020 Oct 24.

Department of Neurology, Ghent University and Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium.

Duchenne muscular dystrophy (DMD) is characterized by chronic inflammation and fibrotic tissue production by fibroblasts. The promyogenic factor nuclear factor of activated T-cells 5 (NFAT5) is virtually present in all cells, responding to hyperosmolar or pro-inflammatory stress. In embryogenic fibroblasts, absence of NFAT5 results in cell cycle arrest. Here, unaffected skeletal muscle fibroblasts from one healthy donor showed NFAT5 nuclear translocation upon hyperosmolar stress and normal cell viability. Absence of NFAT5 translocation under pro-inflammatory conditions resulted in decreased cell growth (Incucyte ZOOM). In DMD skeletal muscle fibroblasts from one DMD patient, NFAT5 was merely located in the nucleus. Exposure to hyperosmolar conditions or pro-inflammatory cytokines IFN-γ, IL-1β and TNF-α had no influence on NFAT5 physiology (immunofluorescence, western blotting, RT-qPCR). Hyperosmolarity resulted in decreased cell viability and pro-inflammatory stress in unaltered cell growth. These findings suggest that NFAT5 is vital to DMD fibroblast survival. Exposure to pro-inflammatory or hyperosmolar stress in DMD fibroblasts results in an unexpected NFAT5 response, where fibroblasts are not triggered by inflammatory cytokines and do not withstand hyperosmolarity. Chronic inflammation could be viewed as a non-restrictive factor in the formation of fibrosis in DMD. Abnormal NFAT5 physiology could provide a molecular explanation for permanent fibrotic matrix production by DMD fibroblasts.
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http://dx.doi.org/10.3390/ijms21217888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660673PMC
October 2020

Myotonic dystrophy type 1 as a major risk factor for severe COVID-19?

Acta Neurol Belg 2020 Oct 14. Epub 2020 Oct 14.

Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.

The coronavirus disease 2019 (COVID-19) pandemic is challenging health care systems worldwide. People with myotonic dystrophy type 1 (DM1) represent a high-risk population during infectious disease outbreaks, little is known about the potential impact of COVID-19 on patients with DM1. We studied the clinical course of COVID-19 in three hospitalized patients with myotonic dystrophy type 1 or Steinert's disease, between April 1, 2020-April 30-2020. All three had advanced Steinert's disease receiving non-invasive nocturnal home ventilatory support. Two of them lived in a residential care centre. Two patients had a limited respiratory capacity, whereas one patient had a rather preserved functional capacity but more comorbidities. Two out of three patients were obese, none of them had diabetes mellitus. Two patients received hydroxychloroquine. Despite maximal supportive care with oxygen therapy, antibiotics, intensive respiratory physiotherapy and non-invasive positive pressure ventilation, all three patients eventually died due to COVID-19. Our case series of three patients with DM1 admitted for COVID-19 confirms that they are at high risk for severe disease and poor outcome. Clinical trials are needed to define best practices and determinants of outcomes in this unique population.
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http://dx.doi.org/10.1007/s13760-020-01514-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556549PMC
October 2020

No association of CpG SNP rs9357140 with onset age in Belgian C9orf72 repeat expansion carriers.

Neurobiol Aging 2021 01 15;97:145.e1-145.e4. Epub 2020 Aug 15.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

We investigated the impact of the recently described chromosome 6 open reading frame 10 (C6orf10)/LOC101929163 locus as age-at-onset modifier in an extended cohort of Belgian chromosome 9 open reading frame 72 (C9orf72) GC repeat expansion carriers. We genotyped the tagging CpG single-nucleotide polymorphism rs9357140 in 224 confirmed C9orf72 repeat expansion carriers, 102 index cases and 122 relatives, and tested association with onset age. The C9orf72 repeat expansion cohort consisted of 131 symptomatic carriers, that is, 78 with dementia only, 13 with frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS), and 40 ALS only, and 93 presymptomatic carriers. Cox proportional hazard regression analysis failed to identify significant association (adjusted hazard ratio = 1.15, p = 0.3). We further extended our analysis to a Belgian cohort of unrelated, mutation-negative FTD index patients (n = 230), but also found no association (adjusted hazard ratio = 0.96, p = 0.3). Overall, our findings suggest that in the Belgian cohort, the C6orf10/LOC101929163 locus cannot explain the marked variability in age at onset, and other genetic or environmental modifiers must drive the clinical heterogeneity observed among C9orf72 repeat expansion carriers.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.07.021DOI Listing
January 2021

New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.

Brain 2020 09;143(9):2696-2708

Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.
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http://dx.doi.org/10.1093/brain/awaa228DOI Listing
September 2020

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents.

Int J Mol Sci 2020 Jun 28;21(13). Epub 2020 Jun 28.

Department of Head and Skin, Division of Neurology, Ghent University and Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium.

In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.
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http://dx.doi.org/10.3390/ijms21134596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369834PMC
June 2020

Myo-Inositol Transporter SLC5A3 Associates with Degenerative Changes and Inflammation in Sporadic Inclusion Body Myositis.

Biomolecules 2020 03 30;10(4). Epub 2020 Mar 30.

Department of Neurology; Laboratory for Neuropathology, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium.

Myo-inositol exerts many cellular functions, which include osmo-protection, membrane functioning, and secondary messaging. Its Na/myo-inositol co-transporter SLC5A3 is expressed in muscle tissue and further accumulates in myositis. In this study we focused on the peculiar subgroup of sporadic inclusion body myositis (IBM), in which auto-inflammatory responses and degenerative changes co-exist. A cohort of nine patients was selected with clinically confirmed IBM, in which SLC5A3 protein was immune-localized to the different tissue constituents using immunofluorescence, and expression levels were evaluated using Western blotting. In normal muscle tissue, SLC5A3 expression was restricted to blood vessels and occasional low levels on muscle fiber membranes. In IBM tissues, SLC5A3 staining was markedly increased, with discontinuous staining of the muscle fiber membranes, and accumulation of SLC5A3 near inclusions and on the rims of vacuoles. A subset of muscle-infiltrating auto-aggressive immune cells was SLC5A3 positive, of which most were T-cells and M1 lineage macrophages. We conclude that SLC5A3 is overexpressed in IBM muscle, where it associates with protein aggregation and inflammatory infiltration. Based on our results, functional studies could be initiated to explore the possibilities of therapeutic osmolyte pathway intervention for preventing protein aggregation in muscle cells.
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http://dx.doi.org/10.3390/biom10040521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226596PMC
March 2020

Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility.

Hum Mutat 2020 05 12;41(5):998-1011. Epub 2020 Feb 12.

Department of Biomolecular Medicine, Center for Medical Genetics Ghent, Ghent University Hospital, Ghent University, Ghent, Belgium.

Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.
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http://dx.doi.org/10.1002/humu.23993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187288PMC
May 2020

The myokine GDF-15 is a potential biomarker for myositis and associates with the protein aggregates of sporadic inclusion body myositis.

Cytokine 2020 03 2;127:154966. Epub 2020 Jan 2.

Department of Neurology and Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium.

Background: The cytokine growth differentiation factor-15 (GDF-15) has been associated with inflammatory and mitochondrial disease, warranting exploration of its expression in myositis patients.

Methods: GDF-15 protein levels are evaluated in 35 idiopathic inflammatory myopathy (IIM) serum samples using enzyme-linked immunosorbent assays, comparing with levels in samples from healthy individuals and from patients with genetically confirmed hereditary muscular dystrophies and mitochondrial disorders. Muscle tissue expression of GDF-15 protein is evaluated using immunofluorescent staining and Western blotting.

Results: GDF-15 protein levels are significantly higher in IIM sera (625 ± 358 pg/ml) than in that of healthy controls (326 ± 204 pg/ml, p = 0.01). Western blotting confirms increased GDF-15 protein levels in IIM muscle. In skeletal muscle tissue of IIM patients, GDF-15 localizes mostly to small regenerating or denervated muscle fibres. In patients diagnosed with sporadic inclusion body myositis, GDF-15 co-localizes with the characteristic protein aggregates within affected muscle fibres.

Conclusions: We describe for the first time that GDF-15 is a myokine upregulated in myositis and present the cytokine as a potential diagnostic serum biomarker.
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http://dx.doi.org/10.1016/j.cyto.2019.154966DOI Listing
March 2020

Multisystem proteinopathy due to a homozygous p.Arg159His mutation: A tale of the unexpected.

Neurology 2020 02 17;94(8):e785-e796. Epub 2019 Dec 17.

From the Neurogenetics Group (W.D.R., P.D.J., J.B.), Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born-Bunge, Neuromics Support Facility (A.A.), VIB-UAntwerp Center for Molecular Neurology, and Receptor Biology Lab (S.M.), Department of Biomedical Sciences, University of Antwerp; Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Institute of Neuropathology (C.S.C., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen; Centre for Biochemistry (C.S.C., L.E.), Institute of Biochemistry I, and Center for Physiology and Pathophysiology (C.S.C.), Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug Discovery (A.H), Griffith University, Nathan, Brisbane, Queensland; Department of Veterinary Biosciences (A.H.), Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for Neuropathology (J.L.D.B.), Division of Neurology, Ghent University Hospital, Belgium.

Objective: To assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene () mutation previously reported to be pathogenic in the heterozygous state.

Methods: We studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with -related myopathy, and 3 control individuals.

Results: The index patient, homozygous for the known p.Arg159His mutation in , manifested a typical -related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.

Conclusion: We report a patient showing a multisystem proteinopathy due to a homozygous mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into -related pathomechanisms.
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http://dx.doi.org/10.1212/WNL.0000000000008763DOI Listing
February 2020

A Phase 3 Multicenter, Prospective, Open-Label Efficacy and Safety Study of Immune Globulin (Human) 10% Caprylate/Chromatography Purified in Patients with Myasthenia Gravis Exacerbations.

Eur Neurol 2019 25;81(5-6):223-230. Epub 2019 Oct 25.

Grifols Bioscience Research Group, Sant Cugat del Vallès, Spain.

Background: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. Exacerbations may involve increasing bulbar weakness and/or sudden respiratory failure, both of which can be critically disabling. Management of MG exacerbations includes plasma exchange and intravenous immunoglobulin (IVIG); they are equally effective, but patients experience fewer side effects with IVIG. The objective of this study was to assess the efficacy and safety of immune globulin caprylate/chromatography purified (IGIV-C) in subjects with MG exacerbations.

Methods: This prospective, open-label, non-controlled 28-day clinical trial was conducted in adults with MG Foundation of America class IVb or V status. Subjects received IGIV-C 2 g/kg over 2 consecutive days (1 g/kg/day) and were assessed for efficacy/safety on Days 7, 14, 21, and 28. The primary efficacy endpoint was the change from Baseline in quantitative MG (QMG) score to Day 14. Secondary endpoints of clinical response, Baseline to Day 14, included at least a 3-point decrease in QMG and MG Composite and a 2-point decrease in MG-activities of daily living (MG-ADL).

Results: Forty-nine subjects enrolled. The change in QMG score at Day 14 was significant (p < 0.001) in the Evaluable (-6.4, n = 43) and Safety (-6.7, n = 49) populations. Among evaluable subjects, Day 14 response rates were 77, 86, and 88% for QMG, MG Composite, and MG-ADL, respectively. IGIV-C showed good tolerability with no serious adverse events.

Conclusions: The results of this study show that IGIV-C was effective, safe, and well tolerated in the treatment of MG exacerbations.
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http://dx.doi.org/10.1159/000502818DOI Listing
July 2020

Healthcare utilization at the end of life in people dying from amyotrophic lateral sclerosis: A retrospective cohort study using linked administrative data.

J Neurol Sci 2019 Nov 31;406:116444. Epub 2019 Aug 31.

End-of-Life Care Research Group, Vrije Universiteit Brussel & Ghent University, Brussels & Ghent, Belgium.

Background: ALS is an incurable neurodegenerative disorder, with the recommendation that symptom management and palliative care start immediately or soon after diagnosis. However, little is known about healthcare utilization at the end of life in this patient group.

Aim: To describe healthcare utilization at the end of life in patients who died from ALS.

Design: We performed a retrospective cohort study using population-level administrative databases. The description of healthcare utilization was based on (1) validated quality indicators for end-of-life care, and (2) the European Federation of Neurological Societies guidelines on the clinical management of ALS.

Setting: We included all people who died from ALS in Belgium between 2010 and 2015 (using ICD-10 code G12.2).

Results: 1636 people died from ALS in Belgium between 2010 and 2015. The mean age at death was 71 years (SD11.3), and 56% were men. Specialized palliative care was used by 44% at some point in the last two years of life. In the last month of life, 13% received tube feeding, 48% received diagnostic testing, 41% were admitted to a hospital, and 25% were admitted to an emergency department. Medications were used mainly to treat pain (43%), insomnia and fatigue (33%) and thrombosis (32%); 39% used riluzole. Non-invasive ventilation was used by 18%. 39% died at home.

Conclusion: Administrative data provide a valuable source to describe healthcare utilization in small populations such as ALS, but more clinical evidence is needed on the advantages and disadvantages initiating or terminating treatments at the end of life.
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http://dx.doi.org/10.1016/j.jns.2019.116444DOI Listing
November 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

Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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

Current evidence for treatment with nusinersen for spinal muscular atrophy: a systematic review.

Acta Neurol Belg 2019 Dec 6;119(4):523-533. Epub 2019 Aug 6.

Department of neurology, Ghent University Hospital, Belgium, C.-Heymanslaan 10, 9000, Ghent, Belgium.

Recent discovery of nusinersen, an antisense oligonucleotide drug, has provided encouragement for improving treatment of spinal muscular atrophy. No therapeutic options currently exist for this autosomal recessive motor neuron disorder. Nusinersen is developed for intrathecal use and binds to a specific sequence within the survival motor neuron 2 pre-messenger RNA, modifying the splicing process to promote expression of full-length survival motor neuron protein. We performed a MEDLINE and CENTRAL search to investigate the current evidence for treatment with nusinersen in patients with spinal muscular atrophy. Four papers were withheld, including two phase-3 randomized controlled trials, one phase-2 open-label clinical trial and one phase-1 open-label clinical trial. Outcome measures concerned improvement in motor function and milestones, as well as event-free survival and survival. Results of these trials are hopeful with significant and clinically meaningful improvement due to treatment with intrathecal nusinersen in patients with early- and later-onset spinal muscular atrophy, although this does not restore age-appropriate function. Intrathecal nusinersen has acceptable safety and tolerability. Further trials regarding long-term effects and safety aspects as well as trials including broader spinal muscular atrophy and age categories are required and ongoing.
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http://dx.doi.org/10.1007/s13760-019-01199-zDOI Listing
December 2019

Idiopathic inflammatory myopathy: Interrater variability in muscle biopsy reading.

Neurology 2019 08 29;93(9):e889-e894. Epub 2019 Jul 29.

From Ghent University Hospital (P.A.O., B.D.P., R.C., J.L.D.B.), Belgium; Academic Medical Centre (E.A., F.B., M.d.V.), University of Amsterdam, the Netherlands; Harvard Medical School (A.A.), Boston, MA; CHU Henri Mondor (D.D.), Créteil, France; Hospital Santa Creu i Sant Pau (E.G.), Barcelona, Spain; Université Paris Est-Créteil (R.G.), France; Charité-Universitätsmedizin Berlin (H.-H.G., W.S.), Germany; John Radcliffe Hospital (D.H.-J.); Oxford University Hospitals (M.H.); UCL Institute of Neurology (J.H.), London, UK; Syddansk Universitet (H.d.S.), Odense, Denmark; and Mayo Clinic (D.S.), Rochester, MN.

Objective: To determine interrater variability in diagnosing individual muscle biopsy abnormalities and diagnosis.

Methods: We developed a scoring tool to analyze consensus in muscle biopsy reading of an ad hoc workgroup of international experts. Twenty-four samples from patients with suspected idiopathic inflammatory myopathy (IIM) were randomly selected, providing sections that were stained with standard histologic and immunohistochemical methods. Sections were made available on an online platform, and experts were queried about myopathologic features within 4 pathologic domains: muscle fibers, inflammation, connective tissue, and vasculature. A short clinical presentation of cases was included, and experts were asked to give a tentative diagnosis of polymyositis, dermatomyositis, inclusion-body myositis, antisynthetase syndrome-related myositis, immune-mediated necrotizing myopathy, nonspecific myositis, or other disease. Fleiss κ values, scoring interrater variability, showed the highest agreement within the muscle fiber and connective tissue domains.

Results: Despite overall low κ values, moderate agreement was achieved for tentative diagnosis, supporting the idea of using holistic muscle biopsy interpretation rather than adding up individual features.

Conclusion: The assessment of individual pathologic features needs to be standardized and harmonized and should be measured for sensitivity and specificity for subgroup classification. Standardizing the process of diagnostic muscle biopsy reading would allow identification of more homogeneous patient cohorts for upcoming treatment trials.
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http://dx.doi.org/10.1212/WNL.0000000000008005DOI Listing
August 2019

Nonsense mutations in alpha-II spectrin in three families with juvenile onset hereditary motor neuropathy.

Brain 2019 09;142(9):2605-2616

Neurogenetics Group, Center for Molecular Neurology, University of Antwerp, Belgium.

Distal hereditary motor neuropathies are a rare subgroup of inherited peripheral neuropathies hallmarked by a length-dependent axonal degeneration of lower motor neurons without significant involvement of sensory neurons. We identified patients with heterozygous nonsense mutations in the αII-spectrin gene, SPTAN1, in three separate dominant hereditary motor neuropathy families via next-generation sequencing. Variable penetrance was noted for these mutations in two of three families, and phenotype severity differs greatly between patients. The mutant mRNA containing nonsense mutations is broken down by nonsense-mediated decay and leads to reduced protein levels in patient cells. Previously, dominant-negative αII-spectrin gene mutations were described as causal in a spectrum of epilepsy phenotypes.
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http://dx.doi.org/10.1093/brain/awz216DOI Listing
September 2019

Pitfalls in the detection of myositis specific antibodies by lineblot in clinically suspected idiopathic inflammatory myopathy.

Clin Exp Rheumatol 2020 Mar-Apr;38(2):212-219. Epub 2019 Jul 4.

Department of Laboratory Medicine, Ghent University Hospital, and Department of Diagnostic Science, Ghent University, Belgium.

Objectives: Today, the contribution of myositis-specific autoantibodies (MSA) in the diagnostic workup of idiopathic inflammatory myopathies (IIM) is on the rise. The aim of this study was to document MSA frequency as detected by lineblot in a set of consecutive MSA requests and to correlate the results with clinical diagnosis, IIM subtype and indirect immunofluorescence (IIF) findings. Additionally, a comparison between two lineblots was performed.

Methods: A total of 118 consecutive samples of patients with suspicion of IIM were analysed on IIF and two lineblots. A total of 107 patients with autoimmune rheumatic diseases served as controls.

Results: MSA were detected in 55% of IIM patients (n=31) and 7.9% (n=12) of patients without clinical diagnosis of IIM or myositis overlap syndrome. All the IIM patients had a MSA-compatible clinical subtype. There was no to fair agreement between both lineblots for the individual antibodies, with most discrepancies observed for anti-TIF1γ (κ=-0.021), anti-SRP (κ=-0.006) and anti-SAE (κ=0.395). Differences between both assays were mostly observed in the non-IIM patients, also showing signi cantly lower blot signal intensities compared to IIM patients (p=0.0013). MSA in the non-IIM patients frequently showed an incompatible IIF pattern.

Conclusions: Lineblot seems to be an interesting tool for MSA detection in a clinical context, allowing the identification of clinical subtypes. However, considerable caution must be exercised in interpreting the results in case of low positive MSA signal intensity, discordant lineblot results and/or an incompatible IIF pattern.
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April 2020

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups.

Ann Rheum Dis 2019 07 28;78(7):996-1002. Epub 2019 May 28.

Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.

Objectives: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies.

Methods: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups.

Results: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10 and HLA-DRB1*03:01, p=3.25×10), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10) and position 9 of HLA-B (p=7.03×10). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies.

Conclusions: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
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http://dx.doi.org/10.1136/annrheumdis-2019-215046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585280PMC
July 2019

FAHN/SPG35: a narrow phenotypic spectrum across disease classifications.

Brain 2019 06;142(6):1561-1572

Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, and Center for Neurology, University of Tübingen, Tübingen, Germany.

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.
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http://dx.doi.org/10.1093/brain/awz102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536916PMC
June 2019

Muscular dystrophy with arrhythmia caused by loss-of-function mutations in .

Neurol Genet 2019 Apr 1;5(2):e321. Epub 2019 Apr 1.

Neurogenetics Group (W.D.R., P.D.J., J.B.), University of Antwerp; the Laboratory of Neuromuscular Pathology (W.D.R., P.D.J., J.B.), Institute Born- Bunge, University of Antwerp; the Neuromuscular Reference Centre (W.D.R., P.D.J., J.B.), Department of Neurology, Antwerp University Hospital, Belgium; Sorbonne Université (I.N., M.B., R.B.Y., G.B.), INSERM U974, Center of Research in Myology, Institute of Myology, G.H. Pitié-Salpêtrière Paris, France; Histology and Cellular Imaging (B.A.), Neuromics Support Facility, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp; Laboratory for Neuropathology (B.D.P., J.D.B.), Division of Neurology, Ghent University Hospital, Belgium; AP-HP, Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile-deFrance (R.B.Y., B.E.), G.H. Pitié-Salpêtrière, Bioinformatics Unit (C.M.), Necker Hospital, AP-HP, and University Paris Descartes, ; Centre National de Recherche en Génomique Humaine (CNRGH) (A.B., J.F.D.), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry; Laboratoire de Neuropathologie (T.M.), G.H. Pitié-Salpêtrière, Paris, France; Center for Medical Genetics (S.S.), Ghent University Hospital, Belgium; Developmental Dynamics, Imperial Centre for Experimental and Translational Medicine (R.S., T.B.), Imperial College London; John Walton Muscular Dystrophy Research Centre (K.J., A.T., V.S.), MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

Objective: To study the genetic and phenotypic spectrum of patients harboring recessive mutations in .

Methods: We performed whole-exome sequencing in a multicenter cohort of 1929 patients with a suspected hereditary myopathy, showing unexplained limb-girdle muscular weakness and/or elevated creatine kinase levels. Immunohistochemistry and mRNA experiments on patients' skeletal muscle tissue were performed to study the pathogenicity of identified loss-of-function (LOF) variants in .

Results: We identified 4 individuals from 3 families harboring homozygous LOF variants in , the gene that encodes for Popeye domain containing protein 1 (POPDC1). Patients showed skeletal muscle involvement and cardiac conduction abnormalities of varying nature and severity, but all exhibited at least subclinical signs of both skeletal muscle and cardiac disease. All identified mutations lead to a partial or complete loss of function of through nonsense-mediated decay or through functional changes to the POPDC1 protein.

Conclusions: We report the identification of homozygous LOF mutations in , causal in a young adult-onset myopathy with concomitant cardiac conduction disorders in the absence of structural heart disease. These findings underline the role of POPDC1, and by extension, other members of this protein family, in striated muscle physiology and disease. This disorder appears to have a low prevalence, although it is probably underdiagnosed because of its striking phenotypic variability and often subtle yet clinically relevant manifestations, particularly concerning the cardiac conduction abnormalities.
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http://dx.doi.org/10.1212/NXG.0000000000000321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501641PMC
April 2019

Exertional rhabdomyolysis: Relevance of clinical and laboratory findings, and clues for investigation.

Anaesth Intensive Care 2019 Mar 9;47(2):128-133. Epub 2019 May 9.

2 Department of Neurology, University Hospital Antwerp, Belgium.

Some degree of exertional rhabdomyolysis (ER), striated muscle breakdown associated with strenuous exercise, is a well-known phenomenon associated with endurance sports. However in rare cases, severe and/or recurrent ER is a manifestation of an underlying condition, which puts patients at risk for significant morbidity and mortality. Selecting the patients that need a diagnostic work up of an acute rhabdomyolysis episode is an important task. Based on the diagnostic work up of three illustrative patients treated in our hospital, retrospectively using the 'RHABDO' screening tool, we discuss the clinical and biochemical clues that should trigger further investigation for an underlying condition. Finally, we describe the most common genetic causes of this clinical syndrome.
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http://dx.doi.org/10.1177/0310057X19835830DOI Listing
March 2019

Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with .

Neurology 2019 06 8;92(23):e2679-e2690. Epub 2019 May 8.

From Sorbonne Université (G.C., C.E., B.F., M.-L.M., F.M., M.P., C.-S.D., G.S., A.D.), Institut du Cerveau et de la Moelle épinière (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière; Department of Genetics (G.C., C.E., M.-L.M., P.C., F.M., G.B., G.S., A.D.), Pitié-Salpêtrière Charles-Foix University Hospital, Assistance publique-Hôpitaux de Paris, Sorbonne Université, Paris, France; Center for Neurology and Hertie Institute for Clinical Brain Research (R.S., M.S., L.S.), University of Tübingen, German Center for Neurodegenerative Diseases; German Center for Neurodegenerative Diseases (R.S., M.S., L.S.), Tübingen; Department of Neurology (B.P.C.v.d.W., E.G.H.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Neurogenetics Group (P.D.J., J.B., T.D., P.M., J.D.B., M.D.), University of Antwerp; Laboratories of Neurogenetics and Neuromuscular Pathology (P.D.J., J.B., T.D., P.M., J.D.B., M.D.), Institute Born-Bunge, University of Antwerp; Department of Neurology (P.D.J., J.B., T.D., P.M., J.D.B., M.D.), Antwerp University Hospital, Belgium; Scientific Institute IRCCS "E. Medea" (A.M.), Conegliano, Italy; Department of Neurology (M.A.), Hôpital de Hautepierre, Strasbourg; Institut de Génétique et de Biologie Moléculaire et Cellulaire (M.A.), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch; Fédération de Médecine Translationnelle de Strasbourg (M.A.), Université de Strasbourg; Department of Neurology (B.F.), Pitié-Salpêtrière Charles-Foix University Hospital, Assistance publique-Hôpitaux de Paris, Sorbonne Université, France; Department of Neurology (T. Klockgether, D.K.), University of Bonn; German Center for Neurodegenerative Diseases (T. Klockgether, D.K.), Bonn; Scientific Institute IRCCS E. Medea Neurorehabilitation Unit (M.G.D.), Bosisio Parini, Lecco, Italy; ULB Center of Human Genetics (I.M.), Brussels, Belgium; Scientific Institute IRCCS E. Medea Laboratory of Molecular Biology (M.T.B.), Bosisio Parini, Lecco, Italy; Department of Neurology With Friedrich-Baur Institute (T. Klopstock), University Hospital of the Ludwig-Maximilians-Universität München; German Center for Neurodegenerative Diseases (T. Klopstock); Munich Cluster for Systems Neurology (T. Klopstock), Germany; Department of Genetics (E.O.-R.), Croix-Rousse University Hospital, Lyon, France; Department of Neurology (C.K.), University of Rostock, Germany; Ecole Pratique des Hautes Etudes (M.P., G.S.), PSL Research University; Sorbonne Université (S.T.d.M.), INSERM, Institut Pierre Louis de Santé Publique, Medical Information Unit, Pitié-Salpêtrière Charles-Foix University Hospital, Assistance publique-Hôpitaux de Paris; and Raymond Escourolle Neuropathology Department (D.S., C.D.), Pitié-Salpêtrière University Hospital, Assistance publique-Hôpitaux de Paris, Sorbonne Université, France.

Objective: We took advantage of a large multinational recruitment to delineate genotype-phenotype correlations in a large, trans-European multicenter cohort of patients with spastic paraplegia gene 7 ().

Methods: We analyzed clinical and genetic data from 241 patients with , integrating neurologic follow-up data. One case was examined neuropathologically.

Results: Patients with had a mean age of 35.5 ± 14.3 years (n = 233) at onset and presented with spasticity (n = 89), ataxia (n = 74), or both (n = 45). At the first visit, patients with a longer disease duration (>20 years, n = 62) showed more cerebellar dysarthria ( < 0.05), deep sensory loss ( < 0.01), muscle wasting ( < 0.01), ophthalmoplegia ( < 0.05), and sphincter dysfunction ( < 0.05) than those with a shorter duration (<10 years, n = 93). Progression, measured by Scale for the Assessment and Rating of Ataxia evaluations, showed a mean annual increase of 1.0 ± 1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n = 65) presented significantly more often with pyramidal signs ( < 0.05), diminished visual acuity due to optic atrophy ( < 0.0001), and deep sensory loss ( < 0.0001) than those with at least 1 missense variant (n = 176). Patients with at least 1 Ala510Val variant (58%) were older (age 37.6 ± 13.7 vs 32.8 ± 14.6 years, < 0.05) and showed ataxia at onset ( < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons.

Conclusions: This is the largest cohort study to date and shows a spasticity-predominant phenotype of LOF variants and more frequent cerebellar ataxia and later onset in patients carrying at least 1 Ala510Val variant.
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http://dx.doi.org/10.1212/WNL.0000000000007606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556095PMC
June 2019

Long-term safety and efficacy of eculizumab in generalized myasthenia gravis.

Muscle Nerve 2019 07 8;60(1):14-24. Epub 2019 Mar 8.

Department of Neurology, University of North Carolina, Chapel Hill, North Carolina, USA.

Introduction: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy.

Methods: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients.

Results: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001).

Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019.
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http://dx.doi.org/10.1002/mus.26447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619057PMC
July 2019

Cladribine in myasthenia gravis: A case urging for prudence.

Muscle Nerve 2019 05 22;59(5):E38. Epub 2019 Feb 22.

Department of Neurology, UZ Gent, Corneel Heymanslaan 10, 9000, Gent, Belgium.

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http://dx.doi.org/10.1002/mus.26446DOI Listing
May 2019

Two successfully completed pregnancies in adult onset Pompe disease, under continued treatment with alglucosidase alfa.

Acta Neurol Belg 2019 Mar 4;119(1):147-149. Epub 2019 Feb 4.

Department of Neurology and Neuromuscular Reference Centre, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Ghent, Belgium.

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http://dx.doi.org/10.1007/s13760-019-01089-4DOI Listing
March 2019

Efficacy and safety of IVIG in CIDP: Combined data of the PRIMA and PATH studies.

J Peripher Nerv Syst 2019 03 15;24(1):48-55. Epub 2019 Feb 15.

CSL Behring, Marburg, Germany, and King of Prussia, Pennsylvania.

Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open-label, single-arm study of IVIG in immunoglobulin (Ig)-naïve or IVIG pre-treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double-blind, randomized study including an open-label, single-arm IVIG phase in IVIG pre-treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235). Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre-treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort, median change from baseline to last observation was -1.0 (interquartile range -2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score. In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. This analysis confirms the efficacy and safety of IgPro10, a recently FDA-approved IVIG for CIDP, in a population of mainly pre-treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.].
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http://dx.doi.org/10.1111/jns.12302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594229PMC
March 2019

Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients.

Genes (Basel) 2018 Oct 26;9(11). Epub 2018 Oct 26.

Dipartimento di Medicina di Precisione, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Napoli, Italy.

Next-generation sequencing (NGS) technologies have led to an increase in the diagnosis of heterogeneous genetic conditions. However, over 50% of patients with a genetically inherited disease are still without a diagnosis. In these cases, different hypotheses are usually postulated, including variants in novel genes or elusive mutations. Although the impact of copy number variants (CNVs) in neuromuscular disorders has been largely ignored to date, missed CNVs are predicted to have a major role in disease causation as some very large genes, such as the dystrophin gene, have prone-to-deletion regions. Since muscle tissues express several large disease genes, the presence of elusive CNVs needs to be comprehensively assessed following an accurate and systematic approach. In this multicenter cohort study, we analyzed 234 undiagnosed myopathy patients using a custom array comparative genomic hybridization (CGH) that covers all muscle disease genes at high resolution. Twenty-two patients (9.4%) showed non-polymorphic CNVs. In 12 patients (5.1%), the identified CNVs were considered responsible for the observed phenotype. An additional ten patients (4.3%) presented candidate CNVs not yet proven to be causative. Our study indicates that deletions and duplications may account for 5⁻9% of genetically unsolved patients. This strongly suggests that other mechanisms of disease are yet to be discovered.
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http://dx.doi.org/10.3390/genes9110524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267442PMC
October 2018

Induction of Osmolyte Pathways in Skeletal Muscle Inflammation: Novel Biomarkers for Myositis.

Front Neurol 2018 11;9:846. Epub 2018 Oct 11.

Department of Neurology and Neuromuscular Reference Center, Ghent University Hospital, Ghent, Belgium.

We recently identified osmolyte accumulators as novel biomarkers for chronic skeletal muscle inflammation and weakness, but their precise involvement in inflammatory myopathies remains elusive. In the current study, we demonstrate that, in myoblasts and myotubes exposed to pro-inflammatory cytokines or increased salt concentration, mRNA levels of the osmolyte carriers SLC5A3, SLC6A6, SLC6A12, and AKR1B1 enzyme can be upregulated. Induction of SLC6A12 and AKR1B1 was confirmed at the protein level using immunofluorescence and Western blotting. Gene silencing by specific siRNAs revealed that these factors were vital for muscle cells under hyperosmotic conditions. Pro-inflammatory cytokines activated mitogen-activated protein kinases, nuclear factor κB as well as nuclear factor of activated T-cells 5 mRNA expression. In muscle biopsies from patients with polymyositis or sporadic inclusion body myositis, osmolyte pathway activation was observed in regenerating muscle fibers. In addition, the osmolyte carriers SLC5A3 and SLC6A12 localized to subsets of immune cells, most notably to the endomysial macrophages and T-cells. Collectively, this study unveiled that muscle cells respond to osmotic and inflammatory stress by osmolyte pathway activation, likely orchestrating general protection of the tissue. Moreover, pro-inflammatory properties are attributed to SLC5A3 and SLC6A12 in auto-aggressive macrophages and T-cells in inflamed skeletal muscle.
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http://dx.doi.org/10.3389/fneur.2018.00846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193116PMC
October 2018