ACTA MYOLOGICA (Myopathies, Cardiomyopathies and Neuromyopathies)

Vol. XXXIX - September 2020

Official Journal of Mediterranean Society of Myology and Associazione Italiana di Miologia

Founders: Giovanni Nigro and Lucia Ines Comi

Three-monthly

EDITOR-IN-CHIEF Luisa Politano

ASSISTANT EDITOR Vincenzo Nigro

CO-EDITORS Lefkos Middleton Gabriele Siciliano Giuseppe Novelli Haluk Topaloglu Reinhardt Rüdel Antonio Toscano

Official Journal of Mediterranean Society of Myology and Associazione Italiana di Miologia

Founders: Giovanni Nigro and Lucia Ines Comi

Three-monthly

SCIENTIFIC BOARD

Corrado Angelini, “San Camillo” Hospital, Venice, Italy Anders Oldfors, University of Gothenburg, Sweden Enrico Bertini, “Bambino Gesù” Hospital, Rome, Italy Elena Pegoraro, University of Padua, Italy Serge Braun, AFM-Telethon, Paris, France Heinz Reichmann, University Hospital, Technische Kevin P. Campbell, University of Iowa, Iowa City, USA Universität, Dresden, Germany Marinos Dalakas, University of Athens,Greece Filippo Maria Santorelli, IRCCS Stella Maris, Pisa, Italy Feza Deymeer, University of Instanbul, Turkey Serenella Servidei, Catholic University, Rome, Italy Salvatore Di Mauro, Columbia University, New York, USA Piraye Serdaroglu, University of Instanbul, Turkey Denis Duboc, Cochin Hospital, Paris, France Yeuda Shapira, University of Jerusalem, Israel Victor Dubowitz, Imperial College, London, UK Osman I. Sinanovic, University of Tuzla, Bosnia and Massimiliano Filosto, University of Brescia, Italy Herzegovina Fayçal Hentati, University of Tunis, Tunisia Michael Sinnreich, University of Basel, Switzerland Michelangelo Mancuso, University of Pisa, Italy Andoni J. Urtizberea, AP-HP Marin Hospital, Hendaye, Giovanni Meola, University of Milan, Italy France Eugenio Mercuri, Catholic University, Rome, Italy Gert-Jan van Ommen, Leiden University Medical Carlo Minetti, University of Genoa, Italy Center, the Netherlands Clemens Muller, Julius-Maximilians-University, Steve Wilton, University of Western Australia, Perth, Würzburg, Germany Australia Francesco Muntoni, University College London, UK Massimo Zeviani, University of Cambridge, UK Carmen Navarro, University Hospital of Vigo, Spain Janez Zidar, University Medical Centre, Ljubljana, Luis Negrao, University of Coimbra, Portugal Slovenia Gerardo Nigro, University of Campania “L. Vanvitelli ”, Naples, Italy EDITOR-IN-CHIEF COPY EDITOR Luisa Politano, Cardiomyology and Medical Genetics - Valentina Bàrberi Dept. of Experimental Medicine, University of Campania [email protected] “L.Vanvitelli” - Piazza Miraglia - 80138 Naples, IT Tel. +39 081 5665300 CO-EDITORS Fax +39 081 5665101 Lefkos Middleton, Imperial College London, London, UK [email protected] Giuseppe Novelli, University of Tor Vergata, Rome, IT [email protected] Reinhardt Rüdel, Ulm University, Ulm, DE ASSISTANT EDITOR Gabriele Siciliano, University of Pisa, Pisa, IT Vincenzo Nigro, University of Campania, “L. Vanvitelli”, Haluk Topaloglu, University of Hacettepe, Ankara, TR Naples, IT - [email protected] Antonio Toscano, University of Messina, Messina, IT EDITORIAL STAFF Chiara Fiorillo, G. Gaslini Hospital, Genoa, IT Lorenzo Maggi, Besta Neurological Institute, Milan, IT Giulia Ricci, University of Pisa, Pisa, IT Lucia Ruggiero, University of Naples “Federico II”, Naples, IT Vincenzo Russo, University of Campania, “L. Vanvitelli”, Naples, IT

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Via A. Gherardesca - 56121 Pisa, Italy Published by Pacini Editore Srl, Pisa, Italy, September 2020 CONTENTS

ORIGINAL ARTICLES Predictors of prognosis in type 1 myotonic dystrophy (DM1): longitudinal 18-years experience from a single centre Marco Mazzoli, Alessandra Ariatti, Gian Carlo Garuti, Virginia Agnoletto, Maurilio Genovese, Manuela Gozzi, Shaniko Kaleci, Alessandro Marchioni, Marcella Malagoli, Giuliana Galassi...... 109

Respiratory function and therapeutic expectations in DMD: families experience and perspective Claudia Brogna, Simona Lucibello, Giorgia Coratti, Gianluca Vita, Valeria A. Sansone, Sonia Messina, Emilio Albamonte, Francesca Salmin, Gloria Ferrantini, Elisa Pede, Chiara Consulo, Lavinia Fanelli, Nicola Forcina, Giulia Norcia, Marika Pane, Eugenio Mercuri...... 121

Endocrine myopathies: clinical and histopathological features of the major forms Carmelo Rodolico, Carmen Bonanno, Alessia Pugliese, Giulia Nicocia, Salvatore Benvenga, Antonio Toscano . . 130

CASE REPORTS Beneficial effects of one-month sacubitril/valsartan treatment in a patient affected by end-stage dystrophinopathic cardiomyopathy Andrea Antonio Papa, Emanuele Gallinoro, Alberto Palladino, Paolo Golino ...... 136

Silent dysphagia in two patients with Steinert disease and recurrent respiratory exacerbations Anna Annunziata, Tullio Valente, Rosa Cauteruccio, Giuseppe Fiorentino ...... 141

NEWS FROM AROUND THE WORLD AIM ...... 144 MSM ...... 144 WMS...... 144

FORTHCOMING MEETINGS...... 145

AIM-ASNP 2020 JOINT CONGRESS – Scientific Program ...... 146

Instructions for Authors...... 171

ACTA MYOLOGICA 2020; XXXIX: p. 109-120 ORIGINAL ARTICLES doi:10.36185/2532-1900-015 Predictors of prognosis in type 1 myotonic dystrophy (DM1): longitudinal 18-years experience from a single center

Marco Mazzoli1, Alessandra Ariatti1, Gian Carlo Garuti2, Virginia Agnoletto3, Maurilio Genovese4, Manuela Gozzi5, Shaniko Kaleci6, Alessandro Marchioni7, Marcella Malagoli4, Giuliana Galassi1 1 Department of Biomedical, Metabolic and Neural Sciences, University Hospitals of Modena, Italy; 2 Respiratory Unit, Mirandola Hospital, Italy; Cardiology Unit, University Hospitals of Modena, Italy; 4 Neuroradiology Unit, University Hospitals of Modena, Italy; 5 Radiology Unit, University Hospitals of Modena, Italy; 6 Department of Surgical, Medical, Dental and Morphological Science with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Italy; 7 Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospitals of Modena, Italy

The aim of the study was to identify possible predictors of neurological worsening and need of non-invasive ventilation (NIV) in individuals affected by myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy. Received: May 11, 2020 Accepted: September 8, 2020 Methods. A retrospective observational cohort study was undertaken. Thirty-three patients with genetic diagnosis of DM1 were followed at our Neuromuscular unit Correspondence in Modena. Abnormal trinucleotide repeat (CTG) expansion of dystrophy protein Giuliana Galassi kinase gene (MDPK) on chromosome 19q 13.3 was the prerequisite for inclusion. Department of Biomedical, Metabolic, Neural Sciences, The number of CTG repeats was determined. All the participants were older than University Hospitals of Modena, via P. Giardini 1355, Modena, Italy. E-mail: [email protected] 14 at the time of enrolment, therefore they could be included into the juvenile or adult form of the disease. Participants were neurologically evaluated every 6-8 Conflict of interest months up to 18 years. Neurological impairment was assessed by Muscular Im- The Authors declare no conflict of interest pairment Rating (MIRS), Medical Research Council (MRC), and modified Rankin (mRS) scales. The independent variables considered for prognosis were age at first How to cite this article: Mazzoli M, Ariatti A, Garuti evaluation, duration of the disease, CTG repeat number, gender, and presence of GC, et al. Predictors of prognosis in type 1 myotonic cardiac and vascular morbidities. dystrophy (DM1): longitudinal 18-years experience from a single center. Acta Myol 2020;39:109-20. Male patients were 51.5% and female patients 48.5%. Sixteen patients were young- https://doi.org/10.36185-2532-1900-015 er than the mean age of 30.1 years, while the remaining 17 were up to 65. Twelve subjects (36.4%) underwent NIV before the end of follow-up. Muscle force and © Gaetano Conte Academy - Mediterranean Society of disability scores showed statistically significant deterioration (p < 0.001) during Myology follow-up. The worsening was significantly higher among patients carrying higher number of CTG repeats and of younger age. The presence of cardio-vascular OPEN ACCESS involvement has significant impact on neurological and respiratory progression. This is an open access article distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution- Neurological worsening is predicted by CTG expansion size, young age and pres- NonCommercial-NoDerivatives 4.0 International) license. The ence of cardio-vascular morbidities. article can be used by giving appropriate credit and mentioning the license, but only for non-commercial purposes and only in the original version. For further information: https:// Key words: myotonic dystrophy type I, muscular impairment rating scale, CTG trinu- creativecommons.org/licenses/by-nc-nd/4.0/deed.en cleotide repeat

109 Marco Mazzoli et al.

Introduction approved by the local Ethical Committee (N°325/2019). A multidisciplinary team including neurologists, pulmo- Myotonic dystrophy type 1 (DM1) is the most com- nologists and cardiologists, evaluated the subjects during mon form of adult-onset muscular dystrophy with a prev- a follow-up which lasted from the first to the last visit or 1-12 alence in Europe of 3-15/100.000 inhabitants . DM1 to death. Patients were followed for at least 24 months. is caused by an unstable expansion of the cytosine thy- mine-guanine (CTG) trinucleotide repeat located in the Predictive variables and assessments 3′UTR of DMPK gene, chromosome 19q13.3, encoding a serine/threonine protein kinase (DMPK) trinucleo- Our genetic reference laboratory defined subjects as tide 8-19. The disease is transmitted across generations in E1 with number of repeats less than 200, E2 from 201 to an autosomal dominant fashion with incomplete pene- 699 repeats, and E3 from 700 and larger. All participants trance, variable phenotypic expression and somatic mo- were older than 14 at the time of enrollment, therefore 24-27 saicism 1,3,6,8-12,19-21. Anticipation, i.e. increased number of with juvenile or adult form of the disease . Patients CTG repeats in subsequent generations, is associated with were further classified according to onset of symptoms increased severity of disease, more marked with maternal at an age above or below 30.1 years, which was the mean transmission 1,3,5,8,11,12,21-24. The disorder is multisystemic in our cohort. Clinical onset in patients with very mild/ and affects muscles and central nervous, ocular, respira- asymptomatic disease was set at the date of their first tory, heart, digestive, endocrine systems in relation to the clinical/genetic diagnosis or it was retrieved from previ- variable number of triple repeats in each organ 2-5,7-12,24-30. ous medical history. For the specific purpose of the study, Regular cardiological and ventilatory assessment is im- the following data were included: muscle impairment and portant in DM1, as respiratory failure accounts for almost disability scores, gender, serum creatine kinase (CK) titer 40% of mortality at an average age of 53 years 4,24,29-37. assessed at least once per year, and electromyographical The introduction of non-invasive ventilation (NIV) com- changes. In addition, the presence or absence of multisys- bined with treatments for cardiac manifestations have im- temic involvement such as cardiac, vascular, endocrine, proved survival in DM1 4,30-32. Due to the broad clinical ophthalmological and hematological disorders was as- spectrum, DM1 subjects can be classified into five clin- sessed at the time of enrollment and in subsequent fol- ical forms according to age of onset of first symptoms: low-up. Each neurologist collected the informations at congenital, infantile, juvenile, adult, and late onset 24-26. the time of enrollment on presence/absence of the above The progression rate of muscle strength loss in different mentioned conditions. phenotypes (juvenile, adult and late onset) needs to be Muscle strength was determined with manual mus- documented and has an impact on patient prognosis. Our cle testing (MMT) by three neurologists (GG, AA, MM) study was aimed at identifying predictors of neurologic using Medical Research Council Scale (MRC) in six and respiratory impairment in an Italian cohort of patients muscles for each limb in upper (UE) and lower (LE) affected by DM1, followed longitudinally up to 18 years. extremities: deltoid, biceps brachii, extensor digitorum communis, ileopsoas, quadriceps and anterior tibial. The maximal score for each muscle ranged between 0 and 5, Patients and methods and the total score obtained was 60. Disability was measured with the Rankin Scale (mRS) (range 0-5). Muscular Setting and study population Impairment Rating Scale (MIRS), a validated DM1-spe- We conducted a retrospective observational study in cific rating scale, was also used 9,25-27. a single neuromuscular disease center (Center for Neuro- Respiratory assessments included arterial blood gas muscular Diseases, University Hospital of Modena, Ita- analysis and pulmonary function tests (PFTs) with eval- ly). Inclusion criteria were as follows: diagnosis of DM1 uation of forced vital capacity (FVC), forced expirato- attested by clinical evaluation and molecular genetic test- ry volume in 1 sec (FEV1) and FEV1/FVC (Tiffeneau ing. No patients at the time of enrolment had end-stage index) performed at the time of enrollment and at ev- lung diseases (chronic obstructive pulmonary disease, in- ery follow-up visit. Arterial blood gases were measured terstitial lung disease, severe kyphoscoliosis and disorders in samples drawn at rest from the radial artery. Arterial of the chest walls). Between January 1st, 2000 and De- oxygen partial pressure (PaO2) and arterial carbon diox- cember 2018, 33 patients with clinical diagnosis of DM1 ide partial pressure (PaCO2) were determined within 10 were included according to genetic diagnosis. All patients minutes of sampling. Hypercapnia was defined as PaCO2 enrolled showed an abnormal expansion of CTG in the > 45 mmHg and hypoxemia as PaO2 < 80 mmHg 3,29- 3′ untranslated region of the Myotonic Dystrophy Pro- 31. NIV (meaning the use for more than 4 hours/daily) tein Kinase (MDPK) assessed by long-PCR and Southern included initiation of Nocturnal Positive Airway Pressure blot analysis gene (MIM #160900) The study design was (NPAP), either continuous (CPAP) or bilevel (BPAP) 31.

110 Long term prognosis of DM1

NIV was planned by a pulmonologist in the presence of Data were presented as median with minimum–maxi- symptoms suggestive of chronic respiratory failure (dys- mum range or as mean with standard deviation (SD). pnea at rest, daytime hypersomnolence, orthopnea), plus For comparison of change between independent groups, at least one of the following criteria: FVC less than 50% Mann-Whitney U test was used for continuous variables predicted in seated position, apnea/hypopnea index great- and Mantel-Haenszel Chi Square Exact test for ordered er than 15 events/hour, nocturnal arterial saturation less categorical variables. The differences in MRC, mRS, than 88% for more than 2 cumulative minutes, arterial pH and MIRS between baseline and times of follow-up were < 7.35 and PaCO2 > 45 mmHg 2,4,31-33,35. computed using t-test. Kaplan-Meier method was used Cardiological evaluations included clinical assess- to estimate progression with respect to outcomes; curves ment, basal blood pressure, ECG, 24h ECG Holter mon- were compared with Log-rank test to determine any dif- itoring, and trans-thoracic echocardiography. Impulse ference in terms of age at the time of onset of end points. conduction abnormalities and arrhythmias on a standard Hazard ratio and 95% confidence interval (CI) from Cox ECG, including sinus rate < 50 BPM, PR interval > 200 proportional hazard regression model were used to esti- ms, QRS duration > 100 ms, left anterior or posterior fas- mate the risk of each end point, based on clinical attributes cicular block, abnormal Q waves, atrial tachycardia and at baseline (i.e. gender, age, CTG expansion, presence fibrillation (AF) or flutter were considered indicative of of cardiovascular morbidities). The impact of clinical cardiac involvement. We measured systolic left ventric- variables on MIRS and NIV requirement was evaluated ular dysfunction as reduction of ejection fraction (EF) using a logistic regression model. To improve statistical below 50% 4,22,29,30,38,39. strength, genotypes based on number of CTG repeats Only 4 cases could be studied with 1.5T Magnetic were pooled into two groups that were E1 vs E2 plus E3. Resonance Imaging (MRI) scan of limb girdle, thigh and Clinical factors associated with P values below 0.05 in lower leg to assess muscular hypotrophy or atrophy, mus- the univariable model were analyzed in a multivariable cle edema and fat replacement on T1, T2 and on short model with a stepwise forward selection. Missing data on time inversion recovery (STIR) sequences with fat sup- MRC, MIRS, and mRS during follow-up were estimated pression. After clinical indication, a brain neuroradiologi- by multiple imputation method (MI) using either linear 41 cal study either with CT or MRI was obtained or reviewed or ordinal regression, if appropriate . Variance analysis in 17 subjects at the median age of 44.5 years (range 20- (ANOVA) and Tukey-Kramer test were used to compare 70, IQR 23.7). The retrospective quantitative evaluation clinical scores at baseline and at 24, 48, 72 and 96 months of available images was carried out by two neuroradiolo- in patients having different genetic profiles. gists looking for structural abnormalities, such as whole brain atrophy, and white matter subcortical and periven- Results tricular changes especially in the temporal pole 40. White matter temporal changes were detected in 31.2% of the Patients baseline clinical data subjects. During follow-up, no patients exhibited detect- Demographic characteristics of patients are listed in able ischemic lesions. Table I. Mean duration of follow up was 121.6 months ± 69.4 (median 100 months, range 24-220, IQR 125). End points Median duration of illness was 237 months (range 24- Primary end points of the study were analysis of clin- 553, IQR 202). Demographic analysis of DM1 popu- ical and genetic parameters associated with significant lation showed a 1:1 male to female ratio with 17 males (51.5%) and 16 females (48.5%). The age of onset had neurological impairment, defined as worsening in 2 out similar gender distribution. Median age of diagnosis was of the 3 neurological assessment scales applied. A change 31 years (range 14-65). Ten patients (30.3%) had lower of ≥ 1 point in MIRS was considered significant, as well number of expansions (E1) whereas those classified as E2 as a worsening of ≥ 7 points in total MRC score, of ≥ 4 were 39.4%, and E3 were 30.3%. points in UE MRC score, of ≥ 3 points in LE MRC score At baseline, the median total MRC muscle strength and a change of ≥ 1 point in mRS. Secondary outcome assessed with MMT was 48 (range 30-60, IQR 12; was the identification of clinical and genetic parameters mean 48.8, ± 7.74), and 24 (range 18-30 IQR 8; mean associated with functional impairment and need for NIV. 24.4 ± 3.5) in UE and 24 in LE (range 10-30, IQR 6, mean 24.3 ± 4.4). Regarding disability scores, mean MIRS was Statistical analysis 3.66 ± 0.88 and mRS was 2.1 ± 1.30. At baseline, muscle Statistical analysis was performed using Stata 14.2 strength, either computed as total or separately in UE and (Stata Corporation, College Station, TX, USA). Patient LE, and mRS were not significantly different among gen- characteristics were analysed using descriptive statistics. ders (p = 0.66); conversely, MIRS scores in females were

111 Marco Mazzoli et al.

Table I. Summary of demographic and clinical characteristics of our patients. Overall [33 (100%)] Gender [n (%)] Male 17 (51.5%) Female 16 (48.5%) Age of onset/diagnosis (y) [median (range)] 31 (14-65) Male 32 (15-65) Female 29.5 (14-53) Duration of follow-up (mo) [median (range)] 100 (24-220, IQR 125) Duration of disease (mo) [median (range)] 237 (24-553, IQR 202) CTG repeat [n (%)] E 1 10 (30.3%) E 2 13 (39.4%) E 3 10 (30.3%) Death [n (%)] 4 (12.1%) Male [n (%)] 2/4 (50.0%) Age (y) [median (range)] 64 (54-67) Pace maker or ICD [n (%)] 5 (15.2%) Male [n (%)] 4/5 (80.0%) Age (y) [median (range)] 51 (42-68) Systemic involvement [n (%)] 30 (90.9%) significantly worse than in males (p = 0.03). Abnormal docrine dysfunction requiring treatments in 51.5%. The EMG findings were detected in 63.6% of cases, and CK cardiac abnormalities were detected in 63,6% of cases level above 170 IU/L was found in 48. and included conduction disturbances (66%) namely, prolonged PR interval (A-V block of I°), bradyarrhyth- Multisystemic involvement mias, II° and III° atrioventricular blocks, AF, ventricular arrhythmias, left ventricular systolic dysfunction with Multisystemic involvement was detected in 90% of depressed EF and clinical heart failure, and mitral valve cases. Cataract occurred in 78.8%, while thyroid and en- prolapse. No ventricular tachycardia was detected. Vascu-

Table II. Outcome measures at baseline and at last follow-up in patients according to genotypes. Genotype Genotypes Overall P E1 P E2, E3 P Base- Last overall Base- Last P basal Base- Last P final line f-up line f-up line f-up pCO2 41.8 43.0 40.4 40.3 42.6 44.2 EGAa (mmHg) (±6.4) (± 6.8) 0.15 (± 4.04) (± 3.9) 0.95 0.07 (± 7.1) (± 7.5) 0.46 0.04 pO2 80.8 83.5 86.9 86 78.2 82.4 (mmHg) (±14.0) (± 13.1) 0.33 (± 10.3) (± 8.1) 0.83 0.07 (± 14.7) (± 14.8) 0.33 0.24 FVC (% 75.4 67.2 82.9 78.9 72.1 62.1 Spirometry predicted) (±18.5) (± 21.4) 0.002 (± 7.4) (± 9.8) 0.31 0.03 (± 21.04) (± .1) 0.13 0.006 48.8 37.8 55.4 50.4 46 32.3 MRC Total (±7.74) (± 12.3) < 0.001 (± 6.1) (± 10.3) 0.20 0.002 (± 6.6) (± 8.6) < 0.001 < 0.001 Upper 24.4 19.7 27.4 25.4 23.2 17.3 limbs (±3.5) (± 5.81) < 0.001 (± 3.2) (± 5.0) 0.30 0.003 (± 2.9) (± 4.2) < 0.001 < 0.001 Lower 24.3 18 28 25 22.7 15.1 limbs (±4.4) (± 6.81) < 0.001 (± 2.9) (± 5.3) 0.13 < 0.001 (± 3.9) (± 5.0) < 0.001 < 0.001 3.66 4.24 2.9 3.2 4 4.6 MIRS (± 0.88) (± 1.0) 0.001 (± 0.99) (± 1.3) 0.56 < 0.001 (± 0.6) (± 0.5) < 0.001 < 0.001 2.1 3.0 1. 1 1.6 2.6 3.6 mRS (± 1.30) (± 1.4) 0.001 (± 1.2) (± 1.7) 0.45 0.003 (± 1.0) (± 0.8) < 0.001 < 0.001 EGA: arterial blood gas analysis. pCO2/O2: partial blood pressure of CO2/O2. FVC: forced vital capacity. MRC: Medical Research Council. MIRS: muscular impairment rating scale. mRS: modified Rankin Scale. The values are expressed as mean with standard deviation (SD) in brackets. P overall expresses the significance between baseline and last follow-up for each variable. P basal and p finalexpress respectively the significance of the comparisons between subjects carrying the different genotype at baseline and at the last follow-up for each studied variable. Significance: p < 0.05 two tailed. Significant results are in bold. See text for details.

112 Long term prognosis of DM1 lar comorbidities included severe hypertension (systolic MIRS gave the following results: at baseline and at last blood pressure ≥ 180 mmHg and/or diastolic blood pres- assessment in group E1, neither MRC nor MIRS and dis- sure ≥ 120 mmHg) and large vessel atherosclerosis; the ability scores worsened significantly (p > 0.05), whereas latter, for statistical purposes, were pooled in the analysis in E2/E3 groups the worsening in total MRC and MRC with cardiac abnormalities. Regarding cardiac therapies, subdivided in UE and LE, in MIRS and mRS was statis- patients were treated according to published guidelines tically significant (p = 0.002, 0.003 and below 0.001, re- with angiotensin II receptor blockers, angiotensin con- spectively). We further calculated clinical and functional verting enzyme inhibitors, beta-blockers, diuretics, oral scores at baseline and at end of follow-up between groups, anticoagulants, and flecainide, if appropriate 38,39. Five pa- and we found that groups E1 and E2/E3 were statistically tients had prophylactic pace-maker (PM) implantation; in different: basal p and final p expresses the significance of 2 cases, an implantable cardioverter defibrillator (ICD) the comparison for each variable between the groups, E1 was subsequently applied. on one side and E2/E3 on the other. We calculated with a Cox regression analysis the probability of surviving to worsening on MIRS in patients Predictors of neurological with different CTG expansion size: Kaplan-Meier curve worsening is shown in Figure 1b (p = 0.016 at Log rank test). The A statistically significant decline between baseline latter result was confirmed by a logistic regression anal- and last visit was seen in the whole sample for all the ysis, after adjustment with clinically relevant variables: clinical outcome measures; 54.5% of subjects showed de- higher than 200 CTG triplet repeat number had an inde- terioration in all the scales. A significant decline in global pendent prognostic effect on worsening in MIRS (HR muscle force (total MRC scores) was found in 27 cas- 5.09, CI 1.34-19.36, p = 0.017) (Tab. III). Furthermore, es (81.8%): loss of strength in LE was found in 78.6% we assessed the influence of genotypes on the probability of cases, and 66.6% worsened in UE with no significant of surviving to worsening in muscle strength assessed by difference between UE and LE (p = 0.87 and 0.10, re- total MRC, as shown in Fig 1d with Kaplan-Meier curve spectively). The worsening occurred at mean age of 43.2 (p = 0.004 at Log rank). Figure 2a and 2c show the proba- y (± SD 13.2) in LE and of 43.9 y (± SD 13.3) in UE. A bility of being free from worsening in muscle strength for worsening in mRS and in MIRS was found in 60.6 and in UE and LE in the three genotypes E1, E2, E3 (p < 0.001 63.6% of patients respectively. at Log rank), with the number at risk and of survivors belonging to each genotype in relation to age. The box Expansion size plot in Figure 2d shows MIRS measurements at baseline and at 24, 48, 72 and 96 months; a significant difference Table II shows the measures of muscle strength, was found between genotypes E1 vs E2, and E1 vs E3 MIRS and disability scores obtained at baseline and at last (p < 0.01). follow-up in the whole cohort and in patient groups subdivided according to lower or higher than 200 CTG triplet Baseline age repeats (i.e. E1 and E2/E3). The significance of clinical and functional scores in the whole cohort (p overall) and Seventeen patients were older than 30.1 years; the in those carrying genotype E1 were compared to pooled oldest subjects carried either genotype E1 (7, 21.2%) or E2/E3 genotypes and estimated at the beginning and at genotype E2 (9, 27.2%), and only 1 (3%) had genotype the end of follow-up. The estimation of MRC, mRS and E3. At baseline, the youngest and the oldest subjects were

Table III. Results from univariate and multivariate Cox regression analysis of worsening on MIRS (≥ 1 point). Worsening ≥ 1 point in MIRS HR 95% CI P 1.13 0.46-2.77 0.78 Gender (female) (0.55) (0.19-1.53) (0.25) 0.26 0.10-0.68 0.006 Age at onset (> 30.1 y) (0.26) (0.09-0.78) (0.01) 3.9 1.28-11.8 0.016 CTG repeat number > 200 (i.e E2, E3) (5.09) (1.34-19.36) (0.017) HR: hazard ratio. 95% CI: 95% confidence interval.p : p-value. MIRS score. Age at onset > 30.1 years (y). CK: creatine kinase level ≥ upper limit of normal. Genotypes are classified according to CTG repeat number. Adjusted values are reported in brackets. Signifi- cance: p < 0.05 two tailed. Significant results are in bold.

113 Marco Mazzoli et al.

Figure 1. Cox analysis and Log rank test. Fig 1a) Kaplan-Meier survival curves expressing the probability of worsening in MIRS from age of onset in subjects with age either above or below the mean age p = 0.003, at Log rank test; b) Kaplan-Meier survival curves expressing the probability of worsening in MIRS from age of onset in genotypes E1 or E2 and E3, p = 0.016 at Log rank test; c) Kaplan-Meier survival curves expressing the risk of NIV from age of onset in subjects with age above or below the mean age, p < 0.04 at Log rank test; d) Kaplan-Meier survival curves expressing the probability of worsening in MRC total scores in genotypes E1 or E2 and E3, p < 0.004 at Log rank test. not significantly different as measured by MIRS, mRS Gender and muscle strength both in total (p > 0.05) and in UE At the end of follow-up, muscle force in UE was di- (p = 0.1) and LE (p = 0.09). minished by 22% in male patients versus 17% in females. Univariate Cox proportional hazard analysis showed In LE, the decrease from baseline was 29% in males ver- that worsening in MIRS was significantly predicted by sus 23% in females. MIRS scores worsened by 17% in younger age at baseline. Kaplan Meier survival curves in males versus 10% in females, and mRS decline reached Fig 1a show the probability of worsening on MIRS in sub- 50% in males versus 32% in females. However, the pro- jects aged either above or below the mean of 30.1 years portion of worsening was never statistically significant (Log rank test p = 0.003). Multivariate Cox regression between genders, and males did not differ from females analysis, as shown in Table III, confirmed lower risk of in assessment scale scores at the end of follow-up (data progression (HR 0.26, CI 0.09-0.78, p = 0.01) in the old- not shown). est patients. This result was further validated by a logistic model with multiple imputed data, where old age of onset Cardiac and vascular involvement (OR 0.30, CI 0.15-0.59, p < 0.001) and female gender (OR 0.15, CI 0.075-0.30, p = 0.001) showed a protective In our cohort, during follow-up, cardiac involvement effect towards the risk of worsening on MIRS (Tab. IV). occurred in 75% of patients aged below 30.1 years vs

114 Long term prognosis of DM1

Figure 2. Cox analysis and Log rank test. a) and c) Kaplan-Meier survival curves expressing the probability of being free of worsening in strength, assessed by MRC in UE and in LE in the three genotypes. For both analysis p < 0.001, at Log rank test; Anova model: b) Box plot showing the time to NIV in months in the three genotypes. The boxes repre- sent 25th, 50th and 75th percentiles. The diamond inside each box shows the median and the wriskers shows the range. Two comparaisons highlighted with lines are significant at TK comp test; d) Box plot showing the changes in MIRS at baseline and during follow-up at 24, 48, 72 and 96 months since onset in patients carrying different genotypes. The diamond inside each box shows the median and the wriskers show the range. Two comparisons highlighted with the lines are significant; p-value < 0.01.

52.9% in older patients, without statistically significant was 195 months (Range 24- 553, IQR 200; mean difference between groups. 214.9 ± 130.1). The presence of cardiac and vascular morbidities pooled together confirmed at 8-years’ follow-up a signif- Expansion size and need for NIV icant impact on worsening in MIRS scores (OR 3.57, CI Median time to NIV in genotype E1 was 348 months 2.00 -6.37, p < 0.002) (Tab. IV). versus 240 months in genotype E3. The times to start NIV differed significantly among genotypes E1 vs E3, and E2 Progression to NIV vs E3 (p < 0.05) as shown in Figure 2b. Regarding blood NIV, either CPAP or BIPAP, was initiated during gas analysis, only pCO2 on last assessment differed in follow-up in 12 cases (36.4%) with equal occurrence E2 and E3 group from basal pCO2 (p = 0.04), where- between genders. The median age at NIV start was as among E1 patients the worsening was not significant 50.5 years (Range 33-54, IQR12.5; mean 48.0 ± 9.41) (Tab. II). A significant difference between FVC value was and the median time from onset/diagnosis to NIV detected between group E1, E2 and E3 already at baseline

115 Marco Mazzoli et al.

(p basal = 0.03), and more obviously on last assessment ing the progression in the distribution of strength loss, (p = 0.006), confirming that FVC is a reliable indicator of we could not find a statistically significant difference of progression 31. decline in UE as compared to LE. This result differs from that obtained by other authors 1,9,25,27 and could be due to Influence of baseline age, gender and cardiac our sample size, to the key muscle group chosen, or to involvement on the need for NIV bias related to the measurement method. Interestingly, Among the 12 patients who received NIV, 41% (5) we recorded a difference in strength of UE and LE limbs were older and 58% (7) younger than mean age. The me- among ventilated as compared to non-ventilated subjects dian survival time to NIV was 324 months (Range 88- (p = 0.01 and 0.02, respectively). 553) in the youngest, and 123 months (range 24-288) in Role of expansion size the oldest subjects. Kaplan-Meier curve (Fig. 1c) indi- cated that the age of onset influenced survival to NIV: Although caution should be kept in using CTG repeat younger patients showed longer survival, but higher risk size to predict future symptoms, there is reliable consen- of NIV requirement, as demonstrated in univariate (HR sus that patients with small CTG expansions generally 4.96, CI 1.07-22.8, p = 0.04) and multivariate Cox regres- have milder symptoms, whereas increased expansion sion analysis (HR 7.54, CI 1.43-39.7, p = 0.01)(unshown size is broadly associated with earlier disease onset and results). increased clinical severity 1,4,8,9-12,24,27,30,31. Vivekanand et Regarding gender, the median time to NIV initiation al. 31 suggested a cumulative influence on disease severity did not show a statistically significant difference: 187 of size of trinucleotide repeat and length of patient expo- months in males (range 55-553), and 217 months in fe- sure to the expanded CTG, i.e. their age at presentation. males (range 24-362). In our study, we confirm a significant association be- The presence of cardiac involvement was inde- tween worsening in all outcome measures and expansion pendently associated with an increased risk of NIV re- size, as shown by survival graphs in Figure 1b and 1d. quirement at 96 months, as resulted in MI data analysis Furthermore, patients with high number of CTG repeats (OR 11.5, CI 1.17-113.7, p = 0.03) (Tab. IV). showed lower muscle strength as well as worse disability scores at baseline. Moreover, we found a statistically significant difference in extremity strength bewteen ventilat- Discussion ed and non-ventilated subjects, meaning that respiratory In the present study we describe the effect of clinical impairment is linked to strength loss in the limbs 33. Rossi and genetic parameters on neurological and respiratory et al. 30 concluded that CTG expansion is an independent outcome in a group of DM1 patients followed-up to 18 predictor of respiratory restriction, and Boussaïd et al. 2,3 years. found that a higher CTG repeat number was associated Knowledge about the progression of strength decline with larger decreases over time in PFTs. Hawkins et al. 43 is crucial in DM1 1-4,9,24-27. Only a few longitudinal studies highlighted the issue of central versus peripheral respi- of DM1 have documented quantitatively the decline of ratory control, where alveolar hypoventilation could be muscle strength with repeated measurements 9,25-27,42. We partially related to respiratory muscle weakness, and par- demonstrated a significant worsening at the end of fol- tially to involvement of the respiratory center in the brain low-up in all selected clinical outcome measures. Regard- stem, causing chronic hypercapnia. On the contrary, Thil

Table IV. Results from univariate and multivariate logistic regression analysis expressing the risk of NIV and of worsening on MIRS (≥ 1 point) as outcome. NIV Worsening on MIRS (≥ 1 point) OR 95% CI P OR 95% CI P 1.1 0.26-4.54 0.89 0.35 0.20-0.59 < 0.001 Gender (female) (0.71) (0.13-3.74) 0.69 (0.15) (0.075-0.30) (< 0.001) 0.53 0.12-2.2 0.39 0.34 0.10-0.60 < 0.001 Age at onset (> 30.1 y) (0.89) (0.16-4.72) 0.89 (0.30) (0.15-0.59) (0.001) 12.1 1.31-111.2 0.028 3.73 2.15-6.48 < 0.001 Cardiac /vascular comorbidities (11.5) (1.17-113.7) (0.03) (3.57) (2.00-6.37) (< 0.002) OR: odds ratio. 95% CI: 95% confidence interval. In brackets, adjusted results. The last three columns display results obtained at 8-years’of follow-up with multiple imputation method (MI). (see methods for details) p significant < 0.05 two tailed. Significant results are in bold.

116 Long term prognosis of DM1 et al. 44 found no association between longitudinal lung with assessment only of lower limb strength: their female function impairment and number of CTG repeats or blood patients showed a statistically significant change at five gas analysis. Our results on respiratory impairment con- years in hip flexors (-1.3%), whereas in males there was firm that CTG expansion size showed a significant effect a significant decrease in all examined muscle groups. on respiratory impairment and NIV need. Mathieu et al. 42, in 50 DM1 subjects studied cross-sec- tionally showed a decrease of 1.2-1.6% per year for prox- Role of baseline age imal muscle groups and of 2.0-3.0% per year for distal muscle groups with no significant difference between Different clinical phenotypes are recognized accord- genders (0.99% in females and 1.54% in males per year). ing to age of onset. De Antonio et al. 24 provided strong evidence for a disease classification model based on five Cardiac and vascular involvement clinical forms; their data demonstrated that all forms of DM1 differ in terms of CTG expansion size, frequency Cardiac complications are the second leading cause of symptoms and age of onset of disease manifestations. of death in DM1 4,5,8,22,28, 30,31,37,45-47. Overall, the cardiac In our cohort, all the patients were older than 14 years at phenotype of DM1 is complex and includes an approx- the time of enrollment, therefore they could be included imately three-fold higher risk of sudden cardiac death into juvenile or adult form of the disease. We made the compared to age-matched healthy controls.29,30 Metabolic choice of splitting our sample into two groups, based on abnormalities, including diabetes mellitus, hypertension, age of onset. Our patients, either younger or older than atherosclerosis, hyperlipidemia are known risk factors of mean age, were not different at baseline in MIRS and anticipated mortality in DM1 4. Moreover, an autonomic muscle strength scores. However, as shown by the surviv- nervous system dysfunction, diagnosed on the basis of al curve (Fig. 1a), we found an expected effect of younger heart rate variability and increased temporal dispersion age on progression: longer survival to MIRS worsening of myocardial repolarization argues in favor of a heart in- in terms of age for older patients as compared to younger volvement in DM1 that might go beyond the known con- 4 ones. Regarding NIV requirement as end point, youngest duction system involvement . Cardiac arrhythmias are 4,29,46 subjects exhibited higher risk of occurrence, but longer common in DM1 and have been shown by Kaminsky 29 survival to the event. et al. to have a broad correlation in severity with age, muscular impairment, male gender, lung involvement and Effect of gender extent of the molecular defect. Cardiac involvement in DM1patients occurs as a At baseline neither muscle strength measures nor degenerative process, with progressive fibrosis and fatty disability scores significantly differed between genders, replacement of the myocardium, which involves not only except for MIRS where females were significantly worse the specialized conduction system, but also other areas, than males at baseline. The latter finding is interesting initially unaffected, of the working atrial and ventric- and could be due to an uneven prevalence of some clinical ular myocardium 46,47. As pointed out by Russo et al. 47 signs in males and females. According to Dogan et al. 8, this pathologic substrate facilitates conduction disorders men more frequently exhibit myotonia, cardiac signs, re- and systolic dysfunction in populations with DM1. Sev- strictive syndrome and muscle weakness, whereas wom- eral clinical, metabolic and endocrine features of DM1 en more often show cataracts, dysphagia, digestive tract phenotype usually affect the elderly, and signs of accel- dysfunction, thyroid disorders and obesity. erated aging in DM1 are cardiac conduction disturbance At the end of follow-up the change in strength, MIRS and endocrine abnormalities, as glucose intolerance and and disability scores did not differ statistically between dyslipidemia 29. Cardiac symptoms and signs and other genders; however, at 8-years of follow-up, the risk of vascular morbidities in our patients had an incidence sim- worsening in MIRS was significantly lower in females, ilar to previous reports 4,7,29,30. Another interesting finding suggesting a different rate of progression. Gagnon et al. 25 to be further investigated was the increased risk for NIV documented, in a 9-year study on 100 DM1 subjects, a requirement in patients with cardiac involvement, possi- higher loss in distal muscle groups with a decrease over bly reflecting the interrelated multisystem nature of the 50%. This significant loss of strength was found for both disease 29,30. men and women separately; however, men had greater strength decline over time than women for all muscle groups, suggesting that the stronger the participants were Limitations of the study at baseline, the more important was the strength loss at Inherent limitations of this study lie in the design 9 years. Hammaren et al. 26 pooled results from differ- based on a retrospective analysis of clinical medical re- ent clinical phenotypes in a 5-years’ study on 43 patients cords although most of the patients were followed pro-

117 Marco Mazzoli et al. spectively at our Center since the time of the diagnosis on long-term cardiac outcomes in DM1 patients with normal ECG for a very long longitudinal care. A further limitation at baseline at an Italian clinical centre. J Neurol 2018;265:885-95. might the small sample size which is due the fact that https://doi.org/10.1007/s00415-018-8773-3 we included only subjects with a diagnosis confirmed by 5 Chong-Nguyen C, Wahbi K, Algalarrondo V, et al. Association be- genetic molecular testing in the subjects. However, our tween mutation size and cardiac involvement in myotonic dystro- data are comprehensive and repeatidly validated by three phy type 1: an analysis of the DM1-Heart registry. Circ-Cardiovasc neurologists Genet 2017;10. 6 Contardi S, Pizza F, Falzone F, et al. Development of a disabili- Conclusions ty scale for myotonic dystrophy type 1: functional disability scale for DM1 patients. Acta Neurol Scand 2012;125:431-8. https://doi. By concluding, large CTG expansions and age of dis- org/10.1111/j.1600-0404.2011.01587.x ease onset were significantly associated with neurologic 7 Cudia P, Bernasconi P, Chiodelli R, et al. Risk of arrhythmia in and respiratory impairment during a follow-up period type I myotonic dystrophy: the role of clinical and genetic vari- of more than 24 months. Moreover, our study suggests ables. J Neurol Neurosurg Psychiatry 2009;80:790-3. https://doi. that females showed lower relative risk of neurological org/10.1136/jnnp.2008.162594 worsening at 8 years. Finally, multisystem involvement, 8 Dogan C, De Antonio M, Hamroun D, et al. Gender as a modifying especially through cardiac diseases, exerts a significant factor influencing myotonic dystrophy type 1 phenotype severity negative effect on neurological progression and respira- and mortality: a Nationwide Multiple Databases cross-section- tory impairment. These results should be confirmed in al observational study. PLos One 2016;11:e0148264. https://doi. prospective trials on a larger population of DM1 patients. org/10.1371/journal.pone.0148264 In a clinical setting, the management of DM1 pa- 9 tients should be carried out with a multidisciplinary ap- Gagnon C, Chouinard MC, Laberge L, et al. Health supervision proach which includes a periodic cardiac and respiratory and anticipatory guidance in adult myotonic dystrophy type 1. assessment 4,29-31,46,47,51-54. Particular attention should be Neuromuscul Disord 2010;20:847-51. https://doi.org/10.1016/j. paid especially to those patients who carry large CTG nmd.2010.08.006 expansions. 10 Mahadevan M, Tsilfidis C, Sabourin L, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3’ untranslated region of Disclosure statements the gene. Science 1992;255:1253-5. https://doi.org/10.1126/science.1546325 The authors declare no conflict of interest or sources 11 of funding Meola G. 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120 ACTA MYOLOGICA 2020; XXXIX: p. 121-129 doi: doi:10.36185/2532-1900-016 Respiratory function and therapeutic expectations in DMD: families experience and perspective

Claudia Brogna1,2, Simona Lucibello1,2, Giorgia Coratti1,2, Gianluca Vita3, Valeria A. Sansone4, Sonia Messina3,5, Emilio Albamonte4, Francesca Salmin4, Gloria Ferrantini1,2, Elisa Pede1,2, Chiara Consulo3, Lavinia Fanelli2, Nicola Forcina2, Giulia Norcia2, Marika Pane1,2, Eugenio Mercuri1,2 1 Pediatric Neurology, Università Cattolica del Sacro Cuore, Rome, Italy; 2 Centro Clinico Nemo, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 3 Nemo SUD Clinical Centre, University Hospital “G. Martino”, Messina, Italy; 4 The NEMO Center in Milan, Neurorehabilitation Unit, University of Milan, ASST Niguarda Hospital, Milan, Italy; 5 Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

CB, SL, GC, are all First Authors

Received: September 1, 2020 Accepted: October 1, 2020 Objective. The aim of this study was to use a structured questionnaire in a large cohort of Duchenne Muscular Dystrophy (DMD) patients to assess caregivers and Correspondence Eugenio Mercuri patients views on respiratory function and to establish if their responses were re- Pediatric Neurology, Università Cattolica del Sacro Cuore, lated to the patients’ age or level of functional impairment. Rome, Italy; Centro Clinico Nemo, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Gemelli Methods. Questionnaires were administered to caregivers in 205 DMD patients of 00168, Rome, Italy. Tel.: +39 06 30155340. Fax: +39 06 age between 3 and 36 years (115 ambulant, 90 non-ambulant), and to 64 DMD pa- 30154363. E-mail: [email protected] tients (3 ambulant, 61 non-ambulant) older than 18 years, subdivided into groups according to age, FVC, ambulatory and ventilatory status. Conflict of interest Study participants did not receive any form of compensation. Results. Some differences were found in relation to FVC % values (p = 0.014), am- All the authors are involved in several studies in Duchenne bulatory (p = 0.043) and ventilatory status (p = 0.014). Nearly half of the caregivers muscular dystrophy (Sarepta, Santhera, PTC, Pfizer, expected deterioration over the next years, with the perspective of deterioration Italfarmaco, Roche). EM has participated to advisory more often reported by caregivers of non-ambulant (p = 0.018) and ventilated pa- boards from the same companies. tients (p = 0.004). Caregivers appeared to be aware of the relevance of respiratory function on quality of life (84%) showing willingness to enter possible clinical tri- How to cite this article: Brogna C, Lucibello S, als if these were aiming to stabilize the progression of respiratory function with a Coratti G, et al. Respiratory function and therapeutic very high number of positive responses across the spectrum of age, FVC, ambula- expectations in DMD: families experience and tory and ventilatory status. The boys older than 18 years showed similar results. perspective. Acta Myol 2020;39:121-9. https://doi. org/10.36185-2532-1900-016 Conclusions. Our study showed that the concern for respiratory function increases with age and with the reduction of FVC or the need for ventilation, but the need for in- © Gaetano Conte Academy - Mediterranean Society of tervention was acknowledged across the whole spectrum of age and functional status. Myology Key words: Duchenne muscular dystrophy, respiratory, quality of life, patient reported OPEN ACCESS outcome measures This is an open access article distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution- NonCommercial-NoDerivatives 4.0 International) license. The article can be used by giving appropriate credit and mentioning Introduction the license, but only for non-commercial purposes and only in the original version. For further information: https:// Over the last few years, there has been increasing attention to the creativecommons.org/licenses/by-nc-nd/4.0/deed.en natural history of respiratory function in Duchenne Muscular dystrophy

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(DMD). It has become increasingly obvious that after the Materials and methods age of 10 years percent predicted Forced Vital Capacity (% FVC) show progressively reduced values 1-3. Steroid This is a multicentric study conducted in Italy in naïve DMD patients have an earlier onset of deterioration, three centers (Nemo Center, Policlinico Gemelli, Catho- approximately 2 years before steroid treated patients, but lic University, Rome; Nemo Center, University of Messi- in both groups, once established, the rate of progression na; Nemo Center, Milan). is similar 1-3. The study was approved by the Ethical Committees of The changes are relatively regular and, with increas- all the participating centers. Parents/caregivers of partici- ing age, the decrease in % FVC reaches values that are pants (minor/children) and patients above age of 18 were generally associated with nocturnal hypoventilation and asked to sign a dedicated consent form that also includes subsequent need for noninvasive ventilation (NIV), ini- consent for sharing academic data and for publication. tially restricted to nighttime and, later on in life, increas- A face to face or telephone interview based on a ingly used also during the day 4. This data has been par- structured questionnaire was administered to caregivers ticularly useful at the time of designing or interpreting the of DMD patients, irrespective of the patients’ age. Pa- results of clinical trials targeting respiratory function as tients older than 18 years used a self-reported version of primary or secondary measures 5-8. the questionnaire. Telephone interviews were conduct- While several studies have explored patient and care- ed only if patients had been seen within the previous 3 givers’ perspective about quality of life, care burden or months and the results of their respiratory assessments motor aspects 9, less has been investigated in relation to were available. A trained clinician conducted the in-per- clinical relevance of respiratory function at different ag- son interviews and telephone interviews using the same es 10-12. semi-structured data collection sheet. As recently suggested by the United States Food and A number of questions were asked to investigate spe- Drug Administration (FDA) the use of patient reported cific respiratory aspects and caregivers/patients’ view on scales should be strongly encouraged to include the pa- possible changes over the next 5 years and the impact of tient and caregivers perspective to determine the rele- respiratory function on quality of life. In the second part vance of observed functional changes 13. caregivers/patients were asked about their expectations Assessing the relevance of respiratory function in regarding the possibility to enter clinical trials focusing DMD at different ages, including patients in the first on respiratory function by investigating what would be decade can however be more challenging than when the minimal change in respiratory function (slowing de- assessing motor function. While clinical signs of motor terioration, stability, improvement) that would justify the deterioration are increasingly present in the first decade, participation into a clinical trial. The interviews lasted 10- especially after the age of 7 years, overt signs of respira- 15 min on average. tory impairment often become obvious only in the sec- Table I reports details on the questions asked in both ond part of the second decade 14. As a constant decrease the caregivers and self-reported questionnaire. in % FVC and more generally a progressive respiratory FVC impairment already start by the age of 10 years 1,3,14, it would be of interest to understand if and how DMD pa- From the age of 6 years all DMD patients are rou- tients and their families are already concerned about the tinely asked to perform, depending on their compliance, early changes in % FVC and, more generally, how their FVC. FVC was assessed by qualified and certified eval- level of concern varies at different ages and in relation to uators according to a standard protocol, which reflects, different functional respiratory levels. established international guidelines for lung function The aim of this study has been to investigate care- testing (American Thoracic Society, European Respira- givers/patients’ views on respiratory function using a tory Society). The patients were appropriately instructed structured questionnaire investigating different aspects of on the use of the spirometer before the FVC assessments respiratory function, including rate of infections or use of were initiated. In cases where the patient could not per- antibiotics. More specifically we wished to assess their form a mouth seal reliably with the clinic-based Spirome- relevance as meaningful indicators of the progression of ter, a scuba mouthpiece or a facemask should be used. In the disease and whether the level of responses changes agreement with natural history studies, reporting % pre- according to age or functional based on their FVC % dicted FVC, we will also focus on this measure as this is values and forced expiratory volume (FEV) scores. We more comparable with previous studies 1-3. also wished to assess caregivers/patients’ expectations re- For all respiratory assessments, the patient was regarding clinical trials targeting primarily or secondarily quested to repeat each test 3 to 5 times and the highest respiratory function. value was used.

122 Caregivers and patients views on respiratory function in Duchenne muscular dystrophy

Table I. Question asked in the caregivers and self-reported questionnaire. Caregivers /self-reported questionnaire Question 1: How many respiratory infections did your child have/did you have, over the past last year? Question 2: How many times did your child/did you need to take antibiotics for respiratory problems, over the last year? How do you expect your child’s/your breathing capacity will change over the next 5 years, according to the Question 3: evolution of the disease and growth? Question 4: Could an improvement in your child’s /your respiratory function have a positive effect on him quality of life? Question 5: Would you consider enrolling/to be enrolled in a clinical trial with drugs targeting respiratory function? What reason would convince you to consider enrolling/to be enrolled in a clinical trial with drugs targeting Question 6: respiratory function? Would you consider enrolling/to be enrolled in a clinical trial with drugs that could reduce the number of Question 7: respiratory infections? Key to legend: Words in italic reports the self-reported version of the questionnaire.

Statistical analysis who were too weak and more severely impaired, their FVC was too low to be reliably recorded and was ar- Descriptive analysis, with absolute and percentage bitrarily labelled as below 10%. Another 13 patients frequencies, was performed to establish the range of re- who were reported as unable to perform FVC, 9 be- sponses in relation to the different age, ventilation assis- cause too young and 4 due to the presence of behav- tance, motor and respiratory functional levels. Responses between groups were compared for significant difference ioral or cognitive problems. using the Chi-square test. A p-value of < 0.05 was con- Thirty-two of the 205 patients (15.6%) used NIV. sidered significant. Question 1: number of respiratory infections Over 88% reported no infections (65.9%) or only one Results infection (22.4%). Two infections were reported in 8.8% Caregivers’ questionnaires and more than 2 in 3%. The number of infections did not change significantly in relation to age, but some differ- Questionnaires from the main caregiver for 205 ences were found in relation to FVC% values (p = 0.014). DMD patients (115 ambulant and 90 non ambulant) of There was also a difference according to ambulatory and age between 3 and 36 years were collected (mean 13.48 ventilatory status with more infections found in non-am- ± 6.06 SD). With a few exceptions the main caregiver bulant vs ambulant patients (p = 0.043) and in ventilated was the mother. versus non ventilated patients (p = 0.014). Caregivers’ questionnaires were subdivided in 5 groups according to the age of the patients: group 1 in- Question 2: number of antibiotics cluded 18 patients aged 3.0-6.9 years. In this group FVC was recorded only in the 9 patients older than 6 years Over 90 % reported no antibiotics (73.7%) or only with a mean % FVC of 81.89%; group 2 included 50 one (20%). Two antibiotics were reported in 3.9% and patients aged 7.0-10.9 years. FVC could be reliably re- more than 2 in 2.5%. The number of antibiotics did not corded in 48/50, with a mean % FVC of 84.75%; group change significantly in relation to age, ambulatory status 3 included 55 patients aged 11.0-13.9 years. FVC could or FVC % values, but there was a difference according to be reliably recorded in 53/55, with a mean % FVC of ventilatory status with more antibiotics reported in venti- 82.08%; group 4 included 42 patients aged 14.0-17.9. lated versus non ventilated patients (p = 0.001). FVC could be reliably recorded in 40/42, with a mean % FVC of 57.73%; group 5 included 40 patients 18 years Question 3: possible respiratory changes over the next and above. FVC could be reliably recorded in 34/40, 5 years with a mean % FVC of 27.42%. Nearly 48% anticipated a stable course with no ma- In the 184 patients who were able to perform jor changes, 47.8% a deterioration and 4.4% an improve- FVC, 73/184 (39.7%) had FVC% ≥ 80%; 46 (25%) ment. The expectations did not change in relation to age had FVC% between 60-80%; 16 (8.7%) had FVC% or FVC% but some differences were found in relation to between 50-60%; 10 (5.4%) had FVC % between ambulatory and ventilatory status, with the perspective of 40-50%; another 10 (5.4%) had FVC% between 30- a deterioration more often reported in non-ambulant vs 40%; 7 (4.0%) had FVC% between 20-30% and in 22 ambulant patients (p = 0.018) and in ventilated versus non (11.9%) had FVC% below 20%. In 8 patients (4.3%), ventilated patients (p = 0.004).

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Question 4: effect of respiratory function on quality Question 6: reasons to consider enrolling in a trial of life targeting respiratory function Nearly 84% felt that an improvement in respiratory Nearly 87% of the caregivers replied that they would function would result in an improvement in quality of life consider participation if the treatment would aim to at while 2.9% replied no and 13.2 % reported that they did least slow down deterioration; an additional 3.4% replied not have a clear opinion about it. The distribution of re- that would consider it if the treatment would aim to stop sponses did not change significantly in relation to age, deterioration, and an additional 3.5% if there was the pos- FVC %, ambulatory and ventilatory status. sibility of an improvement. Approximately 5% did not Table II and Figure 1 show details of the distribution have a clear opinion and 1 % would not consider entering of the responses for questions 1-4. in a trial. The distribution of responses did not change significantly in relation to age, FVC %, ambulatory and Question 5: enrolling in a clinical trial with drugs ventilatory status. targeting respiratory function Nearly 71% of the caregivers would consider enroll- Question 7: enrolling in a clinical trial that could ing in a clinical trial targeting respiratory function, 2% reduce the number of respiratory infections replied they wouldn’t and 27.3% replied that they did not Over 72% replied that they would consider participa- have a clear opinion about it as this would depend on a tion, 8.3% replied they wouldn’t and 19.5% replied that number of variables such as possible side effects, trial this would depend on a number of variables such as possi- burden, etc. ble side effects, burden of the trial etc. The distribution of The distribution of responses changed in relation to responses did not change significantly in relation to age, age (p = 0.012), FVC % values (p = 0.037) and ventilato- FVC %, ambulatory and ventilatory status. ry status (p = 0.044). There was no difference in relation Table III and Figure 2 show details of the distribution to ambulatory status. of the responses for questions 5-7.

Table II. Caregivers’ responses distribution (N, %) by age and FVC% subgroups for questions 1 to 4. Age (years) FVC% 3-7 7-10 10-14 14-18 > 18 All < 20% 20-30% 30-40% 40-50% 50-60% 60-80% > 80% All (n:18) (n:50) (n:55) (n:42) (n:40) (n:205) (n:22) (n:7) (n:10) (n:10) (n:16) (n:46) (n:73) (n:184) 0 11 36 43 23 22 135 10 3 7 7 11 34 54 126 (61.1%) (72.0%) (78.2%) (54.8%) (55.0%) (65.9%) (45.5%) (42.5%) (70.0%) (70.0%) (68.8%) (73.9%) (74.0%) (68.5%) 1 7 10 7 11 11 46 9 1 2 1 2 8 15 38 (38,9%) (20.0%) (12.7%) (26.6%) (27.5%) (22.4%) (40.9%) (14.3%) (20.0%) (10.0%) (12.5%) (17.4%) (20.5%) (20.7%) 2 0 3 3 6 6 18 2 2 1 2 3 3 3 16 (0,0%) (6.0%) (5.5%) (14.3%) (15.0%) (8.8%) (9.1%) (28.6%) (10.0%) (20.0%) (18.8%) (6.5%) (4.1%) (8.7%) QUESTION 1 3 0 1 1 1 1 4 0 1 0 0 0 1 1 3 (0.0%) (2.0%) (1.8%) (2.4%) (2.5%) (2.0%) (0.0%) (14.3%) (0.0%) (0.0%) (0.0%) (2.2%) (1.4%) (1.6%) > 3 0 0 1 1 0 2 1 0 0 0 0 0 0 1 (0.0%) (0.0%) (1.8%) (2.4%) (0.0%) (1.0%) (4.5%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (0.5%) 0 11 40 45 29 26 151 12 3 9 9 14 37 57 141 (61.1%) (80.0%) (81.8%) (69.0%) (65.0%) (73.7%) (54.5%) (42.9%) (90.0%) (90.0%) (87.5%) (80.4%) (78.1%) (76.6%) 1 7 8 8 8 10 41 7 2 0 0 2 7 16 34 (38.9%) (16.0%) (14.5%) (19.0%) (25.0%) (20.0%) (31.8%) (28.6%) (0.0%) (0.0%) (12.5%) (15.2%) (21.9%) (18.5%) 2 0 1 1 4 2 8 2 1 1 1 0 2 0 7 (0.0%) (2.0%) (1.8%) (9.5%) (5.0%) (3.9%) (9.1%) (14.3%) (10.0%) (10.0%) (0.0%) (4.3%) (0.0%) (3.8%) 3 0 1 1 0 2 4 0 1 0 0 0 0 0 1 QUESTION 2 (0.0%) (2.0%) (1.8%) (0.0%) (5.0%) (2.0%) (0.0%) (14.3%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (0.5%) >3 0 0 0 1 0 1 1 0 0 0 0 0 0 1 (0.0%) (0.0%) (0.0%) (2.4%) (0.0%) (5.0%) (4.5%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (5.0%) Improving 1 3 2 1 2 9 1 0 1 0 2 0 3 7 (5.6%) (6.0%) (3.6%) (2.4%) (5.0%) (4.4%) (4.5%) (0.0%) (10.0%) (0.0%) (12.5%) (0.0%) (4.1%) (3.8%) No change 12 32 24 16 14 98 7 2 6 6 4 24 38 87 (66.7%) (64.0%) (43.6%) (38.1%) (35.0%) (47.8%) (31.8%) (28.6%) (60.0%) (60.6%) (25.0%) (52.2%) (52.1%) (47.3%) Worsening 5 15 29 25 24 98 14 5 3 4 10 22 32 90 QUESTION 3 (27.8%) (30.0%) (52.7%) (59.5%) (60.0%) (47.8%) (63.6%) (71.4%) (30.0%) (40.0%) (62.5%) (47.8%) (43.8%) (48.9%) No 0 1 3 1 1 6 1 0 0 0 1 0 4 6 (0.0%) (2.0%) (5.5%) (2.4%) (2.5%) (2.9%) (4.5%) (0.0%) (0.0%) (0.0%) (6.3%) (0.0%) (5.5%) (3.3%) Don’t know 4 12 8 1 2 27 0 0 0 1 2 5 16 24 (22.2%) (24.0%) (14.5%) (2.4%) (5.0%) (13.2%) (0.0%) (0.0%) (0.0%) (10.0%) (12.5%) (10.9%) (21.9%) (13.0%) Yes 14 37 44 40 37 172 21 7 10 9 13 41 53 154 QUESTION 4 (77.8%) (74.0%) (80.0%) (95.2%) (92.5%) (83.9%) (95.5%) (100%) (100%) (90.0%) (81.3%) (89.1%) (72.6%) (83.7%)

124 Caregivers and patients views on respiratory function in Duchenne muscular dystrophy

Figure 1. Caregivers’ responses distribution by age for questions 1 to 4. (A) Question 1, (B) Question 2, (C) Question 3, (D) Question 4. Key to panels A&B: White= 0; Light grey= 1; Dark grey= 2; Light Black= 3; Black=> 3. Key to panel C: Dotted white= Improvement; Dotted light grey= No change; Dotted black= Worsening. Key to panel D: White texture= No; Light grey texture = I don’t know; Black texture= Yes

Self-reported questionnaires in patients older than 18 only one infection (26.6%). Two infections were reported years in 10.9% and more than 2 infections in 3.1%. The number of infections did not change significantly according Questionnaires from 64 DMD patients older than 18 years (3 ambulant and 61 non ambulant) were available. to ventilatory status, but some differences were found in These included 45 patients for whom caregivers’ ques- relation to FVC % values (p = 0.021). tionnaires were also available. Seven patients could not Question 2: number of antibiotics perform FVC because too weak (n:4) or had a tracheos- tomy (n:3), the remaining 57 were able to perform FVC. Over 80% reported no (71.9%) or only one (17.2%) Only 2/57 (3.5%) had FVC% ≥ 80; 4 (7%) had FVC% antibiotics. Some differences were found in relation between 60-80, 2 (3.5%) between 50 and 60, 7 (12.3%) to ventilatory status and according to FVC % values between 40 and 50; 8 (14%) between 30 and 40; 4 (7%) (p = 0.041). between 20-30 and the remaining 30 (52.6%) below 20. Forty-four of the 64 patients (68.7%) used NIV. Question 3: possible respiratory changes over the next 5 years Question 1: number of respiratory infections Nearly 38% anticipated a stable course with no ma- Over 88 % reported either no infections (59.4%) or jor changes, 53.1% a deterioration and 9.4% an improve-

125 Claudia Brogna et al.

Table III. Caregivers’ responses distribution (N, %) by age and FVC% subgroups for questions 5 to 7. Age groups (years) FVC% 3-7 7-10 10-14 14-18 > 18 All < 20% 20-30% 30-40% 40-50% 50-60% 60-80% > 80% All (n:18) (n:50) (n:55) (n:42) (n:40) (n:205) (n:22) (n:7) (n:10) (n:10) (n:16) (n:46) (n:73) (n:184) No 2 0 1 0 1 4 1 0 0 0 0 1 1 3 (11.1%) (0.0%) (1.8%) (0.0%) (2.5%) (2.0%) (4.5%) (0.0%) (0.0%) (0.0%) (0.0%) (2.2%) (1.4%) (1.6%) 5 21 16 8 6 56 2 0 0 1 8 11 29 51 Don’t know (27.8%) (42.0%) (29.1%) (19.0%) (15.0%) (27.3%) (9.1%) (0.0%) (0.0%) (10.0%) (50.0%) (23.9%) (39.7%) (27.7%) 11 29 38 34 33 145 19 7 10 9 8 34 43 130 QUESTION 5 yes (61.1%) (58.0%) (69.1%) (81.0%) (82.5%) (70.7%) (86.4%) (100%) (100%) (90-0%) (50.0%) (73.9%) (58.9%) (70.7%) No 1 0 1 1 0 3 0 0 0 0 0 0 2 2 (5.6%) (0.0%) (1.8%) (2.4%) (0.0%) (1.5%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (2.7%) (1.1%) 2 6 8 3 5 24 2 1 0 1 6 5 7 22 Don’t know (11.1%) (12.0%) (14.5%) (7.1%) (12.5%) (11.7%) (9.1%) (14.3%) (0.0%) (10.0%) (37.5%) (10.9%) (9.6%) (12.0%) 15 44 46 38 35 178 20 6 10 9 10 41 64 160

QUESTION 6A yes (83.3%) (88.0%) (83.6%) (90.5%) (87.5%) (86.8%) (90.9%) (85.7%) (100%) (90.0%) (62.5%) (89.1%) (87.7%) (87.0%) No 1 0 0 0 0 1 0 0 0 0 0 0 1 1 (5.6%) (0.0%) (0.0%) (0.0%) (0.0%) (0.5%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (1.4%) 0.5%) 2 3 5 4 5 19 2 1 1 1 4 4 4 17 Don’t know (11.1%) (6.0%) (9.1%) (9.5%) (12.5%) (9.3%) (9.1%) (14.3%) (10.0%) (10.0%) (25.0%) (8.7%) (5.5%) (9.2%) 15 47 50 38 35 185 20 6 9 9 12 42 68 166

QUESTION 6B yes (83.3%) (94.0%) (90.9%) (90.5%) (87.5%) (90.2%) (90.9%) (85.7%) (90.0%) (90.0%) (75.0%) (91.3%) (93.2%) (90.2%) No 1 0 0 0 0 1 0 0 0 0 0 0 1 1 (5.6%) (0.0%) (0.0%) (0.0%) (0.0%) (0.5%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (0.0%) (1.4%) (0.5%) 1 3 2 2 4 12 1 1 0 1 2 1 4 10 Don’t know (5.6%) (6.0%) (3.6%) (4.8%) (10.0%) (5.9%) (4.5%) (14.3%) (0.0%) 810.0%) (12.5%) (2.2%) (5.5%) (5.4%) 16 47 53 40 36 192 21 6 10 9 14 45 68 173

QUESTION 6C yes (88.9%) (94.0%) (96.4%) (95.2%) (90.0%) (93.7%) (95.5%) (85.7%) (100%) (90.0%) (87.5%) (97.8%) (93.2%) (94.0%) No 2 4 6 3 2 17 4 0 0 0 1 2 9 16 (11.1%) (8.0%) (10.9%) (7.1%) (5.0%) (8.3%) (18.2%) (0.0%) (0.0%) (0.0%) (6.3%) (4.3%) (12.3%) (8.7%) 4 14 12 5 5 40 2 1 0 0 4 9 21 37 Don’t know (22.2%) (28.0%) (21.8%) (11.9%) (12.5%) (19.5%) (9.1%) (14.3%) (0.0%) (0.0%) (25.0%) (19.6%) (28.8%) (20.1%) 12 32 37 34 33 148 16 6 10 10 11 35 43 131 QUESTION 7 yes (66.7%) (64.0%) (67.3%) (81.0%) (82.5%) (72.2%) (72.7%) (85.7%) (100%) (100%) (68.8%) (76.1%) (58.9%) (71.2%)

Figure 2. Caregivers’ responses distribution by age for questions 5 to 7. (A) Question 5, (B) Question 6, (C) Question 7. Key to panels A&C: White texture= No; Light grey texture= I don’t know; Black texture= Yes. Key to panel B: Dotted white= At least slow down; Dotted light grey= At least slow down; Dotted dark grey= At least improve, Dotted light black= I don’t know, Dotted black= No. ment. The distribution of responses did not show signif- plied that they did not have a clear opinion about it. Some icant changes in relation to FVC and ventilatory status. differences were only found in relation to ventilatory status (p = 0.028). Question 4: effect of respiratory function on quality of life Question 5: enrolling in a clinical trial with drugs Nearly 80% replied yes, 6.3% felt that this would not targeting respiratory function produce an improvement in Quality of life and 14.1% re- Over 70% of patients replied that they would consid-

126 Caregivers and patients views on respiratory function in Duchenne muscular dystrophy er participation, 7.8% replied they wouldn’t and 20.3% rolled in studies targeting respiratory function. We were replied that they had not a clear idea. The distribution of interested in recording what was the general perception responses did not show significant changes in relation to from the families and to establish if their responses were FVC and ventilatory status. related to the patients’ age or level of functional impairment, expressed by different parameters FVC, ventilatory Question 6: reasons to consider enrolling in a trial and ambulatory status. targeting respiratory function When asked to report the number of infections, we Nearly 70 % of patients replied that they would con- found that the overall number of infections was relatively sider participation if the treatment targeted to at least low, with no infections or only one infection in 65.9%. slow down deterioration; an additional 17.2% replied that There was an increased number of infections in patients would consider it if the treatment would aim to stop de- with the lowest FVC and a difference between ambulant terioration, and an additional 7.8% if there was the possi- and non-ambulant and between ventilated and non-ven- bility of an improvement. Approximately 5% did not have tilated. The number of patients with frequent infections a clear opinion and 1.6 % would not consider entering in was however relatively low even in the non-ambulant a trial. The distribution of responses did not show sig- ventilated patients with very low FVC, probably related nificant changes according to FVC or ambulatory status, to the implementation of care recommendations suggest- but some differences were found in relation to ventilatory ing the use of vaccinations, In-Exufflator and other rec- status (p = 0.023). ommendations 4. The number of antibiotics was similar and only slightly lower than the reported number of in- Question 7: enrolling in a clinical trial that could fections, this suggesting a low number of reported minor reduce the number of respiratory infections infections not requiring antibiotics. Nearly 60 % of patients replied that they would con- It is of interest that even though in 41.4% of the cases sider participation, 7.8% replied they wouldn’t and 32.8% the age of the patients was over 10 years, that is the age replied that they did not have a clear opinion about it as when respiratory tests start showing a mild but progres- this would depend on a number of variables such as pos- sive decline, nearly half of the responders did not foresee sible side effects, burden of the trial etc. The distribution a deterioration over the next 5 years. The perspective of of responses did not show significant changes in relation deterioration, found in less than half of the patients, was to FVC or ventilatory status. more often reported by caregivers of non-ambulant and ventilated patients or in those with very reduced % FVC. These results suggest that even if caregivers are informed Discussion of a possible respiratory impairment in their children as The advent of clinical trials specifically targeting re- part of the progression of the disease, the progressive de- spiratory function or including FVC and other respirato- terioration starting at the end of the first decade is in some ry indexes as secondary measures 5, 6, 8,15 has highlighted cases underestimated. This is probably due to the fact that the need for better understanding of the progression of in the first phase respiratory decline is often not associat- respiratory impairment in DMD children. While in the ed with any overt clinical respiratory sign, unlike motor last few years several papers have reported longitudinal difficulties that are obvious since the time of diagnosis. In natural history data on FVC and FEV, showing concor- ambulant patients, loss of ambulation is seen as the major dance on the age when FVC and FEV decline and on their life changing event and is probably the biggest cause of rate of progression 1-3, less has been reported about pa- concern, overshadowing other aspects that do not require tient reported outcome measures or, more generally, on immediate intervention. Caregivers however appear to be the patients’ and caregivers’ perspective on respiratory aware of the relevance of respiratory function as demon- function, with the exception of some studies mainly fo- strated by their responses on the effect on quality of life cusing on ventilated patients 10. One of the aims of our and by their willingness to enter possible clinical trials questionnaire was to investigate the awareness of clinical targeting respiratory function. Less that 3% felt that an signs in caregivers of DMD patients with a wide range of improvement in respiratory function would not results in age and respiratory impairment from very young patients an improvement in their quality of life, with a very high to older adults with severe respiratory impairment. The number of positive responses (84%) across the spectrum questionnaire included a first part evaluating the frequen- of age, FVC, ambulatory and ventilatory status. In our cy of infections and antibiotics and general questions on study we did not use structured assessments to measure the expectations on respiratory function over time and its quality of life but it is of interest that these results are effect on their quality of life and a second part assessing consistent with previous findings also reporting Quality the willingness of the caregivers to have their children en- of life in ventilated patients 10,11.

127 Claudia Brogna et al.

Similarly, there were a very high percentage (70%) studies reporting respiratory functional data. Not surpris- of caregivers considering having their children enrolled ingly the concern on respiratory function increases with in clinical trials targeting respiratory function. The rela- age and with the reduction of % FVC or the need for ven- tively high percentage of caregivers who responded that tilation but the need for intervention was acknowledged they did not have a clear idea, was mainly related to the across the whole spectrum of age and functional status. need to have more details about the possible trials, includ- Further studies also using other respiratory measure and ing the severity of possible side effects. It is of interest more structured assessments of quality of life may help to that despite the results of question 3, with a significant better define the correlation between these aspects. proportion of caregivers reporting a stabilization over the next 5 years, nearly 87% of the caregivers felt that they Funding would consider participating in a clinical trial if, in the This study is part of larger natural history study fund- absence of significant side effects, the intervention would ed by the Italian Telethon. Additional funding has been even only slow down the rate of deterioration. There was received by Sarepta and Santhera. The funders had no a much smaller percentage of patients with no clear idea, role in the design of the study and collection, analysis, mainly in the younger groups with more preserved FVC, and interpretation of data. but this percentage decreased, with an increase of positive responses to over 90 and nearly 95% if the prospect was stabilization or improvement, therefore including nearly References the totality of caregivers, irrespective of age and function- 1 McDonald CM, Gordish-Dressman H, Henricson EK, et al. Longi- al status. tudinal pulmonary function testing outcome measures in Duchenne When we asked the DMD patients older than 18 muscular dystrophy: long-term natural history with and without years to fill the same questions of the questionnaire using glucocorticoids. Neuromuscul Disord 2018;28:897-909. https:// a self-reported procedure, we observed that the responses doi.org/10.1016/j.nmd.2018.07.004 were often similar but not identical to the responses re- 2 Ricotti V, Selby V, Ridout D, et al. Respiratory and upper limb corded by caregivers of patients in the same age group. A function as outcome measures in ambulant and non-ambulant correlation between caregivers and patients however was subjects with Duchenne muscular dystrophy: a prospective mul- not entirely possible as some adult patients came to clinic ticentre study. Neuromuscul Disord 2019;29:261-8. https://doi. not accompanied by their caregivers and in some cases org/10.1016/j.nmd.2019.02.002 the questionnaire was given only to the caregivers if the 3 Bello L, D’Angelo G, Villa M, et al. Genetic modifiers of respi- patient had moderate or severe cognitive or behavioural ratory function in Duchenne muscular dystrophy. Ann Clin Transl problems. The main difference between patients and care- Neurol 2020. https://doi.org/10.1002/acn3.51046 givers was on the question exploring their willingness to 4 Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and manage- participate in a clinical trial. The percentage of patients ment of Duchenne muscular dystrophy, part 2: respiratory, car- who would consider a clinical trial if the expectations was diac, bone health, and orthopaedic management. Lancet Neurol slowing down deterioration was overall high but lower in 2018;17:347-61. https://doi.org/10.1016/S1474-4422(18)30025-5 patients than in in caregivers. The percentage increased 5 McDonald CM, Meier T, Voit T, et al. Idebenone reduces respira- when the expected result was stabilization. tory complications in patients with Duchenne muscular dystrophy. One of the limitations of this study is that we did not Neuromuscul Disord 2016;26:473-80. https://doi.org/10.1016/j. systematically collect economic status or schooling in the nmd.2016.05.008 caregivers and in the patients. Although we did exclude patients with severe behavioral or cognitive problems, 6 Buyse GM, Voit T, Schara U, et al. Efficacy of idebenone on respi- at the time of collecting the questionnaires we felt that ratory function in patients with Duchenne muscular dystrophy not patients were often emotionally or cognitively less ma- using glucocorticoids (DELOS): a double-blind randomised place- ture than their age and this may have contributed to their bo-controlled phase 3 trial. Lancet 2015;385:1748-57. https://doi. reduced awareness of the severity of their respiratory im- org/10.1016/S0140-6736(15)60025-3 pairment or on their expectations. 7 Gogou M, Pavlou E, Haidopoulou K. Therapies that are available and under development for Duchenne muscular dystrophy: what about lung function? Pediatr Pulmonol 2020;55:300-15. https://doi. Conclusions org/10.1002/ppul.24605 Even with these limitations, our study provides the 8 Khan N, Eliopoulos H, Han L, et al. Eteplirsen treatment attenuates views of caregivers and older patients on respiratory respiratory decline in ambulatory and non-ambulatory patients with function in relation to different variables such as age or Duchenne muscular dystrophy. J Neuromuscul Dis 2019;6:213-25. functional status and is an ideal complement to the recent https://doi.org/10.3233/JND-180351

128 Caregivers and patients views on respiratory function in Duchenne muscular dystrophy

9 Landfeldt E, Edstrom J, Buccella F, et al. Duchenne muscular dys- 13 Qian Y, McGraw S, Henne J, et al. Understanding the experienc- trophy and caregiver burden: a systematic review. Dev Med Child es and needs of individuals with spinal muscular atrophy and their Neurol 2018;60:987-96. https://doi.org/10.1111/dmcn.13934 parents: a qualitative study. BMC Neurol 2015;15:217. https://doi. 10 Crescimanno G, Greco F, D’Alia R, et al. Quality of life in long org/10.1186/s12883-015-0473-3 term ventilated adult patients with Duchenne muscular dystrophy. 14 McDonald CM, Henricson EK, Abresch RT, et al. Long-term ef- Neuromuscul Disord 2019;29:569-75. https://doi.org/10.1016/j. fects of glucocorticoids on function, quality of life, and survival in nmd.2019.06.599 patients with Duchenne muscular dystrophy: a prospective cohort 11 Kohler M, Clarenbach CF, Boni L, et al. Quality of life, physical study. Lancet 2018;391:451-61. https://doi.org/10.1016/S0140- disability, and respiratory impairment in Duchenne muscular dys- 6736(17)32160-8 trophy. Am J Respir Crit Care Med 2005;172:1032-6. https://doi. org/10.1164/rccm.200503-322OC 15 McDonald CM, Campbell C, Torricelli RE, et al. Ataluren in pa- 12 Ahlstrom G, Gunnarsson LG, Kihlgren A, et al. Respiratory tients with nonsense mutation Duchenne muscular dystrophy function, electrocardiography and quality of life in individu- (ACT DMD): a multicentre, randomised, double-blind, place- als with muscular dystrophy. Chest 1994;106:173-9. https://doi. bo-controlled, phase 3 trial. Lancet 2017;390:1489-98. https://doi. org/10.1378/chest.106.1.173 org/10.1016/S0140-6736(17)31611-2

129 ACTA MYOLOGICA 2020; XXXIX: p. 130-135 doi:10.36185/2532-1900-017 Endocrine myopathies: clinical and histopathological features of the major forms

Carmelo Rodolico*, Carmen Bonanno*, Alessia Pugliese, Giulia Nicocia, Salvatore Benvenga, Antonio Toscano Department of Clinical and Experimental Medicine, University of Messina, Italy

*These two authors contributed equally to the paper

Endocrinopathies, such as thyroid and parathyroid diseases, disorders of the adrenal axis, and acromegaly are included among the many causes of myopathy. Muscle disturbances caused by endocrine disorders are mainly due to alterations in the protein and carbohydrate metabolisms. Either a deficiency or excess of hormones produced by the glands can cause muscle dysfunction that can be reversed by starting hormone replacement therapy or acting on hormone dysfunction. The diagnosis is usually easy if a muscle disorder occurs in an overt endocrinopathy; however, in few patients, myopathy could be the first manifestation of the underlying endocrinopathy. In this article we discuss pathophysiology, clinical features and management of muscle involvement related to the major endocrine diseases.

Key words: endocrine myopathies, muscle weakness, creatine kinase, hypothyroidism, Received: September 30, 2020 myalgia, rhabdomyolysis Accepted: October 14, 2020

Correspondence Carmelo Rodolico Introduction Department of Clinical and Experimental Medicine, Unit of Neurology and Neuromuscular Disease, University of Skeletal muscle disorders can arise from a variety of endocrine diseases, Messina, via Consolare Valeria 1, 98122 Messina, Italy. including those affecting thyroid, adrenal glands, pituitary, parathyroid. Either Tel.: +39 090 2213501. E-mail: [email protected] a deficiency or excess of hormones produced by the glands can cause muscle Conflict of interest dysfunction that can be reversed by starting hormone replacement therapy or The Authors declare no conflict of interest acting on hormone dysfunction 1. The prevalence of neuromuscular diseases as a complication of endocrine disorders is not easily ascertainable and is like- How to cite this article: Rodolico C, Bonanno C, Pugliese A, et al. Endocrine myopathies: clinical and ly to be underestimated. Non-specific muscular symptoms such as cramps, histopathological features of the major forms. Acta myalgias, proximal or generalized weakness and exertional pain, may be part Myol 2020;39:130-5. https://doi.org/10.36185- of the variable clinical pictures of hypothyroidism, hyperparathyroidism, hy- 2532-1900-017 peradrenocorticism 2. Moreover, in some cases as in hypothyroidism, myopathy becomes evident with increased CK levels, progressive proximal muscle © Gaetano Conte Academy - Mediterranean Society of 1-3 Myology weakness and electromyographic abnormalities . Furthermore, some disorders can be considered typical of certain endocrinopathies, such as periodic OPEN ACCESS paralysis in thyrotoxicosis. We review the main endocrine dysfunctions that can cause muscle disorders and their treatment. This is an open access article distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution- NonCommercial-NoDerivatives 4.0 International) license. The article can be used by giving appropriate credit and mentioning Thyroid disorders the license, but only for non-commercial purposes and only in the original version. For further information: https:// Thyroid gland acts on several organ systems working as a meta- creativecommons.org/licenses/by-nc-nd/4.0/deed.en bolic regulatory centre through the secretion of L-thyroxine (T4) and

130 Endocrine myopathies

3,5,3’-triiodo-L-thyroxin (T3) whose production is regu- Morphological changes described in hypothyroid lated by thyroid stimulating hormone (TSH) 4. myopathy are largely non-specific and include fiber size variation, type 1 fiber predominance, type 2 atrophy, in- Hypothyroidism ternal nuclei, sporadic necrosis and regeneration, glycogen 2,3 A thyroid hormone deficiency of is often the result of accumulation, damaged mitochondria . Core-like struc- a lack of dietary iodine, autoimmune thyroiditis or, less tures, mainly evident in type 1 fibers, are a frequent feature commonly, post-treatment ablation 5. Hypothyroidism is in long-standing overt hypothyroidism (Fig. 1A). These usually more common in women. Symptoms are initially structures had histochemical and ultrastructural appearanc- nonspecific and constitutional, with muscle cramps, ideo- es of targetoid fibers and unstructured central cores, with motor slowdown, later a myxedema may develop, with evidence of abnormal deposition of intermediate filament hair loss, thick skin, and heart enlargement. Hypothy- proteins (i.e. desmin) at immunocytochemistry (Fig. 1B). roidism, when suspected, can be confirmed by measuring At ultrastructural study, the core areas show disorganized TSH and T4 blood tests 6. myofibrils, Z-band streaming, rod formation, paucity of mitochondria and glycogen granules (Fig. 1C). Cores often Hypothyroid Myopathy disappear after treatment with levo-thyroxine. The percentage of patients affected by hypothyroid- Hyperthyroidism ism experiencing neuromuscular symptoms varies from 30 to 80% 4. The prevalence of hyperthyroidism in women is be- Proximal weakness, muscle stiffness and cramp- tween 0.5-2% and it is 10 times less common in men. ing, slow reflexes, and myoedema are the spectrum of The most common causes are Graves’ disease, toxic neuromuscular symptoms of hypothyroidism and may multinodular goiter, and autonomously functioning thy- exhibit also as presenting symptoms of the endocrine roid adenoma. Rare causes of hyperthyroidisms are: pitu- disease. Weakness is most common complaint followed itary adenoma, autoimmune thyroiditis (Hashitoxicosis), by cramps 3,4,7. Slow reflexes, best seen in the ankle jerk levothyroxine overdose, inadequate iodine supplementa- response, also represents a peculiar precocious sign of tion (amiodaron induced hyperthyroidism, iodine-based neuromuscular involvement in hypothyroidism 8. Another contrast media), hCG excess (pregnancy, gestational tro- possible acute presentation of hypothyroidism is rhabdo- phoblastic disease, germ-cell tumors) 14. myolysis 9,10. Myoedema is uncommon and hence often underval- Hyperthyroid myopathy ued by clinicians but it is, in most instances, one of clas- Muscle involvement has been reported to occur in sical signs of hypothyroid myopathy. It is a phenomenon about 80% of thyrotoxic patients 15. Hyperthyroidism of mounding of muscle tissue as a response to pressure mainly leads to symptoms like muscle wasting and weak- or percussion 11. Hypothyroidism may present as Hoff- ness such as proximal muscle weakness, involving both the mann’s Syndrome, which is a rare form of hypothyroid upper and lower extremities, although distal muscle weak- myopathy that occurs in adults and is characterized by ness is also described, associated to brisk reflexes. In addi- the presence of hypothyroidism, pseudohypertrophy of tion to muscle weakness, muscle fatigue is often reported muscles and varying degrees of muscle weakness 3,12. Un- and generally described by patients as exercise intolerance. usually, it is sometimes observed in children with hypo- Various authors have suggested that thyrotoxic my- thyroidism a muscular enlargement which is referred to opathy is a result of the overall constellation of weight as Kocher-Debre-Semelaigne syndrome 13. loss and generalized asthenia of hyperthyroidism 15. In Muscular disturbances in hypothyroidism can be as- fact, thyrotoxic myopathy is rarely described as the onset cribed to the slow or reduced protein turnover and im- symptom in thyrotoxic patients. However, cases of a ful- paired carbohydrate metabolism due to the lack of thyroid minating myopathy in hyperthyroidism are reported, due hormone 4. to the involvement of respiratory and bulbar muscles 16,17. Thyrotoxic periodic paralysis are another rare mani- Diagnosis and management festation of muscular disease in hyperthyroidism charac- It can be based on the following findings: a low thy- terized by a rapidly progressing paralysis, greater in the roid hormone value, elevated up to ten times normal cre- proximal segments of lower limbs. This phenomenon oc- atine kinase (CK) levels, possible myopathic pattern at curs in susceptible individuals after an intracellular shift the electromyography (EMG). Establishing a replacing in potassium associated to a dilatation of sarcoplasmic therapy may lead to euthyroid state and muscle symptoms reticulum; however, the underlying relation between dil- recovery 4. atation of sarcoplasmic reticulum and excess of thyroid

131 Carmelo Rodolico et al.

Figure 1. Histopathological findings in hypothyroid and hypercortisolism associated myopathies A: cores in type 1 fibers, NADH-TR (magnification 280 X); B: immunocytochemistry revealing increased desmin binding in two cores (magnification 280 X); C: Electron microscopy showing two core areas with disorganized myofibrils, rod bodies, and lack of mitochondria and glycogen (magnification 6800X); D: ATPase pH 9.4 stain showing a marked type 2 fibers atrophy in steroid myopathy (magnification 110 X). hormone is not clear. Thyrotoxic periodic paralysis mani- The management of these myopathies is based on fests with hypokalemia in the acute state 18. achieving euthyroid state. It is demonstrated that be- The pathogenesis of muscle dysfunction in hyperthy- ta-blocker agents, such as propranolol, improve muscle roidism is likely due to an upregulation of metabolic ac- function 4. On the other hand, it is important to obtain a tivity which leads to increased catabolism in muscle cells, smooth reduction of FT4 to minimize the risk of a hypo- primary target of thyroid hormones. thyroidism related myopathy, especially in patients susceptible to hormonal change 19. Diagnosis and management Muscle enzymes, including CK, are generally nor- Parathyroid disorders mal. At the EMG, a myopathic pattern can be observed. Parathyroid glands are four small glands of the en- Muscle biopsy is frequently normal. docrine system located behind the thyroid which have a

132 Endocrine myopathies regulatory role with action as a thermostat in the systemic Diagnosis and management calcium homeostasis to ensure tight regulation of serum Creatinine kinase levels and EMG in hyperparathy- calcium concentrations and appropriate skeletal miner- roidism are usually normal. Muscle biopsy shows fibers alization. They produce a hormone called parathyroid atrophy usually not associated with degeneration. Surgi- hormone (PTH) that raises the blood calcium level by cal approach is considered the way to treat primary hyper- increasing calcium gut absorption, bone resorption and parathyroidism leading to a regression of the myopathic ++ 20 reducing renal clearance of calcium (Ca ) . disorder. Hyperparathyroidism secondary to renal disease is more difficult to treat, but administration of vitamin D Hypoparathyroidism and reduction of phosphorous intake may be helpful 28. It results from PTH deficiency or end-organ unrespon- siveness to PTH. Permanent hypoparathyroidism is the Adrenal glands disorders most common long-term complication after total thyroid- ectomy, but it can also occur as hereditary form, pseudohy- Adrenal glands are responsible for glucocorticoids poparathyroidism or as a consequence of severe hypomag- (GCs) production under the hypothalamus-pituitary-ad- nesemia. Its incidence varies from 30 to 60% 20,21. renal (HPA) axis. These glands are involved in several mechanism for homeostasis and metabolism. In particu- Hypoparathyroidism myopathy lar, cortisol, whose production is stimulated by adreno- Hypoparathyroidism rarely determines muscle in- corticotropic hormone (ACTH), acts as suppressant of volvement. However, mild CK elevation and muscle inflammation, in response to metabolic dysfunction and weakness have been described. More frequently, hypo- stress situations 29. parathyroidism results in hypocalcemia which leads to muscle tetany (increased neuromuscular irritability may Hypercortisolism be demonstrated by eliciting a Chvostek or Trousseau Hypercortisolism can arise from both an iatrogenic 21 sign and poor reflexes) . condition and an endogenous overproduction. Further- more, several pathological states associated with muscle Diagnosis and management damage, such as sepsis, diabetes, acidosis, chronic ob- Calcium and magnesium serum concentration should structive pulmonary disease, cancer, are accompanied by be evaluated. CK in hypoparathyroidism can be normal an increase of GC production 29. or variably elevated 22,23. No remarkable findings at EMG and muscle biopsy. A cardiological evaluation with QT Iatrogenic hypercortisolism 24 interval analysis should be performed . Correcting cal- As a result of an overdosage of steroids, prescribed 24 cium and magnesium levels is the treatment guideline . for therapeutic purposes, an iatrogenic steroid myopathy can occur. The onset is subacute characterized by proxi- Hyperparathyroidism mal muscle weakness followed by atrophy 30. Muscle at- Hyperparathyroidism should result from primary hy- rophy results both by a decrease of protein synthesis and perparathyroidism (HPT), which is due to a growth regu- by an increase of protein degradation in skeletal muscles. latory disturbance in one or several parathyroid glands It has also been suggested that GCs impair angiogenesis (such as hyperplasia or adenomas), or from secondary decreasing capillary number 31. hyperparathyroidism, which develops in patients with uremia, due to phosphate retention, hypocalcemia, and Diagnosis and management reduced active vitamin D levels, causing parathyroid hy- In corticosteroid myopathy CK value are usually perplasia and eventually development of parathyroid tu- normal. The EMG shows a myophatic pattern with small, mors and hypercalcemia 25. polyphasic potentials and no spontaneous activity. A peculiar finding of steroid myopathy is represented by a Hyperparathyroid myopathy selective and in some cases marked type 2 muscle fiber Hyperparathyroidism can develop both central and atrophy at muscle biopsy which could be useful in diag- peripheral neurological symptoms. Muscle typical in- nosis, in particular to differentiate from an inflammatory volvement is a proximal weakness with easy fatiguabil- myopathy (Fig. 1D) 32. ity, atrophy and hyperreflexia 26. In some cases, a clinical Steroid myopathy treatment is based on safety ste- picture mimicking motor neuron disease has been report- roid dose reduction to the lowest possible dose, using ed, characterized by muscular atrophy and weakness with alternate-day dosing or switching to a nonfluorinated ste- hyperreflexia and spasticity 27. roid 32.

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Endogenous hypercortisolism based on hypothyroidism. Endocrinol Diabetes Metab Case Rep Endogenous hypercortisolism can be related to an 2016;2016:16-0083. https://doi.org/10.1530/EDM-16-0083 overproduction of ACTH due to pituitary adenomas 11 Vignesh G, Balachandran K, Kamalanathan S, et al. Myoedema: a (Cushing’s disease) or to an ectopic hormone secretion of clinical pointer to hypothyroid myopathy. Indian J Endocrinol Me- either ACTH or GCs. tab 2013;17:352. https://doi.org/10.4103/2230-8210.109672 Patients affected by endogenous hypercortisolism 12 Achappa B, Madi D. Hoffmann’s syndrome – a rare form of hypo- may complain of muscle weakness, typically proximal. thyroid myopathy. J Clin Diagn Res 2017;11:OL01-2. https://doi. The clinical picture varies from myalgias to severe mus- org/10.7860/JCDR/2017/21234.9913 cle weakness and atrophy. Patient examination in these 13 Cimbek EA, Şen Y, Yuca SA, et al. Kocher-Debré-Semelaigne cases reveal peculiar signs of steroid excess, such as syndrome with rhabdomyolysis and increased creatinine. J Pedi- moon facies, buffalo hump, abdominal striae. atr Endocrinol Metab 2015;28:1383-5.https://doi.org/10.1515/ jpem-2014-0411 Diagnosis and management 14 Łacka K, Fraczek MM. Podział i etiopatogeneza nadczynnoś- Diagnostic findings in endogenous hypercortisolism ci tarczycy [Classification and etiology of hyperthyroidism]. Pol are overall the same of those described for the iatrogenic Merkur Lekarski 2014;36:206-11. one. Therapy is based on the removal of the oversecreting 15 Olson BR, Klein I, Benner R, et al. Hyperthyroid myopathy and tissue, leading to a restoration of hormone homeostasis the response to treatment. Thyroid 1991;1:137-41. https://doi. and to the resolution of the myopathy 33,34. org/10.1089/thy.1991.1.137 16 Boddu NJ, Badireddi S, Straub KD, et al. 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Ventricular arrhythmia precipitated by severe hy- 1995;88:272-4. pocalcaemia secondary to primary hypoparathyroidism. Case Rep 9 Salehi N, Agoston E, Munir I, et al. Rhabdomyolysis in a patient Cardiol 2019;2019:4851073. https://doi.org/10.1155/2019/4851073 with severe hypothyroidism. Am J Case Rep 2017;18:912-8. 25 Bilezikian JP, Bandeira L, Khan A, et al. Hyperparathyroid- https://doi.org/10.12659/ajcr.904691 ism. Lancet 2018;391:168-78. https://doi.org/10.1016/S0140- 10 Katipoglu B, Ates I, Acehan F, et al N. Rhabdomyolysis case 6736(17)31430-7

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26 Pappu R, Jabbour SA, Reginato AM, et al. Musculoskeletal manifesta- 31 Shimizu N, Yoshikawa N, Ito N, et al. Crosstalk between glucocorti- tions of primary hyperparathyroidism. Clin Rheumatol 2016;35:3081- coid receptor and nutritional sensor mTOR in skeletal muscle. Cell 7. Erratum in: Clin Rheumatol 2017;36:735. Regianto, AM [corrected Metab 2011;13:170-82. https://doi.org/10.1016/j.cmet.2011.01.001 to Reginato, AM]. https://doi.org/10.1007/s10067-016-3450-3 32 Gupta A, Gupta Y. Glucocorticoid-induced myopathy: patho- 27 Patten BM, Engel WK. Phosphate and parathyroid disorders as- physiology, diagnosis, and treatment. Indian J Endocrinol Metab sociated with the syndrome of amyotrophic lateral sclerosis. Adv 2013;17:913-6. https://doi.org/10.4103/2230-8210.117215 Neurol 1982;36:181-200. 33 Nieman LK, Ilias I. Evaluation and treatment of Cushing’s syn- 28 Lu CL, Yeih DF, Hou YC, et al. The emerging role of nutrition- drome. Am J Med 2005;118:1340-6. https://doi.org/10.1016/j.am- al vitamin d in secondary hyperparathyroidism in CKD. Nutrients jmed.2005.01.059 2018;10. pii:E1890. https://doi.org/10.3390/nu10121890 34 Caplan A, Fett N, Rosenbach M, et al. Prevention and manage- 29 Vegiopoulos A, Herzig S. Glucocorticoids, metabolism and meta- ment of glucocorticoid-induced side effects: a comprehensive bolic diseases. Mol Cell Endocrinol 2007;275:43-61. https://doi. review: ocular, cardiovascular, muscular, and psychiatric side ef- org/10.1016/j.mce.2007.05.015 fects and issues unique to pediatric patients. J Am Acad Dermatol 30 Schakman O, Kalista S, Barbé C, et al. Glucocorticoid-induced 2017;76:201-7 https://doi.org/10.1016/j.jaad.2016.02.1241 skeletal muscle atrophy. Int J Biochem Cell Biol 2013;45:2163-72. https://doi.org/10.1016/j.biocel.2013.05.036

135 ACTA MYOLOGICA 2020; XXXIX: p. 136-140 CASE REPORT doi:10.36185/2532-1900-018 Beneficial effects of one-month sacubitril/ valsartan treatment in a patient affected by end- stage dystrophinopathic cardiomyopathy

Andrea Antonio Papa1, Emanuele Gallinoro1, Alberto Palladino2, Paolo Golino1 1 Department of Cardiology, University of Campania “L. Vanvitelli”, Monaldi Hospital, Naples, Italy; 2 Medical Genetics and Cardiomyology, University of Campania “L. Vanvitelli”, Naples, Italy

Dystrophinopathic cardiomyopathy (DCM) is an almost constant manifestation in Becker muscular dystrophy (BMD) patients significantly contributing to morbidity and mortality. The nearly complete replacement of the myocardium by fibrous and fatty connective tissue results in an irreversible cardiac failure, characterized by progressive reduction of the ejection fraction. According to PARADIGM-HF trial results, the European Society of Cardiology (ESC) guidelines recommend the use of sacubitril/valsartan in ambulatory patients with heart failure and reduced ejection fraction, who remain symptomatic despite an optimal medical therapy. To date, little Received: May 10, 2020 is still known about the use of sacubitril/valsartan in DCM. We report the case of a Accepted: June 12, 2020 patient with dystrophinopathic end stage dilated cardiomyopathy with reduced ejection fraction who successfully responded to sacubitril/valsartan treatment. Correspondence Emanuele Gallinoro Key words: dystrophinopathic cardiomyopathy, heart failure, sacubitril/valsartan, Department of Cardiology, University of Campania “Luigi Vanvitelli”, Monaldi Hospital, via L. Bianchi, 80131 Becker muscular dystrophy Naples, Italy E-mail: [email protected] Conflict of interest Introduction The Authors declare no conflict of interest Dystrophynopathies are X-linked recessive disorders characterized by How to cite this article: Papa AA, Gallinoro E, partial (benign dystrophinopathy, BMD) or total (severe dystrophinopathy, Palladino A, Golino P. Beneficial effects of one-month DMD) dystrophin deficiency 1. Cardiac involvement is a common finding sacubitril/valsartan treatment in a patient affected by in muscular dystrophies 2 and often precedes the skeletal muscle one; in end-stage dystrophinopathic cardiomyopathy. Acta Myol 2020;39:136-40. https://doi.org/10.36185- dystrophinopathies, left ventricular systolic dysfunction leading to dilated 2532-1900-018 cardiomyopathy (DCM) and intractable heart failure represents the typical 2-4 5-6 © Gaetano Conte Academy - Mediterranean Society of picture . Patients may often require the use of mechanical devices or 7 Myology need heart transplantation . In late stages, DCM may be complicated by atrial fibrillation or atrial flutter, and/or by ventricular arrhythmias, that OPEN ACCESS predispose the patients to an increased risk of sudden cardiac death 8. Despite mild muscle symptoms, over 70% of patients with BMD de- This is an open access article distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution- velop dystrophinopathic cardiomyopathy, that evolves toward the picture NonCommercial-NoDerivatives 4.0 International) license. The of an intractable heart failure 3, regardless an appropriate pharmacological article can be used by giving appropriate credit and mentioning treatment 9. Given the lack of specific guidelines on the issue, the treat- the license, but only for non-commercial purposes and only in the original version. For further information: https:// ment of dystrophinopathic DCM usually follows the general guidelines for creativecommons.org/licenses/by-nc-nd/4.0/deed.en treating genetic cardiomyopathies 10.

136 Beneficial effects of one-month sacubitril/valsartan treatment

Sacubitril/valsartan (LCZ696) (SAV) has recently been approved for the treatment of patients with refractory heart failure and reduced ejection fraction (HFrEF), as it showed a reduction in mortality and hospitalization compared with standard drugs 11. Sacubitril/valsartan be- longs to the class of angiotensin receptor-neprilysin inhibitors (ARNi), endopeptidases which cleave natriuretic peptides 11. The effectiveness and safety of this drug re- ceives constant confirmation in daily practice. However, no data are still available about its possible clinical use in patients affected by dystrophinopathic dilated cardiomyopathy with HFrEF. We report for the first time the case of a patient with dystrophinopathic dilated cardiomyopathy and HFrEF Figure 1. B-mode echocardiography. Enlarged left ven- who successfully responded to sacubitril/valsartan treat- tricle with an end-diastolic volume evaluated through the ment, after just 30 days of therapy. biplane method in apical 4-chambers view (291 ml).

Case report rate (hr): 95 bpm; arterial blood pressure: 110/70 mmhg). A 46-year-young man, affected by familial dystroph- Two-dimensional and M-mode echocardiograms showed inopathic cardiomyopathy, was hospitalised for the exac- reduced systolic indices, including fractional shortening erbation of signs and symptoms of congestive HF. The (9%) and ejection fraction (EF) (18%) (Fig. 1). Echo- patient was followed by the age of 23 years for cardiac cardiography showed high filling pressure (E/E’ average symptoms characterized by exertional dyspnoea, and sev- 27.3) and a global longitudinal strain (GLS) of -6.4% eral episodes of tachycardia. The diagnosis of dystroph- (Fig. 2). Right ventricle function, tricuspid annular plane inopathic cardiomyopathy was made because of family systolic excursion (TAPSE = 13 mm) and right ventricle history (the older brother died at the age of 28 from in- velocity (RVs’= 8 cm/s) were also reduced. tractable heart failure, awaiting heart transplantation) and ProBNP was 1578 pg/ml. The patient complained a confirmed by genetic analysis, that showed the deletion concomitant involvement of motor abilities, with a reduc- of exons 45-49 of the dystrophin gene, typical of BMD tion of the 6MWT (270 meters), SpO2 (92%), and an in- phenotype. The patient had no muscle symptoms. The crease in HR (110 bpm). Exertion was perceived as hard, cardiological investigation showed a dilation of the heart rated 4-5 on the Borg scale. According to the current chambers and a reduced ejection fraction, consistent with indications in patients with HFrEF 28, the therapy with a picture of dystrophinopathic dilated cardiomyopathy, ACE-inhibitors was switched to SAV, 24/26 mg b.i.d. that was confirmed at the endomyocardial biopsy. Treat- After 30 days of SAV therapy, the patient referred ment with ACE-inhibitors (delapril 45 mg/die), steroids a dramatic improvement in his symptoms and functional (deflazacort) and antioxidants (vitamin C and E, and Co- status, with disappearance of dyspnoea for mild effort. enzyme Q10) was promptly set up, obtaining a stabiliza- The NYHA class changed from III to II. The motor abil- tion of the cardiological parameters for about 12 years. ities also improved (6MWT up to 315 meters, and SpO2 At the age of 40, a bicameral cardioverter defibrilla- up to 98%). The exertion was perceived as slight, ac- tor (ICD) was implanted because the evidence of severely cording to the Borg scale (rate 2). The ProBNP values dilated left ventricular cavity with diffuse hypokinesis and decreased significantly to 610 pg/ml (Tab. I). The echo- onset of symptoms and signs of HFrEF. In that occasion, cardiography showed an improvement in cardiac func- the pharmacological therapy of HF was titrated according tion: EF increased to 28% with a concomitant increase to ESC guidelines: delapride 30 mg/die, carvedilol 25 mg/ in stroke volume; GLS confirmed an improvement in left die, furosemide 25 mg/die and spironolactone 25 mg/die, ventricle function showing an Average of -7.5% (Fig. 2). obtaining relative well-being for about 5 years. Left ventricle volume and filling pressure were slightly At the age of 45 years, a cardiorespiratory episode of decreased (E/e’ 19.8). An improvement in right ventri- infectious origin, which required hospitalization in health cle systolic function was also recorded (TAPSE 19 mm; care facility, further compromised the precarious cardio- RVs’= 11 cm/s) (Tab. I). The drug was well tolerated; vascular balance of the patient, who experienced after few none of the common PARADIGM HF side effects was months dyspnoea on mild exertion and poor tolerability of reported. SAV therapy was confirmed and a new evalua- daily activities (NYHA class III; basal spo2: 96%; heart tion scheduled, at three-month of treatment.

137 Andrea Antonio Papa et al.

Table I. Clinical and laboratory data at baseline and after 30 days of therapy with sacubitril/valsartan. Baseline 30 days 6MWT Heart rate (bpm) Baseline 80 75 3 minutes 102 90 6 minutes 110 102 SpO2 (%) Baseline 98 98 3 minutes 95 98 6 minutes 92 98 Meters 3 minutes 136 153 6 minutes 270 315 Dyspnoea Moderate Mild Borg scale 4-5 2 Echocardiographic parameters EF (%) Teicholz 14 23 Biplane 18 38 LVEDd (mm) 78 74 LVESd (mm) 73 66 IVSd (mm) 8 8 LVPWd (mm) 10 10 LVEDv (ml) 291 230 LVESv (ml) 236 166 LAVI (ml/m2) 76 68 E/e’ 27.31 19.88 TAPSE (mm) 13 19 S’ (cm/sec) 8 11 GLS Avg (%) -6.4 -7.5 Laboratory data Serum creatinine (mg/dl) 0.76 0.75 Potassium (mg/dl) 4.5 4.9 BUN (mg/dl) 50 57 Pro-BNP (pg/ml) 1578 610 LVEDd: left ventricular end-diastolic diameter; LVESd: left ventricular end-systolic diameter; IVSd: interventricular septum diameter; LVPWd: left ventricular posterior wall diameter; LVEDv: left ventricular end-diastolic volume; LVESV: left ventricular end-systolic volume; LAVI: left atrial volume index; TAPSE: Tricuspid annular plane systolic excursion; GLS Avg: global longitudinal strain average; BUN: Blood Urea Nitrogen

Discussion However, little is still known about the safety and effectiveness of SAV in patients with dystrophinopathic The treatment of HF related to myocardial involve- cardiomyopathy, in which the reduced mobility due to ment in muscular dystrophies is still challenging and no muscular impairment can be aggravated by the heart fail- guidelines exist about this issue. As reported in several ure, further limiting their daily activities. papers 11-15, SAV improves the effort tolerance, by reduc- In the case here reported, the use of SAV produced ing both end-diastolic and systolic left ventricle volumes, an improvement in symptoms, NYHA class and motor induces reverse remodelling of SAV on left ventricle 12, function. The effectiveness of SAV was also demonstrat- in turn resulting into a better quality of life. Furthermore, ed by the reduction in pro-BNP plasma levels, associated in patients with chronic HFrEF not related to muscular to a reduction in haemodynamic stress and cardiovascu- dystrophies, SAV has shown to be superior to enalapril in lar events 14. Furthermore, an improvement in longitudinal reducing mortality and HF hospitalizations 13. contraction of cardiomyocytes, an event that may contrib-

138 Beneficial effects of one-month sacubitril/valsartan treatment

Figure 2. Top. GLS at baseline. Longitudinal strain curves (a) and the 17-segments “Bull’s eye” (b). A GLS average of -6.4% with systolic dysfunction involving especially the anterior and lateral walls is shown.; Bottom. GLS after 30 days of SAV. An increase in GLS average (-7.5%) with an improvement of anterior and lateral walls longitudinal strain is shown. ute to the ejection fraction increasing, was seen by GLS. confirmed by a comprehensive echocardiographic assess- Interestingly, the improvement was mainly observed in the ment that included the strain evaluation. No relevant side left ventricle at the antero-lateral wall level, while the ear- effects were reported. lier and most frequent myocardial involvement is usually The use of SAV in a larger cohort of patients with observed in the infero-lateral wall in dystrophinopathic dystrophinopathic cardiomyopathy is desirable to con- patients. This result is not unexpected if we consider that firm its efficacy and safety; moreover, it could be a good a) the anterolateral wall is later involved in the fibrotic pro- pharmacological option for patients with refractory cess compared to the inferolateral wall, and so it is still able HFrEF not suitable for heart transplantation. to better respond to SAV therapy; and b) SAV is able to improve myocardial cell vitality and reduce fibrotic degen- Aknowledgments eration, as reported in some animal models 15. The authors thank Novartis for bearing the printing To our knowledge, this is the first report on the use costs. of SAV in a patient with dystrophinopathic end stage cardiomyopathy and HFrEF. After only 30 days of therapy, the patient experienced an improvement of clinical References symptoms, effort tolerance and cardiac performance, 1 Bradley WG, Jones MZ, Mussini JM, et al. Becker-type muscular

139 Andrea Antonio Papa et al.

dystrophy. Muscle Nerve 1978;1:111-32. https://doi.org/10.1002/ Exp Opin Orphan Drugs 2016;11:1159-78. https://doi.org/10.1080 mus.880010204 /21678707.2016.1234373 2 Nigro G, Comi LI, Politano L, et al. 45 cardiomyopathies associ- 10 Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines ated with muscular dystrophies. In: Engel AE, Ed. Myology. Mc- for the diagnosis and treatment of acute and chronic heart failure: Graw-Hill Medical Ed. 2004, Cap. 45, pp. 1239-56. the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) devel- 3 Nigro G, Comi LI, Politano L, Evaluation of the cardiomyopathy in oped with the special contribution of the Heart Failure Associa- Becker muscular dystrophy. Muscle Nerve 1995;18:283-91. https:// tion (HFA) of the ESC. Eur Heart J 2016;37:2129-200. https://doi. doi.org/10.1002/mus.880180304 org/10.1093/eurheartj/ehw128 4 Ho R, Nguyen ML, Mather P. Cardiomyopathy in Becker muscular 11 Dargad RR, Prajapati MR, Dargad RR, et al. Sacubitril/valsar- dystrophy: overview. World J Cardiol 2016;8:356-61. https://doi. tan: a novel angiotensin receptor-neprilysin inhibitor. Indian org/10.4330/wjc.v8.i6.356 Heart J 2018;70 (Suppl 1):S102-10. https://doi.org/10.1016/j. 5 Proietti R, Labos C, Davis M, et al. A systematic review and ihj.2018.01.002 meta-analysis of the association between implantable cardiovert- 12 Martens P, Beliën H, Dupont M, et al. The reverse remodeling re- er-defibrillator shocks and long-term mortality. Can J Cardiol sponse to sacubitril/valsartan therapy in heart failure with reduced 2015;31:270-7. https://doi.org/10.1016/j.cjca.2014.11.023 ejection fraction. Cardiovasc Ther 2018;36:e12435. https://doi. 6 Palladino A, Papa AA, Morra S, et al. Are there real benefits to org/10.1111/1755-5922.12435 implanting cardiac devices in patients with end-stage dilated dys- 13 Balmforth C, Simpson J, Shen L, et al. Outcomes and effect of treat- trophinopathic cardiomyopathy? Review of literature and personal ment according to etiology in HFrEF: an analysis of PARADIGM- results. Acta Myol 2019;38:1-7. PMID 31309174 HF. JACC Heart Fail 2019;7:457-65. https://doi.org/10.1016/j. 7 Papa AA, D’Ambrosio P, Petillo R, et al. Heart transplantation in jchf.2019.02.015 patients with dystrophinopathic cardiomyopathy: review of the lit- 14 Solomon SD, Rizkala AR, Gong J, et al. Angiotensin receptor ne- erature and personal series. Intractable Rare Dis Res 2017;6:95- prilysin inhibition in heart failure with preserved ejection fraction: 101. https://doi.org/10.5582/irdr.2017.01024 rationale and design of the PARAGON-HF trial. JACC Heart Fail 8 Chiang DY, Allen HD, Kim JJ, et al. Relation of cardiac dysfunc- 2017;5:471-82. https://doi.org/10.1056/NEJMoa1409077 tion to rhythm abnormalities in patients with Duchenne or Becker 15 Torrado J, Cain C, Mauro AG, et al. Sacubitril/valsartan averts ad- muscular dystrophies. Am J Cardiol 2016;117:1349-54. https://doi. verse post-infarction ventricular remodeling and preserves systolic org/10.1016/j.amjcard.2016.01.031 function in rabbits. J Am Coll Cardiol 2018;72:2342-56. https://doi. 9 Politano L, Nigro G. Managing dystrophinopathic cardiomyopathy. org/10.1016/j.jacc.2018.07.102

140 ACTA MYOLOGICA 2020; XXXIX: p. 141-143 doi: doi:10.36185/2532-1900-019 Silent dysphagia in two patients with Steinert disease and recurrent respiratory exacerbations

Anna Annunziata1, Tullio Valente2, Rosa Cauteruccio1, Giuseppe Fiorentino1 1UOC Pathophysiology and Respiratory Rehabilitation, Intensive Care Department, Azienda Ospedaliera dei Colli, Naples, Italy; 2 UOC Radiology, Azienda Ospedaliera dei Colli, Naples, Italy

We describe two cases of patients with Steinert’s dystrophy or myotonic dystrophy type 1 (DM1) who presented with frequent respiratory exacerbations and pneumonia. They did not report any risk factors for asthma, allergy, bronchopathy or dysphagia in their history. The Videofluoroscopic swallow study test allowed to highlight post-swallowing aspiration phenomena responsible for respiratory exacerbations.

Key words: dysphagia, Steinert disease, respiratory exacerbation

Introduction Received: August 31, 2020 Myotonic dystrophy type 1 (DM1) is characterized by highly variable Accepted: October 5, 2020 clinical manifestations that affect specific tissues, such as distal limbs and Correspondence facial muscles, smooth muscles, eye (primarily the lens), brain (especially Anna Annunziata the anterior temporal and frontal lobes), and endocrine function (testoster- UOC Pathophysiology and Respiratory Rehabilitation, one deficiency, insulin resistance, thyroid dysfunction). Cardiac involve- Intensive Care Department, Azienda Ospedaliera dei Colli, 1 via L. Bianchi, 80131 Naples, Italy ment is noticed in about 80% of cases . E-mail: [email protected] A respiratory dysfunction, predominantly a restrictive ventilatory pattern, is common in myotonic dystrophy and is associated with alveolar Conflict of interest The Authors declare no conflict of interest hypoventilation, chronic hypercapnia, and sleep disturbance in the form of sleep apnoea and sleep related disordered breathing 2. 3 How to cite this article: Annunziata A, Valente T, Aspiration caused by dysphagia is possible in DM1 . Pulmonary aspi- Cauteruccio R, Fiorentino G. Silent dysphagia in two ration syndromes refer to a wide spectrum of pulmonary disorders result- patients with Steinert disease and recurrent respiratory ing from aspiration of foreign material into the lung. Although aspiration exacerbations. Acta Myol 2020;39:141-3. https:// generally triggers coughing, it can be silent, causing difficulties in recog- doi.org/10.36185-2532-1900-019 nizing aspiration as the cause of undiagnosed respiratory diseases. The © Gaetano Conte Academy - Mediterranean Society of severity of aspiration is related to the volume and nature of the aspirate, Myology the chronicity, and the host responses. Aspiration and its consequences can be divided into 3 forms: a) aspi- OPEN ACCESS ration pneumonia and diffuse aspiration bronchiolitis; b) aspiration pneu- This is an open access article distributed in accordance monitis; and c) a foreign body obstruction of a central airway. The first with the CC-BY-NC-ND (Creative Commons Attribution- form generally occurs in elderly, debilitated patients with dysphagia, and NonCommercial-NoDerivatives 4.0 International) license. The usually presents as a ‘community acquired pneumonia’, which tends to article can be used by giving appropriate credit and mentioning be recurrent in patients with diffuse aspiration bronchiolitis. Treatment the license, but only for non-commercial purposes and only in the original version. For further information: https:// consists of broad-spectrum antibiotics and management of the underlying creativecommons.org/licenses/by-nc-nd/4.0/deed.en dysphagia.

141 Anna Annunziata et al.

The aspiration pneumonitis is the consequence of ary compared to the last checks. The cough peak was 240 the aspiration of regurgitated gastric contents, usually L/min in patient # 1, and 220 L/min in patient #2. Both occurring in patients with a marked decreased level of patients did not report dysphagia, difficulty in swallow- consciousness. Treatment in this form is essentially sup- ing, nor did they complain of coughing fits during meals. portive; however, corticosteroids and other immunomod- Allergic tests were negative, as well as the spit test. Both ulating agents may have some effect in these patients 4. patients were already on home therapy with a cough ma- Generally, neuromuscular disorders, esophageal dis- chine. eases, and the presence of a nasogastric (NG) tube or an Chest CT scan showed in patient #1 the lamellar endotracheal (ET) tube are factors that may increase the dysventilation -consolidation of the lower lobe, middle risk of aspiration. Focal or multifocal consolidations in a lobe and lingula and incipient tubular ectasias, mainly dependent location is the most common finding on chest cleansed, of the air lumen of the segmental bronchi of X ray 5. the middle lobe. In patient # 2 CT scan showed right consolidation of lower lobe and bronchiolitis. Both patients underwent videofluoroscopic swallow study (VFSS). The Case report investigation was performed by digital image acquisition We describe two patients affected by myotonic dys- after oral administration of an opaque bolus liquid (gas- trophy type 1 (DM1) or Steinert disease, followed at our trografin diluted to 80%), semi-solid (yogurt + gastrogra- department for respiratory problems. Both patients - #1 fin), and solid (biscuits + gastrografin). aged 64 and # 2 aged 39 years, were females and on In patient # 1 the VFSS showed stagnation in the pha- nocturnal mechanical ventilation due to respiratory in- ryngeal valleys and in the piriform sinuses, minimal pen- sufficiency secondary to sleep apnea. The patient #1 had etration in the liquid phase of the examination (Fig. 1); experienced in the previous six months two episodes of in patient # 2, stagnation of the radiological contrast was pneumonia requiring hospitalization. The patient #2 pre- in the pharyngeal valleys and in the piriform sinuses and sented one episode of respiratory exacerbation/month in determined a sensation of encumbrance, cough and ex- the past 4 months, the last of which was slowly resolv- pectoration of the ingested material especially in the solid ing. When the patients returned to our observation for a phase of the examination. The material stagnated after clinical-functional re-assessment, both presented a mod- breathing and opening of the epiglottis could be aspirated erate restrictive ventilatory deficit at spirometry, station- with post-aspiration swallowing.

Figure 1. Patient #1. VFSS showing stagnation of the radiological contrast in the pharyngeal valleys and in the piriform sinuses (see arrow).

142 Dysphagia in DM1

After the test confirmed the suspicion of dysphagia References in both patients, a nutritional counseling was activated to 1 Nigro G, Papa AA, Politano L. The heart and cardiac pacing modify the diet, and a course of logotherapy prescribed to in Steinert disease. Acta Myol 2012;31:110-6. re-educate the swallowing muscles. No further episodes 2 Hawkins AM, Hawkins CL, Abdul Razak K, et al. Respiratory of respiratory exacerbation occurred during the following dysfunction in myotonic dystrophy type 1: a systematic review. 12 months. Neuromuscul Disord 2019;29:198-212. https://doi.org/10.1016/j. nmd.2018.12.002 Discussion 3 Pilz W, Passos VL, Verdonschot RJ, et al. Swallow-related quality of life and oropharyngeal dysphagia in myotonic dystrophy. Eur Dysphagia is often not recognized in its early stages. Arch Otorhinolaryngol 2020;277:2357-62. It can cause even serious clinical pictures that last in si- 4 lence for many months 6. https://doi.org/10.1007/s00405-020-05964-2 VFSS allows to examine all stages of swallowing, 5 Jones K, Pitceathly RD, Rose MR, et al. Interventions for dyspha- from the preparation stage to the onset of swallowing, gia in long-term, progressive muscle disease. Cochrane Database the passage of the opaque meal in the oropharynx, and Syst Rev 2016;2:CD004303. https://doi.org/10.1002/14651858. of the bolus in the hypopharynx, so it is considered as the CD004303.pub4. PMID: 26859621 procedure of choice in neuromuscular and NIV-treated 6 Hu X, Lee JS, Pianosi PT, et al. Aspiration-related pulmonary patients 2. syndromes. Chest 2015;147:815-23. https://doi.org/10.1378/ The defects mainly detected at VFSS are reduced chest.14-1049 pharyngeal peristalsis, hypopharyngeal stasis and frag- 7 Leonard RJ, Kendall KA, Johnson R, et al. Swallowing in myoton- 5 mented swallowing . In recent studies, the aspiration was ic muscular dystrophy: a videofluoroscopic study. Arch Phys Med seen in half of the patients affected by Steinert disease, Rehabil 2001;82:979-85. https://doi.org/10.1053/apmr.2001.23962 both adults and infants, and mostly during swallowing 7,8. 8 Berggren KN, Hung M, Dixon MM, et al. Orofacial strength, dys- In both cases here described, VFSS documented the arthria, and dysphagia in congenital myotonic dystrophy. Muscle presence of a swallowing disorder; the correction of the Nerve 2018;58:413-7. https://doi.org/10.1002/mus.26176 dietary regimen led to no episode of respiratory exacerba- 9 tion after 12 months. Willaert A, Jorissen M, Goeleven A. Swallowing dysfunction in Data recently appeared in the literature 9 document myotonic dystrophy: a retrospective study of symptomatology and how the food material stagnated in the pharynx can be radiographic findings. B-ENT 2015;11:249-56. aspirated in the post-swallowing phase, even after a few 10 Johnson NE, Butterfield R, Berggren K, et al. Disease burden and minutes. Aspirated food debris can mimic respiratory functional outcomes in congenital myotonic dystrophy: a cross-sec- exacerbations, and the condition can go silent for many tional study. Neurology 2016;87:160-7. https://doi.org/10.1212/ months until it leads to severe respiratory failure. WNL.0000000000002845 We agree that a systematic screening of dysphagia 11 Teuschl Y, Trapl M, Ratajczak P, et al. Systematic dysphagia should be recommended 10 to achieve an early diagnosis screening and dietary modifications to reduce stroke-associated and to set up appropriate dietary modifications and reha- pneumonia rates in a stroke-unit. PLoS One 2018;13:e0192142. bilitation interventions, to avoid aspiration and to prevent https://doi.org/10.1371/journal.pone.0192142. PMID: 29389984; severe respiratory complications in these patients. PMCID: PMC5794132

143 Acta Myologica • 2020; XXXIX: p. 144

NEWS FROM AROUND THE WORLD

AIM WMS In the period between July and September 2020 The virtual 25th Congress of the WMS will be held, the activities of the Italian Association of Myology as announced, from 30th September – 2nd October 2020. were limited and reduced due to the pandemic related The registration is free so that as many of our mem- to SARS-Cov2. bers who might not have been able to travel to Canada Most of the activities were aimed at the remodel- this year as possible can join the WMS spirit of Educa- ing and organization of the joint congress with the Ital- tion, Enjoyment and Excitement! ian Association for the Study of the Peripheral Ner- For more information it is possible to contact vous System (ASNP), which should have been held Clare Beach, WMS Secretariat and 2020 Congress in Matera in June, postponed to December 9-12, and Manager E: [email protected] W: www. which will be carried out in virtual form. wms2020.com In a joint and commendable effort all the Italian The WMS continue to add valuable information Neuromuscular Centers afferent to the AIM have en- about COVID-19 and people with neuromuscular gaged in the elaboration of a survey estimating the disorders: World Muscle Society position and advice impact of COVID-19 pandemic on services provided to the website: https://www.worldmusclesociety.org/ by all the Centers. The results of this interesting study news/view/150 have been published in Acta Myologica (2020; XXX- Once again, we thank all the attendees and our IX: p. 57-66 - doi:10.36185-2532-1900-008). members for the support that has been shown to us and we are here to support others in the field as we all MSM work through these difficult times”. The 14th Meeting of the Mediterranean Society of Myology (MSM) meeting is moved to spring 2021, Sars-Cov2 permiting. Proposals to organize and host the event are welcome.

144 Acta Myologica • 2020; XXXIX: p. 145

FORTHCOMING MEETINGS

2020 December 9-12 th September 25 20 National Congress of Italian Association of Myology and 10th Annual Congress of the Italian Association Stride Registry virtual Investigator Meeting for the for the Study of the Peripheral Nerve. Virtual edition. Southern European Region. Information: website: www. Information: website: https://www.miologia.org ptcbio.com September 25-29 Muscle Study Group Annual Scientific Meeting, 2021 Washington, US. Information: website: https:// February 20 musclestudygroup.org/events/2020-annual-meeting 2nd Annual Conference on Genetics, Paris, France September 30 - October 4 25th Congress of World Muscle Society. Vitual Edition. June 12-15 Information: website: www.wms2020.com The European Human Genetics Conference. Glasgow, United Kingdom. Information: website: https://www.eshg.org October 27-31 ASHG Annual Meeting. San Diego, CA, USA. Information: September 21-25 website: www.ashg.org 26th Congress of World Muscle Society. Prague, Czech November 2-3 Republic. Information: website: www.worldmusclesociety. org Progeria Research Foundation 10th International Research Congress.Webinar Version. Information: October 19-23 website: www.progeriaresearch.org/it/2020/07/20/2020- ASHG Annual Meeting. Montreal, Canada. Information: workshop website: www.ashg.org

145

CONGRESSO CONGIUNTO AIM/ASNP Digital Edition 9-12 Dicembre 2020

PROGRAMME

Mercoledì 9 Dicembre Streaming on CHANNEL 1

14.00 – 14.20 | Greetings and introduction

14.20 - 15.20 Workshop: Innovative therapeutic strategies in genetic neuromuscular diseases (Part I)

14.20 – 14.40 An “antisense” approach for neuromuscular diseases | Toby Ferguson 14.40 - 15.00 Gene therapy for SMA: from an innovative mechanism of action to clinical data| M. Pane 15.00 – 15.20 In vivo gene therapy for Pompe disease | F. Mingozzi

15.20 - 16.40 | Workshop: New tools in the management of patients with neuromuscular disorders

15.20 - 15.40 Genetic modifiers as a tool for personalized treatment of neuromuscular disorders L. Bello 15.40 – 16.00 Animal models as a tool to design novel therapeutical strategies | S. Previtali 16.00 – 16.20 Computation Neurology: devices, data and models for characterization and modelling of neuromuscular diseases | V. Sanguineti 16.20 – 16.40 Digital health solutions to increase sensitivity of outcome measures in clinical and trial settings in neuromuscular disorders | S. Messina

16.40 - 16.50 | Pausa

16.50 - 18.20 | Oral communications 1: “Updating diagnostic tools in neuromuscular disorders”

16.50 – 17.05 Automatic recognition of ragged red fibers in muscle's histological images of patients affected by mithocondrial disorders J. Baldacci, M. Calderisi, A. Rubegni, C. Fiorillo, F.M. Santorelli (Pisa; Genova)

17.05 – 17.20 Ultra-high frequency ultrasound of median nerve. Comparison of different frequencies and correlation with clinical and neurophysiological findings D. Coraci, A. De Luna, A. Fusco, S. Giovannini, L. Padua (Roma; Milano)

– uscle in otonic stroph tpe M. Garibaldi, T. Nicoletti, L. Fionda, E. Bucci, T. Tartaglione, G. Tasca, A. Perna, A. Petrucci, G. Silvestri, G. Antonini (Roma)

– irtual enetic counsellin in euromuscular diseases a pilot teleenetics proect F. Gualandi, M. Neri, M. Farnè, F. Fortunato, G. Vita, M. Pane, G. Rocchi, T. Evangelista, A. Ferlini (Ferrara; Messina; Roma; Pesaro; Paris, France)

– hole eome and enome seuencin for the enetic dianosis of dstrophinopathies R. Selvatici, R. Rossi, F. Mingyan, M.S. Falzarano, P. Rimessi, M. Neri, F. Gualandi, S. Delin, S. Bensemmane, A. Shatillo, L. Bello, E. Pegoraro, A. Ferlini (Ferrara; Shenzhen, China; Zadar, Croatia; Alger; Kharkiv, Ukraine; Padova)

– in iops ma help to distinuish ultiple stem Atrophparinsonism tpe from arinson disease ith orthostatic hpotension V. Donadio, A. Incensi, G. Rizzo, R. De Micco, A. Tessitore, G. Devigili, F. Del Sorbo, S. Bonvegna, M. Magnani, C. Zenesini, L. Vignatelli, R. Cilia, R. Eleopra, G. Tedeschi, R. Liguori (Bologna; Napoli; Milano)

– L. Stuppia

–

– e histopatholoical marers for the dianosis of the mopathies the intae that is updated C. Fiorillo – in iops eond the intraepidermal nere fier densit M. Nolano – enome analses in muscular disorders V. Nigro – in related disorders F. Taroni

– – olecular mechanisms . Obici – linical presentation dianosis and treatment of peripheral neuropath G. Vita – linical and therapeutic aspects of cardiomopath Limongelli

: “nherited neuromuscular disorders”

linical morpholoical and enetic data of patients ith distal and mofirillar mopathies report from the talian netor S. Bortolani, S. Bonanno, G. Vattemi, P. Tonin, M. Monforte, E. Ricci, G. Primiano, S. Servidei, G. Greco, R. Massa, C. Gemelli, M. Grandis, C. Fiorillo, A. Petrucci, M. Filosto, M.L. Valentino, R. Liguori, T. Mongini, M. Garibaldi, G. Antonini, M. Lucchini, M. Mirabella, A. Rubegni, F. M. Santorelli, G. Siciliano, G. Ricci, C. Angelini, A. Ariatti, L. Maggi, G. Tasca (Roma; Verona; Milano; Genova; Brescia; Bologna; Torino; Pisa; Venezia; Modena)

henotpic and enetic characteriation of childhood harcotarieooth disease F.R. Danti, S. Magri, S. Genitrini, E. Pagliano, M. Foscan, A. Ardissone, C. Ciano, P. Saveri, F. Balistreri, D. Di Bella, D. Pareyson, F. Taroni, I. Moroni (Milano)

utations in uperillin cause mopath ith mofirillar disoraniation and autophaic acuoles C. Hedberg-Oldfors, R. Meyer, K. Nolte, Y. Abdul Rahim, C. Lindberg, K. Karason, I. J. Thuestad, K. Visuttijai, M. Geijer, M. Begemann, F. Kraft, E. Lausberg, L. Hitpaß, R. Götzl, E.J. Luna, H. Lochmüller, S. Koschmieder, M. Gramlich, B. Gess, M. Elbracht, J. Weis, I. Kurth, A. Oldfors, C. Knopp (Gothenburg, Sweden; Aachen, Germany; Malmo, Sweden; Worcester, United States; Ottawa, Canada)

linical and ioloical characteriation of a lare series of lateonset patients carrin the mutation P. Saveri, C. Pisciotta, M. Grandis, V. Prada, P. Fossa, R. Mastrangelo, C. Ferri, G. Shackleford, F. Veneri, R. Baldi, G. Lauria, R. Lombardi, C. Ciano, S. Magri, F. Taroni, L. Richard, J.M. Vallat, M. D’Antonio, D. Pareyson (Milano; Genova; Limoges Cedex, France)

A. Pgliese, C. onanno, G. icocia, A. Lica, . Messina, GL. ita, G. ita, A. oscano, C. odolico (Messina)

. esti, M. Filosto, A. Maeo, M. aatelli, M. Ligetti, . Panceri, G. attemi, P. onin, . Cavallaro, G.M. Farii (erona; rescia; Messina; oma)

A. Gallone, . rgnoni, A. Ardissone, . erlii, . Masson, G. icci, F. Magri, F. Gidolin, M.L. alentino, D. Frattini, C. onanno , M. Catterccia, A. Malandrini, G. Primiano, C. Antoi, P. Conalonieri, G. asca, M. Monorte, . icci, G. Astrea, C. icci, M. Garialdi, D. rscci, F. icci, M.. Ferr, .A. Donadio, A. Gentili, . ertini, G. iciliano, D. Piga, G.P. Comi, R. Liguori, I. Moroni, F.M. Santorelli, S. Servidei, A. D’Amico, G. Antonini, A. Evoli, D. ternerg, D. eeson, A. ngel, . Locmller, . Mantegaa, P. ernasconi, C. odolico, L. Maggi (Milano; Piacena; Pisa; rieste; ologna; eggio mila; Messina; oma; iena; Lcca; orino; Crema; Paris, France; xord, ; ocester, M, A; Freirg, Germany; ttaa, Canada)

. oa, D. everi, D. rese, . odice, L. ggiero, . Dioso, . ina, A. ovino, F. Arta, M. elloatto, M. olano, L. antoro, F. Manganelli (aoli)

Lecture: “High Health Service. How long can we afford them?”

–

L. Pada . Gerevini M. Garialdi

– –

–

M. Maei, M. Giannotta, G. Scarini, L. Cirignotta, A. ini ologna

. – . Salvalaggio, F. Catellani, M. Anglani, M. Camagnolo, R. Manara, C. riani adova

. – . M. Roi, M. aoletti, . accini, A. Ferrero, S. arravicini, A. Gardani, A. Aaro, A. icieccio, A. erardinelli avia

. – . D. onviuto, E. Rio, F. Francini, A. uccitelli, A. irici, C. Grillo, L. aretta, F. Fiorentino Roma

. – . F. Magri, G. Manenti, R. rua, . Cicato, R. Del o, F. Fortunato, S. Lucciari, S. agliarani, D. iga, D. elardo, . Sanone, . Mongini, S. Gandoini, S. Corti, M. Moggio, G..Comi, D. Ronci Milano Lecco orino oiio arini

. – . M. eri, F. Fortunato, C. raanelli, . Rimei, R. Selvatici, D. gniene, S. igoni, S. Fini, E. erlii, D. Giacino, ML alentino, LM Roccetti, I. Donati, . liana, E. egoraro, A. ini, M. ane, F. Gualandi, A. Ferlini Ferrara iacena orino, raano ologna Ceena arma adova Roma

. – . D. Saatini, M. Aleander, S. ianello, A. Futo, . Merlo, M. illa, . angaro, F. De acale, G. Sorar, E. egoraro, L. ello adova irmingam AL, .S.A. adova

. – . M. accetti, C. Brusa, R. D’Alessandro, M. Bobbio, M. Spada, R. Turra, F. Ricci, T. Mongini, PEDINE oring grou orino

. – . Abnormal α . Donadio, . Doler, A. Inceni, A. uina, A. anen, . olmann, G. Rio, E. Antelmi, G. lai, C. Sommer, ertel, R. Liguori ologna Marurg, German

–

– C. Croci, P. Mandic, I. Meola, A. eroldi, E. Bellone, A. Accogli, C. Bruno, M. Pedeone, C. Minei, C. Fiorillo, P. aneri enoa Alessandria Milano

– . Casiglione, . Ricci, A. ooni, . Asrea, A. Rocci, F. Baldinoi, A. iannoni, C. Passino, M. Edin, . Siciliano Pisa

– – A. Perucci, . ispi, M. aribaldi, E. Frea, R. Massa, F. Moro, F.M. Sanorelli Roa Pisa

– S. Coi Piccinelli, B. Risi, E. Baldelli, N. Neccini, A. alagni, A. Padoani, R. Brugnoni, . Maggi, M. Filoso Brescia Milano

– – – C. Piscioa, D. Calabrese, . Sanoro, I. Traacere, F. Manganelli, .M. Fabrii, A. Scenone, T. Caallaro, M. randis, S. Preiali, I. Allegri, . Padua, C. Paaglia, A. uarone, P. alenino, S. Tozza, A. Mazzeo, M.C. Trapasso, F. Parazzini, G. Vita, D. Pareyson; for the Italian CMT Network Milano Napoli erona enoa Para Caanaro Messina

– C. Dosi, A. Rubegni, D. Cassandrini, A. Malandrini, . Maggi, F.M. Sanorelli Pisa Siena Milano

– S. Spolerao, F. Taioli, . anee, S. Roio, M. Ferrarini, . Roncari, . Canalupo, .M. Fabrii erona Pesceria del arda

– A. ooni, . Ricci, A. o ero, . Casiglione, . Cal, F. Baldinoi, A. Rocci, M. Edin, . Siciliano Pisa

– F. Taioli, .P. anee, M. Ferrarini, S. Tesi, T. Caallaro, .M. Fabrii erona Pesciera del arda

–

D. Cardellini, F. Taioli, M. Cappellari, M. Milan, . Berolasi, .M. Fabrii, T. Caallaro erona eneia

– M. Catteruccia, D. Diodato, F. Fattori, G. Colia, F. De Mitri, A. D’Amico, E. Berini Roa

– F. ragnani, F. ilio, R. Iulianella, I.F. Pesaloa, F. Corese, A.M. Cipriani, E.M. Pennisi Roa

– E. Panceri, . uglieli, . Nigro, S. Aurino, A. Torella, M. Malaesa, A. eore, A. iorgei, . Toelleri, P. Tonin, . aei erona Napoli

– M. Russo, . enile, . Di Bella, F. Minuoli, F. Cucinoa, . bici, R. Mussinelli, A. Toscano, . ia, A. Maeo Messina Paia

– R.Rossi, M.S. Falarano, M Pinoi, D Balesra, M. Neri, F. Forunao, E. Mercuri, M. Pane, F. ualandi, R. Selaici, A. Ferlini Ferrara Roa

– D. Seeri, S. Toa, E. Spina, M. Belloao, M. Nolano, . Sanoro, F. Manganelli Napoli

– S. Tripodi, . Bello, . Minerini, C. Reggiani, S. ianello, . Booni, . Cauo, P. Rigui, A. upi, C. Berolin, . Sorar, E. Pegoraro Padoa

– S.Toa, D. Seeri, P. rigone, A. eroldi, E. Bellone, P. Mandic, M. Nolano, . Sanoro, F. Manganelli Napoli enoa

–

– M. randis, . bici, . Ferrandes, D. Pareson, C. Briani, C. Danesino, M. Canepa, A. Maeo, . Treisan, S. Fenu, F. Cappelli, F. Pereo, . . Pradoo, F. Benediceni, .M. Fabrii, . Bisogni, M. uigei, P. Riessi, . Melciorri, . Tini, C. eelli, S. Toa, D. Seeri, P. Mandic enoa Paia Milano Padoa Messina Firene ggebbio erbania Bolano erona Roa Ferrara Napoli

– . aaro, . iui, . Merlo, . iaello, . ariai, . amaa, . auce, G. orar, . ello, E. eoraro adoa

– G. carii, M. Giaotta, F. atorelli, A. ii oloa

– C. Fiorillo, C. aicucci, . Doeroort, M. raero, . roda, . Falaerla, . alietro, C. Mietti Geoa

– F. iaci, C. imocii, G. icci, . eracoi, G. iciliao ia Milao

– . arraicii, A. Aaro, C. Cereda, A. oa, A. erardielli aia

– A. Palladino, Torella, R. Petillo, A. M. Scutifero, S. Morra, P. D’Ambrosio, L. Passamano, V. Nigro, L. olitao aoli

– F. orri, G. icci, C. imocii, . Aocia, G. Al, . Cico, D. Caadrii, Di Muio, G. iciliao ia Cieti

– . De aua, F. ia, . Aoi C. uarta, G. lai, . iuori oloa

–

– E. Frea, C. Gallui, G. Greco, . roerio, . Mauro, G. aicol, A. irola, E. Falcier, E. oma, A. aolii, A. iio C. iuori, F. lacidi, .A. aoe, . Maa oma Milao

– . Alerti, F. Cicciello, F. ia, G. Caaletti, M.E. Caaia Moa

– M. Garialdi, . Fioda, E. ucci, F. aoli, . eoardi, A. auletta, G. Alieri, G. Merloi, . Morio, M. eta, G. Atoii oma

– . astellani, S. Mariotto, M. amagnolo, S. errari, . riani Padoa Verona

– . Lai, . Sadoni, . Simoncini, . Ricci, . Siciliano Pisa

– V. Prada, . Maarino, A. Maeo, D. Pareson, L. Santoro, L. Padua, . abrii, A. Scenone and LNA grou . Poggi, L. Mori, M. randis, . emelli, L. entile, A. Tisano, . aallaro, . Pisciotta, M. Montesano, . Manganelli, S. Toa, . Aceto, D. Dellaentura, . Paaglia, . rra, D. oraci, T. aallaro, A. Peretti, L. Roncari enoa Messina Milano Naoli Roma Verona

– S. Lucciari, . Magri, .P. omi, M. Sciacco Milano

–

– A. Modenese, A. Picelli, N. Mattiu, . Panceri, N. Smania, . Vattemi, P. Tonin Verona

– A. Paracini, . Valasina, M. randis, M. lierio, A. Scenone, L. bici Paia

– . Sacc, S. erriAnin, .. laes, R. Mantegaa, . Murai, . agsa, . ousoulaou, M. Larin, T. Leigton, S. Paci Naoli Paris, rance Leuen, elgium Milano Narita, aan ford, nited ingdom ent, elgium

– . Saini, . Asteggiano, L.M. arina, .A.M. andini eeleringsott, S. astianello, A. erardinelli, A. Picieccio Paia London,

– . Torcia, M. Luccini, S. ortolani, M. Monforte, M. Mirabella, . Ricci, . Tasca Roma

– L. Serais, .. Da, D.. De Vio, . irscner, . Mercuri, . Muntoni, P.. Sie, . Tiano, . Desguerre, S. uianoRo, . Saito, M. Droege, . Dabbous, R. erbini, . aldinetti, A. Sa, . an, .A. Anderson, R.S. inel ford, nited ingdom Stanford, A, nited States Ne or,

N, nited States reiburg, erman Roma London, nited ingdom Los Angeles, A, nited States arcelona, Sain Paris, rance arces, rance Too, aan annocburn, L, nited States orcester, MA, nited States rlando, L, nited States

– P. Mantuano, . Sanarica, . aellari, . occanegra, N. Tarantino, . onte, M. De ellis, . M. amerino, S. Pierno, A. De Luca ari

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– . Terracciano, D. aino, P. mmoilli, . Terlii, D. uidetti Piacena

– M. eccanti, . ambieri, L. Libonati, . nesti, M. ngilleri Roma

– V. ooni, . Musso, L. aumo, L. ello, S. Triodi, P. Rigui, . ausin, . abrieli, . ester, . Sorar, M. Plebani, . Pegoraro Padoa

– R. Milani, D. Loe, A. uattrini, R. aio Milano

– P. D’Ambrosio, M.G. Esposito, S. Morra, A. Palladino, L. Passamano, R. Petillo, . Picillo, V. Torre, L. Politano Naoli

– . Pisciotta, . iafaloni , R. uccarino, D. alabrese, P. Saeri, S. enu, . Tramacere, . enoese, N. Dile, N.. onson, . eatole, D.N. errmann, D. Pareson, on bealf of te ATMT stud Milano Rocester, N, SA oa it, A, SA Arenano ologna Ricmond, VA, SA Rocester, N, SA

– R. rusa, . Magri, T. Difono, D. Velardo, S. orti, M. Moggio, M.. Saetti, .P. omi Milano

– . Trucco, M. Scoto, D. Ridout, D. . De Vio, . Darras, . ertini, . oratti, M. Main, A. Mae, . Montes, R. S. inel, . Mercuri, . Muntoni on bealf of te international SMA consortium iSMAc enoa London, Ne or, SA oston,MA, SA Roma Necastle, rlando, lorida, SA

–

– . mbiri, M. ti, . iboti, . iorii, . rs, E. sti, G. ii, M. iri om

– M.G. ispoi, . rri, M. Di Pitro, . Di Sto, A. Di Mio iti Prmo

– M. mpoo, M. iii, . ro, S. rrri, . P, G. ri, A. Sio, . sti, . mbo, . rii Po ro

– . rri, M.G. ispoi, . o, P. Ai, . Di Sto, A. Di Mio iti Prmo

–

– • . Msso • What’s new in the landscape of later onset SMA? M.. Pr

–

– . o, S. Mstro, . mo, P. ii, . ro, M. i, D. Sbbtii, A. sto, . Mro, S. io, E. Porro Po

– G. poito, . D Miis, M. rpo, . , E. Sirii, D. Sri, D. isii, D. riott, G. Siiio, . Mi, A. roio, E. po, P. tri, E. obirio, A. So, . tti, . obbio Go rmo Pis poi Pi Spi Mio oo M

– . ost, M.. oi, . ii, . Porro, . Mroo, . pi, . Aii, G. tti, S. Sti, G. i oo i

–

. ori, A. rii, A. soio, E. Gosi, M. itti, . io, . oi, S. Morio, M. Gribi, G. Atoii om

– roposal of new fnctional otor scales to ealate scle fatie in adlt SMA patients G. ii, A. Gooi, . orto, . ii, A. ori, . M, . iori, M. oi, G. omi, G. Siiio Pis Mio ri oo Ao

– alidation of a new and nction tcoe Measre in indiidals with harcotMarieooth . Pr, M. mi, G. obbio, G. M, A. Groi, A. pp, S. Msso, . rio, . Mori, E. o, P. Mi, M. Gris, A. So Go ori, A, SA

– roteoic profilin of cererospinal flid of nsinersentreated SMA patients M. Srmi, . ii, G.. it, . tri, . Poito, . tito, . i, E. Gitto, S. Mssi, . ii, M. Ao, G. it Mssi Si

– Mscle M as a noel otcoe easre of hereditar transthretin aloidosis a crosssectional cohort std E. i, A. orts, . rs, . Mssii, M. Potti, . Soo, . rr, A. o, . Diii, . Stii, S. stio, G. Mrii, G. Pii, . bii, A. Piiio Pi oo, or, SA Pi s, Sitr

– “nnoatie therapetic approaches”

– Ai therapetic atisiran in hA aloidosis tolerailit and anaeent fro two centre eperience . Gti, M. sso, M. itti, G. isoi, A. Di Potoio, A. omo, . Gimio, M. Sbti, A. oso, G. it, A. Mo Mssi om

– haracoloical chaperone to treat otonia conenita cased trafficindefectie l chloride channel tants proofofconcept with niflic acid . Atmr, E. ot, D. Sbi, G.M. mrio, . Giromo, M. rrt, P. mbrii, . Dsp ri

– notersen to treat hA polneropath tolerailit and anaeent fro two centre eperience M. itti, A. omo, A. Mo, A. Di Potoio, G. isoi, . Gimio, M. sso, . Gti, A. oso, G. it, M. Sbti om Mssi

A. Msr – M. Sri – . immrm – A. ors

–

– . oo, A. Pis, G. ioi, . ooio, A. oso Mssi

– S. otti Piii, . or, . isi, E. i , . ii, A. Gi, . io, A. Poi, M. iosto rsi Pi

– . ii, S. otti Piii, . ro, S. rrri, . isi, E. i, A. Poi, M. iosto rsi ro

– . isi, S. otti Piii, . or, E. i, . ii, A. Gi, . io, A. Poi, M. iosto rsi Pi

– M. omo, D. ori, S. otto, . Gsprotti, S. rrrsi, S. mto, E. mmrt, . P Prmo om rsi oio, Mio

– onset Krabbe’s disease: M. ipitr, . rso, D. Poo, S. rrri, . ro, G. tt, G.M. brii ro Psri Gr

– nnoatie strateies teraeti in se dstroies G. P. omi – danes in te treatent o ereditar aoidosis A. Mo – aenes in treatin : do e see dait D. Prso – e eraeti aroaes in E. Mrri e teraeti strateies in etaboi oaties . Msmi

– –

–

– oner aet and ia o atisiran: oba enabe tension ont ata in atients it ereditar ranstretinediated oidosis D. Ams, A. GoDrt, E. Mriio, . r, . oo, . ir, . Smit, A. Mo, E. rbr, M.. Stsr, M.. it, .. , M. Pois rmiitr, r Mio it, Mio soi, , SA or it, , SA Porto, Port m, S Mstr, Grm Mssi mbri, SA timor, SA

– art : ia and saet o risdia in inants it e sina sar atro G. ro, . Sris, . Msso, M. MriiBełdzińska, K. Rose, D. Vlodavets, H. Xiong, E. oti, M. Eiri, S. rstt, M. Grbr, . Gori, . t, . So, . . Drrs o b o t ES ori Grop Milano; London, UK; Liège, Belgium; Oxford, UK; Gdańsk, Po S, Astri Moso, ssi ii, i So Po, ri Gr it, s, Sitr osto, MA, SA

– stei ene ranser it rrK nreased βaroan ression in atients it ib irde sar stro e .. oiop, E.. Posi, S. is, D.A. Grii, A.S. Mos, P. oo, .. m, . r, .. Mir, M.A. mmrio, .P. os, .. M ombs, io, SA mbri, MA, SA

– ntraenos nasenoene bearoe inia eeoent roras in ina sar tro : nterated aet eort D. , .S. i, E. Mrri, . Msso, . Prsos, . rbii, . itti, A. , M. Mir, . Motomr, D.M. Spro, S.P. , D.E. tr, S. srisisi, .. M obr, , it Stts ro, , it Stts om Mio Aror, , it Stts ombs, , it Stts

– nraein obined intererene and ene tera in itro and in io disease odes as a otentia teraeti strate or . D Gioi, M. iro, S. oo, S. Si, . Mi, S. Piri, E. Abti, . rsoi, G. omi, S. orti, . io Mio

– estin a noe dasatinib oration in d ose ode: toards te rerosin o r trosine inase inibitors in enne sar dstro . Sri, P. Mto, . or, . ppri, E. ot, G.M. mrio, A. trii, . Dor, A. M, M. D is, A. D ri

– oner oo o nasenoene bearoe ene era in ina sar tro e ro ase ria .. M, . S, .. m, M. Mo, .P. os, .. Ao, .. Mir, M.A. mmrio, . r, . rbii, S.P. , .G. ri, . , D.M. Spro, M. Mriioi, D.E. tr, S. Ai ombs, , it Stts obr, , it Stts

– istoatooia eatres in abant atients it eer sar stro: reiinar data ro te iinostat tria oort D. ro, M. ipoo, . Mri, . rs, A. Gooi, S. i, . Pri, P. isto, S. otti, M. Sio, M. Moio, P. tti, G.P. omi Mio Pis oi

– art : ia and saet o risdia in atients it e or nonabant e sina sar atro E. Mrri, . risi, . osp, . Doi, A. ostrPrs, . Msso, E. Mo, A. simto, . Sito, D. ots, . irot, S. rstt, S. rr, M. Grbr, . Gori, . t, . Mrti, .. , .. D o b o t SS ori Grop om rb, roti Pris, r Gt, Gt rsss, im rs, Po Mio ro , Spi oo, p Moso, ssi o, r s, Sitr s, Sitr Gr it, Po Ato, A, SA

–

– reiab in a ase o rerator roni naator eeinatin oneroat it antibodies anti itiab S. srto, E. Siorio, . ossi, A. Di Pitro, io, S. oit, G. s poi

– dentiiation and arateriation o rinederied ste es s b te noe tenoo eetor M.S. ro, . Spito, A. Mrtti, . E Di, . ossi, S. i, P. sii, . o, A. Grii, S. iito, A. rii rrr oo Mo

– tationa roie in atients it antieinassoiated orotein antibod neroat identiies ne teraeti taret . sti, A. isti, M. mpoo, A. Sio, . iotto, . mbo, . Pi, . rti, . rtor, . rii Po

– artiiod in toine erosar iseases A. Gitt, P. rits, S. Smit, . mp, . r, . Prs ir, im

– sonated antisense neotides: a ne teraeti strate or ina sar tro stoati atients E. Piri, M. rsi, M. iti, A. oroi, D. Somo, . rsoi, GP. omi, S. orti, M. iro Mio

– enabe td o atisiran in atients it oidosis ostrtotoi ier ransant . oo, . Gimor, D. Ams, . Mom, A. Mo, . ir, . Ptor, . , S. Arm, .. , . i, . Smi Porto, Port oo, rmi itr, r , Spi Mssi m, S rti, r ro, Spi mbri, MA, SA Mstr, Grm

– nasenoene bearoe ene era in restoati ina sar tro: td date .A. Strss, M.A. rrr, .. Sobo, . Sito, .A. iribo, .S. i, S.. o, .M. rr, .M. o, .. MMi, . Sris, .. M, . Prsos, M. Soto, P.. Si, . im, . itti, M. St, S.P. , .G. ri, S. , D. , D.E. tr, S. srisisi, .E. MGi, D.M. Spro, . Mtoi Strsbr, PA, SA S, S, Astri MA, SA oo, p or, , SA ro, , SA Ds, , SA Gr pis, M, SA Miso, , SA tt, , or, ombs, , SA Aror, , SA oo, os As, A, SA St. ois, M, SA obr, , SA

– onter iat o inotersen on neroat ait o ie o or ereditar transtretin aoidosis it oneroat : oenabe etension at ears . bii, A. o, . oo, A. rs, M. Poo, . Ms, . oio, . rm, S. , G.it, M. itor, M.. o Pi Porto, Port A rptis isbo, Port Port, ro, it Stts Pipi, PA, its Stts Mssi io iro, rsi

–

– riar inetion and a treatent oen estion eort o to ases and reie S. Diom, S. oi, S. rtii, S. rro, . ri, . Gisi, . Giii Si

– stei ene ranser it rrKirodstroin in atients it enne sar stro .. M, . S, . m, . s, .P. os, .. Mir, M.A. mmrio, .. Ao, . i, S. Ai, S. is, . r, . S, . Piro, .A. Pottr, D.A. Grii, E.. Posi, M. o, .. oiop ombs, io, SA mbri, MA, SA

– oe onitorin o dierent otoe easres drin dose adstent o intraenos inoobin in atients it roni inaator neroaties P.E. Do, D. Mi, . Gti, . Gi, G. ibrtor, . ri, M. i, E. obirio Mio

– ia o itiab in rerator astenia rais . io, .M. D Mrtio, M. P, M. Esposito, . btsr poi

– irst and seond ine treatent in roni inaator deeinatin oradioneroat in idren: ears eeriene o tertiar ediatri neroo entre . rsitti, . Pptti, M.A.. rii, . Moro, G. Sor, . io, M. rii om Abor, Dmr

– b taneos noobin in to atients aeted b ti erson sndroe: a oarison std it intraenos noobin . Doio, E. iccia, R. Rinaldi, G.M. Minicuci, R. D’Angelo, L. Bartolomei, R. Liguori (Bologna; i Miro oo

–

– ier se daae in atients it antiiositie deratoositis: a sine entre retrosetie oort . Giromo, M. orro, M. Giii, A. Amti, A. i, M. mpoi, D. Dbbio, . ooto, M. roo, . Sr, . o ri Strsbor, r

– tia te otorensitie ona eroat drin te eatitis irs inetion . D Ais, P. Gi, . Proi, S. oi, . Gisi, . ttisti, . Giii Si

– inioatooia eatres in atients it anti ineediated nerotiin oat: a sineenter eeriene M. Mri, D. ro,M.Mri, . Aroi, A. D os,. rs, M. Mri, . Mtito, . Pri, P. isto, S. orti, . it, M. Moio, M. Sio, G.P. omi Mio oi

– onter ronosis in iainarr ndroe and inia ariants: os on otor and ensor toe S.G. Gristi, . Dmiis, A. pp, . Pr, A. roio, . Dorio, A. So, . tti Go Assri Spi

– arateristis o ornea inneration in atients it astenia rais G. ioi, . oo, A. Pis, D. Motii, E. Postorio, S. Mssi, G. it, P. Aro, A. oso, . ooio Mssi

– ase o assoiated arneaeriabraia ariant o iainarr ndroe G. ibrtor, . D Stis, P.E. Do, . Gti, A. Abs, E. obirio Mio

–

– nti astenia rais resentin it ear redoinant et tries eaness assoiated it reersibe sar atro A. Raera, M. Barillari, D. aalli, . Romito (erona

– soated rania neroat assoiated it antioiid antibodies . etrelli, . Logullo (Macerata

– eriasar aroaes eressin and roote anioenesis in anti ine ediate nerotiin oat . Girolamo, M. ornaro, M. Giannini, L. oladonato, A. Amati, A. Lia, M. amoia, D. Daicco, R. amma, . Annee, M. rrede, D. irgintino, D. Riatti, M. roano, . annone, L. erlenga (Bari; traourg, rance

– ired asetri braia eoat: a desrition o a aseseries . eotti, L. aca, A. Gardani, . accini, . Rognone, M. aoletti, G. oentino, M. lumari, . ereda, A. Berardinelli (aia

– astenia rais and atent berosis netion ase eort M. ardaro, . lamati, . Aniello, M. uero, D. Liui, . Altomare, R. Leone R., D. Giorelli D., . Luciero (Barletta

– eort o an nsa orse o roni atai neroat it disiaos antibodies . cirini, . Merico, . imoncini, A. Gooni, A. Bacci, R. alaree, G. iciliano (ia

– naation in idren it erosar isorders and ee isordered reatin . rucco, . arruter, .. Daie, A. imond, A. Bu, . an (Genoa; London,

–

– ar nerosiooia abnoraities in iainarr ndroe: ear eeriene o erona enter A. Raera, . Romito, A. egatti, . oncon, L. Aleandrini, . Baaldella, A. Badari, . Arcaro, B. Bonetti, G. uintani (erona

– eere inaator oat in a onar arinoa atient treated it ebroiab: an aert or ooists D. elardo, L. eerelli, A. De Roa, . Domina, . icato, G. ita, M. ciacco, M. Moggio, G.. omi (Milano; Lodi

– errent ariant o ier iser ndroe: is a anionoat ase eort

M. ardaro, . lamati, . antoro, R. alaree, . Aniello, . Altomare, R. Leone, . Luciero (Barletta

– btaneos inoobins in astenia rais and anti ositis A. ua, . Demiceli, .G. Grianti, . aona, A. cenone, L. Benedetti, M. Grandi (Genoa

– idood roni naator eeinatin oradioneroat: ase eries A. oo, A. Ardione, . iano, R. Danti, . agliano, . Moroni (Milano

– ase o roressie steise asetria re otor neroat: erss otor . ronci, . Del arro, M. ilii, R. aio (Milano

–

– dianosti dea o ase o neroastrointestina eneaoat . Aruta, G. aaldo, . eloi, A. oino, M. Giauinto, . Romano, R. Rinaldi, . rimarco, . itale, L. Ruggiero (aoli; Aellino; Beneento; Bologna

– oiraate in aiatinnded eriera erotoiit: ore tan nerorotetion . Alerti, A. Malacrida, . emeroni, . Meregalli, . Ballarini, G. aaletti (Mona; Milano

– oeent disorders in idren it a itoondria disease: a rosssetiona sre ro te ationide taian oaboratie etor o itoondria iseases . icci, D. rucci, A. Ardione, . Bertini, . Bruno, . arelli, D. Diodato, A.M. Donati, M. iloto, . La Morgia, . Lamerti, D. Martinelli, . Minetti, M. Moggio, . Mongini, . Montano, . Moroni, . Muumeci, . egoraro, G.rimiano, . rocoio, A. Ruegni, M. ciacco, . eridei, G. iciliano, . imoncini, . onin, A. ocano, M. Mancuo, R. Battini, .M. antorelli (ia; Lucca; Milano; Roma; Genoa; Bologna; irene; Brecia; orino; Meina; adoa; erona

– ain te nerotoi eet o aiatin on dorsa root ania: ass setroetr iain iits aterations to te tisse roteoe . Ballarini, . Alerti, . aroi, . RodrigueMenende, A. mit, G. aaletti, . Magni (Mona

– ar onset rerrent se dsntion assoiated it noe tation A. aaliere, . Giertini, A. Ruggieri, . Blaeic, .R. Danti, L. Maggi, . Moroni (Milano

– ierent eets o oaiatin and isatin inbation on te eetrosiooia roerties o dierentiated es L. Mona, . atori, A. Beccetti, G aaletti, M. Lecci (Mona; Milano

– itoondria abnoraities it t sine deetion in assoiation it a ene raesit ariant: a ase reort

. imoncini, . Montano, G. Ricci, G. Ali, A. Logero, . Baldinotti, M. aligo, G. Lattani, G. enacci, A Barion, M. Mancuo, G. iciliano

–

– inia and eneti std in a atient it etra iid torae isease it oat . Baldelli, . otti iccinelli, B. Rii, . eccini, A. Galagni, A. adoani, M. iloto (Brecia

– nsa ase o otor and dsatonoi neroat de to ai intoiation A. etruelli, . eccio, L. Galliccio, . Reccia, L. Didonna, . Loreglio, G. De alma, . amma (Bari; Brecia

– et eneration seeninbased ene ane tests or te anaeent o dianosis o iid oaties E.M. Pennisi, F. Cortese, F. Gragnani, L. De Giglio, M. Garibaldi, A. D’amico, E. Bertini, F. Fattori (Roma

– ssessent o oaiatininded eriera nerotoiit in dierent ose odes . oi, A. anta, . ggioni, M. Boi, G. aaletti, . Marmiroli (Mona

– oeeoe seenin identiies reessie tations in a ne oen storae oat it retinitis ientosa . Muumeci, A. orella, M. aaree, . Rodolico, A. iranni, R. teri , . Del eccio Blanco, G. oito, . igro, A. ocano (Meina; aoli; auoli (A; elini, inland

– aation o se involvement in Acromegaly and Cushing’s syndrome L. Ruggiero, M.. De Martino, . ina, R. Duioo, . oa, . ionello, . imeoli, R. errigno, . Di aola, R. odice, L. antoro, R. ionello, . Manganelli (aoli

– aiia itoondria oat and rena aire de to biaei tations M. ciacco, M. Riolone, L. aoli, D. iga, D. elardo, . icato, M. Moggio, G.. omi, D. Ronci (Milano

– osano

– : “erin nerosar entities”

– iaei tations in sord ase a oon and otentia treatabe neroat A. ortee, . u, A. Reelo, . egri, . ourel, L. Areu, .. Bacon, . Bai, D.M. Bi Breer, . Bugiardini, . Buglo, M.. Dani, . M eel, A. A. ragouli, . A arid, R. ai, A. an, M. Laur, . Magri, M. ii, . iciotta, . oell, A. M. Roor, . oden, . oa, . androcoa, . Dallman, . Grignani, . Marcioni, .. cerer, B. ang, . Lin, A. AlAmi, R. cle, M. noi, . Maionoe, . tooic, M. AuerGrumac, M. A.

Abdelamed, .A. amed, . ang, F. Manganelli, L. antoro, P. aeri, F. aroni, D. Pareson, . olden, D.. errmann, M.M. eill, M.E. , G. ai, . cner Miami, Florida, A London, Paia oa Cit, oa, A Assit, Egt Milano ocester, , A aoli, tal Coral Gables, Florida, A Paia Piladelia, Pennslania A nan Proince, Cina Alara, ait bingen, German Paris, France ienna, Astria

– atural history course o related congenital centronuclear myoathy a retrosective multicentre talian tudy D. Diodato, M. Catterccia, L. Maggi, . Moroni, E. Pegoraro, P. igi, L. ggiero, M. Garibaldi, A. Berardinelli, M. Pane, G. Atrea, F. Santorelli, E. Bertini, A. D’Amico (Roma; Milano Padoa aoli Paia Pisa

– iallelic C eansion is a common cause o idioathic sensory neuroathy and ganglionoathy . Crr, A. alalaggio, . oa, C. Gemelli, . Domini, . Galassi Deorie, F. Castellani, E. egei, . Etmio, G. Cosentino, E. Alonsi, E. Marcioni, . Colnagi, EM. alente, C. assorelli, MM. eill, . olden, P. Mandic, E. Bellone, M. Grandis, A. cenone, L. antoro, F. Manganelli, C. Briani, A. Cortese Paia Padoa aoli Genoa London,

– mutations result in late onset mitochondrial myoathy ith altered muscle mtA homeostasis D. onci, L. Caorali, G. Manenti, M. Meneri, . Moamed, M. Contin, D. Piga, . Mancinelli, . Corti, M. ciacco, . Carelli, G.P. Comi Milano Bologna

– euromuscular sarcoidosis single center eerience in consecutive atients B. Labella, F. Cinetto, . cara, . Manara, E. Pegoraro, C. Agostini, C. Briani Padoa reiso

: euromuscular eerts atients and Associations

: : – araneolastic neuroathies . Ferrari – resynatic araneolastic disorders o the neuromuscular unction an udate . Ligori – araneolastic disorders o seletal muscles C. odolico

– : “Current theraies in neuromuscular disorders “

– uular Aggregate yoathy caused y activating mutation in a unctional study in myolasts and myotues deriving rom aected atients toard the identiication o ne theraeutic targets E. onte, G.M. amerino, A. Pannnio, M. olccia, M. Mora, . Mai, . aellari, A. De ca, P. mbrici, A. iantonio (Bari; Milano

– An talian ataase to assess the diagnosis athogenesis and eect o theray in ultiocal otor euroathy and its variants a rosective collaorative study P.E. Donedd, D. ocito, A. Maeo, . Benedetti,M. ietti, Faio, . Briani, G. Siciliano, M.Filoto, G. Antonini, G. oentino, R. F. Mananelli, M. nilleri, M. aro, G.A. Maria, G.M Minicci, . Gentile, E. Peci, A. Scenone,M. Sabatelli, ronci, M. amanolo, Scirini E, G. iberatore, E. obileraio or te MM Std Gro (Milano; orino; Meina; Genoa; a Seia; Roma; Padoa; Pia; Brecia; aoli; Roma; Beramo; reilio; icena

– usinersen saety and eects on motor unction in adult sinal muscular atrohy tye and . Mai, . Bello, S. Bonanno, A. Gooni, M. Grandi, . Paamano, F. roi, F. erri, . Booni, . amo, R. Pira, R. anel, E. Saccani, M. Meneri, . acciano, G. Ricci, E. D’Errico, S. Bortolani, R. Zanin, L. Politano, A. Schenone, S. Previtali, A. Berardinelli, M. rri, . erriello, M. occia, R. iori, M. Filoto, G. Marro, G. Siciliano, .. Simone, . Monini, G.P. omi, E. Peoraro (Milano; Padoa; Pia; Genoa; aoli; aliari; rento; Parma; Bolona; Bari; orino; Paia; Bolano; dine; Ancona; Brecia

– esonse to treatment and outcome in late versus early onset F. Paalin, S.. Gidoni, M. Ermani, E. Peoraro, D.M. Boniati (reia; Padoa

– hort and longterm eicacy o lenalidomide theray in atients ith syndrome F. ereni, F. Gentile, F. Gallia, P.E. Donedd, R. Maa, M. Ri, A. oa, E. obileraio (Milano; Paia

– : “New perspectives for Myotubular ” – clinical sectrum eidemiology atis tudy A. D’Amico – istoathology o centronuclear myoathies . o – ene theray .

– : “isimmune and inlammatory neuromuscular disorders”

– mmunemediated necrotiing myoathies clinicalserological eatures o a large talian cohort o atients . oo . ccii . ci . o ii . D oo A. ii . mi . ii . o A. i . io . icci . ioio . mi . iciio . ooico . ioo . ii . oo . ii . oi . Aoii . . i . i io om o i o o i oi i

– erum attern o metalloroteinases and and tissue inhiitors in atients ith chronic inlammatory demyelinating olyneuroathy . oio . Di o . o . Aoi . oi . ii . io . imi i mo

– uscle maniestations and C levels in C inection results o a large cohort o atients inside a andemic C Area A. D o . icci i .o . . iciio . oo A. o i io

– uillainarr yndrome and C an oservational multicenter study rom omardy and eneto taly . oi iccii . i . oi . ii . i . . oio . cioi . i . ii . i . . ici . D o . io . iii . i . ii . mii A. . oi A. omo . io . coii . o A. . ii . . Do . i .. oi .. ii . i . oi . ii . ioi . . oio . D i . io . oi . o . oico . oiio A. oi A. cii . ioo ci mo i o io iio o i mo iic

– uscle indings and correlation ith clinical and immunological arameters in a cohort o atients

. io . oi . oi . Aoo . Di . oi . oio . cci . Aii A. . Aoii . ii om co i

– .. Do D. ocio . i . io . ii . ioo . i . ici . A. o . Aoii . oio .A. i A. o A.. ici . o A. co . iciio . ii . i . oo . i . i . io . oo . i . ci . oci . i . oi iccii .. i . i . oi . i . iccoo . oiio o o i D D o io oio oi o ci o i om i iio i io o

– . io . i D. ocio . io . ii . ioo . i . Aoii . oio . A. o A. o . A. i A. . ici . iciio . o . ii . i . oo . i . . Do . oo . ci . oci . i . oi iccii A. co . oi A. oco . iccoo . i . oiio io oi oio o ci o i om mo i i oo i iio io o

– . i . o . . Do D. ocio . io . ii . ioo . i . i . A. o . Aoii . oio . A. i A. o A.. ici . o A. co . iciio . ii . i . oo . io . ci . oci . i . oi iccii . icci i . i . oi . i . i . oo . oiio oi oio io o ci o o i om i iio i io

ausa

orsop: New terapeutic frotiers i ysiue iseases of uscle NM uctio a periperal erve isorers – induced worsening in myasthenia gravis” A. oi – . i – . i

ral couicatios : “ ”

ongterm oow u in resymtomatic atients n taian euromuscuar enters erience . mci . ii . oii . i .. omi . oi. oi . Aoii . ii . o . iciio . cicc . icci . A. i . . ii . icci A. oco i om oio i io i oi erihera ervous ystem toicity induced y immunechecoint inhiitors in cancer atients singe centre eerience . occi . . Dii . ici . ci . A. . Di icomo . io . iii i

inica athoogica and rognostic heterogeneity in immunechecoint inhiitorsinduced myositis . occi . oi . Dii . ii . A.. Di icomo . io . iii i

euroiament ight chain a ossie serum iomarer or aona damage in chemotherayinduced erihera neurotoicity rat modes . mi A. ioi . oi . o . . i . mioi o oo

inica aoratory and theraeutic oowu o arge cohort o ate nset ome isease atients a singe entre eerience A. i . icoci . i A. ii . i . ooico . i . mci A. oco i

rsenic rioideinduced erihera neuroathy rosective evauation in a cohort o atients with acute romyeocytic euemia . moo . i . cciii . i A. io . i . ii o

iid comosition o ceuar memranes in eutra iid torage isease tye a ossie roe in etioogy o disease .. ii D. i .. o . Diio . . o .i . ioo . o .ii .ii .Aii .m A.co om io ci i

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Manuscripts are examined by the editorial staff and usually evaluated by expert reviewers assigned by the editors. Both clinical and basic articles will also be subject to statistical review, when appropriate. Provisional or final acceptance is based on originality, scientific content, and topical balance of the journal. Decisions are communicated by email, generally within eight weeks. All rebuttals must be submitted in writing to the editorial office.

Starting from 2020, a publication fee of 200 Euros is required. The Corresponding Author must fill in the appropriate form and send it with the corrected proofs. 50% off is offered for members of Associazione Italiana di Miologia (AIM) and/or Mediterranean Society of Myology (MSM) in good standing with dues. A copy of the payment receipt for the current year is mandatory to prove the membership).

On-line submission Manuscript submission must be effected on line: www.actamyologica.it according to the following categories: Original articles (maximum 5000 words, 8 figures or tables). A structured abstract of no more than 250 words should be included. Reviews, Editorials (maximum 4000 words for Reviews and 1600 words for Editorials). These are usually commissioned by the Editors. Before spontaneously writing an Editorial or Review, it is advisable to contact the Editor to make sure that an article on the same or similar topic is not already in preparation. Case Reports, Scientific Letters (maximum 1500 words, 10 references, 3 figures or tables, maximum 5 authors). A summary of 150 words may be included. Letters to the Editor (maximum 600 words, 5 references). Letters commenting upon papers published in the journal during the previous year or concerning news in the myologic, cardio-myologic or neuro-myologic field, will be welcome. All Authors must sign the letter. Rapid Reports (maximum 400 words, 5 references, 2 figures or tables). A letter should be included explaining why the author considers the paper justifies rapid processing. Lectura. Invited formal discourse as a method of instruction. The structure will be suggested by the Editor. Congress Proceedings either in the form of Selected Abstracts or Proceedings will be taken into consideration. lnformation concerning new books, congresses and symposia, will be published if conforming to the policy of the Journal. The manuscripts should be arranged as follows: 1) Title, authors, address institution, address for correspondence; 2) Repeat title, abstract, key words; 3) Text; 4) References; 5) Legends; 6) Figures or tables. Pages should be numbered (title page as page 1). Title page. The AA are invited to check it represents the content of the paper and is not misleading. A short running title is also suggested. Key words. Supply up to six key words. Wherever possible, use terms from Index Medicus – Medical Subject Headings. Text. Only international SI units and symbols must be used in the text. Tables and figures should be cited in numerical order as first mentioned in the text. Patients must be identified by numbers not initials. Illustrations. Figures should be sent in .jpeg or .tiff format. Legends should be typed double-spaced and numbered with Arabic numerals corresponding to the illustrations. When symbols, arrows, numbers, or letters are used to identify parts of the illustrations, each should be explained clearly in the legend. For photomicrographs, the internal scale markers should be defined and the methods of staining should be given. If the figure has been previously published a credit line should be included and permission in writing to reproduce should be supplied. Color photographs can be accepted for publication, the cost to be covered by the authors. Patients in photographs are not to be recognisable Tables. Tables should be self-explanatory, double spaced on separate sheets with the table number and title above the table and explanatory notes below. Arabic numbers should be used for tables and correspond with the order in which the table is first mentioned in the text. References. Indicate all Authors, from 3 to 5. If their number is greater than 5, indicate only the first 3, followed by “et al.”. Arabic numbers in the text must be in brackets. References in the list must be numbered as they appear in the text, with the reference number superscript. DOI number must be included with each reference (when available). If not available, indicate the PMID number. Examples of the correct format for citation of references: Journal articles: Shapiro AMJ, Lakey JRT, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230-8. doi.org/10.14639/0392-100X-1583 Books and other monographs: Dubowitz V. Muscle disorders in childhood. London: WB Saunders Company Ltd; 1978. Please check each item of the following checklist before mailing: • Three-six index terms, short title for running head (no more than 40 letter spaces) on the title page. Name(s) of the author(s) in full, name(s) of institution(s) in the original language, address for correspondence with email address on the second page. • Summary (maximum 250 words). • References, tables and figures cited consecutively as they appear in the text. • Figures submitted actual size for publication (i.e., 1 column wide or 2 columns wide). • Copyright assignment and authorship responsibility signed (with date) by all Authors. • References prepared according to instructions. • English style. • Patients in photographs not recognisable.

171 V. Nigro, President H. Topaloglu, Past President L.T. Middleton, G. Siciliano, Vice Presidents K. Christodoulou, Secretary L. Politano, Treasurer

Cardiomiologia e Genetica Medica, Primo Policlinico, piazza Miraglia, 80138 Napoli, Italy 5665101 [email protected] • [email protected]

* Amount payable: 1 year Euro 100 2 years Euro 180

I enclose cheque made payable to MSM q I enclose copy of the bank transfer to:

Bank name: Intesa San Paolo Bank address: via Toledo 177/178 Account holder: MSM-Mediterranean Society of Myology IBAN code: IT36 F030 6909 6061 0000 0160 879 BIC/SWIFT code (for foreign countries): BCITITMM