Publications by authors named "Jean-Yves Hogrel"

125 Publications

North Star Ambulatory Assessment changes in ambulant Duchenne boys amenable to skip exons 44, 45, 51, and 53: A 3 year follow up.

PLoS One 2021 25;16(6):e0253882. Epub 2021 Jun 25.

Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, Rome, Italy.

Introduction: The aim of this study was to report 36-month longitudinal changes using the North Star Ambulatory Assessment (NSAA) in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53.

Materials And Methods: We included 101 patients, 34 had deletions amenable to skip exon 44, 25 exon 45, 19 exon 51, and 28 exon 53, not recruited in any ongoing clinical trials. Five patients were counted to skip exon 51 and 53 since they had a single deletion of exon 52.

Results: The difference between subgroups (skip 44, 45, 51 and 53) was significant at 12 (p = 0.043), 24 (p = 0.005) and 36 months (p≤0.001).

Discussion: Mutations amenable to skip exons 53 and 51 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had higher scores both at baseline and at follow up.

Conclusion: Our results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253882PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232423PMC
June 2021

Still seeking the holy grail of outcome measures in inclusion body myositis.

Authors:
Jean-Yves Hogrel

J Neurol Neurosurg Psychiatry 2021 Apr 13. Epub 2021 Apr 13.

Neuromuscular Investigation Center, Institute of Myology, Paris, France

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http://dx.doi.org/10.1136/jnnp-2021-326460DOI Listing
April 2021

E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases. Report from the 1st eNMD Congress: Nice, France, March 22-23, 2019.

J Neuromuscul Dis 2021 ;8(4):743-754

Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice, Peripheral Nervous System and Muscle Department, Rare Neuromuscular Disease Reference Center, ERN-Euro-NMD, Nice, France.

By definition, neuromuscular diseases are rare and fluctuating in terms of symptoms; patients are often lately diagnosed, do not have enough information to understand their condition and be proactive in their management. Usually, insufficient resources or services are available, leading to patients' social burden. From a medical perspective, the rarity of such diseases leads to the unfamiliarity of the medical staff and caregiver and an absence of consensus in disease assessment, treatment, and management. Innovations have to be developed in response to patients' and physicians' unmet needs.It is vital to improve several aspects of patients' quality of life with a better comprehension of their disease, simplify their management and follow-up, help their caregiver, and reduce the social and economic burden for living with a rare debilitating disease. Database construction regrouping patients' data and symptoms according to specific country registration on data privacy will be critical in establishing a clear consensus on neuromuscular disease treatment.Clinicians also need technological innovations to help them recognize neuromuscular diseases, find the best therapeutic approach based on medical consensus, and tools to follow patients' states regularly. Diagnosis also has to be improved by implementing automated systems to analyze a considerable amount of data, representing a significant step forward to accelerate the diagnosis and the patients' follow up. Further, the development of new tools able to precisely measure specific outcomes reliably is of the matter of importance in clinical trials to assess the efficacy of a newly developed compound.In this context, creation of an expert community is essential to communicate and share ideas. To this end, 97 clinicians, healthcare professionals, researchers, and representatives of private companies from 9 different countries met to discuss the new perspective and challenges to develop and implement innovative tools in the field of neuromuscular diseases.
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http://dx.doi.org/10.3233/JND-210655DOI Listing
January 2021

Free-Living Physical Activity and Sedentary Behaviour in Autoimmune Myasthenia Gravis: A Cross-Sectional Study.

J Neuromuscul Dis 2021 ;8(4):689-697

Bioingénierie, Tissus et Neuroplasticité, EA Université Paris-Est Créteil, Créteil, France.

Background: Muscle weakness and fatigability, the prominent symptoms of autoimmune myasthenia gravis (MG), negatively impact daily function and quality of life (QoL). It is currently unclear as to what extent symptoms limit activity and whether physical activity (PA) behaviours are associated with reduced QoL.

Objectives: This study aimed to describe habitual PA patterns and explore relationships between PA metrics, clinical MG characteristics, and health-related QoL (HRQoL).

Methods: PA data from a tri-axial trunk accelerometer worn for seven days, was collected from females with generalized, stable MG and compared to control subjects. MG-specific evaluations, the six-minute walk test and knee extension strength were assessed in individuals with MG (IwMG). Mann-Whitney tests were used to study between-group differences. Spearman rank correlation coefficient was performed to explore relationships between variables.

Results: Thirty-three IwMG (mean (SD) age 45 (11) years) and 66 control subjects were included. IwMG perform less vigorous-intensity PA than control subjects (p = 0.001), spend more time sedentary (p = 0.02) and engage in less and shorter durations of moderate-vigorous-intensity PA (MVPA). For IwMG, habitual PA correlated positively with 6 min walking distance (rho = 0.387, p = 0.029) and negatively with body mass index (rho = -0.407, p = 0.019). We did not find any association between PA or sedentary behaviour and; HRQoL, symptom severity nor lower limb strength.

Conclusions: Individuals with stable MG perform less PA, at lower intensities, and are more inactive than control individuals. Further research is warranted to understand factors influencing PA patterns in MG and whether interventions could be successful in increasing PA quantity and intensity in IwMG.
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http://dx.doi.org/10.3233/JND-210637DOI Listing
January 2021

A novel PHKA1 mutation associating myopathy and cognitive impairment: Expanding the spectrum of phosphorylase kinase b (PhK) deficiency.

J Neurol Sci 2021 May 18;424:117391. Epub 2021 Mar 18.

APHP-GH Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, Myology Institute, Paris, France. Electronic address:

Muscle phosphorylase kinase b deficiency (PhK) is a rare disorder of glycogen metabolism characterized by exercise-induced myalgia and cramps, myoglobinuria and progressive muscle weakness. PhK deficiency is due to mutations in the PHKA1 gene inherited in an X-linked manner and is associated to glycogenosis type VIII (GSD VIII also called GSD IXd). PHKA1 gene codes for the αM subunit of the PhK, a multimeric protein complex responsible for the control of glycogen breakdown in muscle. Until now, few patients have been reported with X-linked recessive muscle PhK deficiency due to PHKA1 mutations. All reported patients presented with exercise intolerance and mild myopathy and one of them had cognitive impairment, leading to speculate about a central nervous system involvement in GSD VIII. Here we report in a sibling a novel mutation in the PHKA1 gene associated with a progressive myopathy, exercise intolerance, muscle hypertrophy and cognitive impairment as an associated feature. This report expands the genetic and clinical spectrum of the extremely rare PHKA1-related PhK deficiency and presents new evidences about its involvement in brain development.
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http://dx.doi.org/10.1016/j.jns.2021.117391DOI Listing
May 2021

Reply to 'Letter to the editor: is maximal diaphragm tissue velocity suited for the assessment of diaphragm contractility?'

J Physiol 2021 04 18;599(8):2343-2344. Epub 2021 Mar 18.

Laboratoire de Physiologie et Evaluation Neuromusculaire, Institut de Myologie, Paris, France.

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http://dx.doi.org/10.1113/JP281433DOI Listing
April 2021

Assessing Dysferlinopathy Patients Over Three Years With a New Motor Scale.

Ann Neurol 2021 05 26;89(5):967-978. Epub 2021 Feb 26.

Department of Neurology Children's National Health System, Washington, DC.

Objective: Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD.

Methods: We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories.

Results: The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline.

Interpretation: The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967-978.
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http://dx.doi.org/10.1002/ana.26044DOI Listing
May 2021

Development of new outcome measures for adult SMA type III and IV: a multimodal longitudinal study.

J Neurol 2021 May 2;268(5):1792-1802. Epub 2021 Jan 2.

Laboratoire D'Imagerie Biomédicale, Sorbonne Université, CNRS, INSERM, Paris, France.

Objective: The aim of this study was the comprehensive characterisation of longitudinal clinical, electrophysiological and neuroimaging measures in type III and IV adult spinal muscular atrophy (SMA) with a view to propose objective monitoring markers for future clinical trials.

Methods: Fourteen type III or IV SMA patients underwent standardised assessments including muscle strength testing, functional evaluation (SMAFRS and MFM), MUNIX (abductor pollicis brevis, APB; abductor digiti minimi, ADM; deltoid; tibialis anterior, TA; trapezius) and quantitative cervical spinal cord MRI to appraise segmental grey and white matter atrophy. Patients underwent a follow-up assessment with the same protocol 24 months later. Longitudinal comparisons were conducted using the Wilcoxon-test for matched data. Responsiveness was estimated using standardized response means (SRM) and a composite score was generated based on the three most significant variables.

Results: Significant functional decline was observed based on SMAFRS (p = 0.019), pinch and knee flexion strength (p = 0.030 and 0.027), MUNIX and MUSIX value in the ADM (p = 0.0006 and 0.043) and in TA muscle (p = 0.025). No significant differences were observed based on cervical MRI measures. A significant reduction was detected in the composite score (p = 0.0005, SRM = -1.52), which was the most responsive variable and required a smaller number of patients than single variables in the estimation of sample size for clinical trials.

Conclusions: Quantitative strength testing, SMAFRS and MUNIX readily capture disease progression in adult SMA patients. Composite multimodal scores increase predictive value and may reduce sample size requirements in clinical trials.
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http://dx.doi.org/10.1007/s00415-020-10332-5DOI Listing
May 2021

Lean regional muscle volume estimates using explanatory bioelectrical models in healthy subjects and patients with muscle wasting.

J Cachexia Sarcopenia Muscle 2021 02 29;12(1):39-51. Epub 2020 Dec 29.

Institute of Myology, Neuromuscular Investigation Center, Neuromuscular Physiology and Evaluation Laboratory, Paris, France.

Background: The availability of non-invasive, accessible, and reliable methods for estimating regional skeletal muscle volume is paramount in conditions involving primary and/or secondary muscle wasting. This work aimed at (i) optimizing serial bioelectrical impedance analysis (S ) by computing a conductivity constant based on quantitative magnetic resonance imaging (MRI) data and (ii) investigating the potential of S for estimating lean regional thigh muscle volume in patients with severe muscle disorders.

Methods: Twenty healthy participants with variable body mass index and 20 patients with idiopathic inflammatory myopathies underwent quantitative MRI. Anatomical images and fat fraction maps were acquired in thighs. After manual muscle segmentation, lean thigh muscle volume (lV ) was computed. Subsequently, multifrequency (50 to 350 kHz) serial resistance profiles were acquired between current skin electrodes (i.e. ankle and hand) and voltage electrodes placed on the anterior thigh. In vivo values of the muscle electrical conductivity constant were computed using data from S and MRI gathered in the right thigh of 10 healthy participants. Lean muscle volume (lV ) was derived from S measurements using this newly computed constant. Between-day reproducibility of lV was studied in six healthy participants.

Results: Electrical conductivity constant values ranged from 0.82 S/m at 50 kHz to 1.16 S/m at 350 kHz. The absolute percentage difference between lV and lV was greater at frequencies >270 kHz (P < 0.0001). The standard error of measurement and the intra-class correlation coefficient for lV computed from measurements performed at 155 kHz (i.e. frequency with minimal difference) against lV were 6.1% and 0.95 in healthy participants and 9.4% and 0.93 in patients, respectively. Between-day reproducibility of lV was as follows: standard error of measurement = 4.6% (95% confidence interval [3.2, 7.8] %), intra-class correlation coefficient = 0.98 (95% confidence interval [0.95, 0.99]).

Conclusions: These findings demonstrate a strong agreement of lean muscle volume estimated using S against quantitative MRI in humans, including in patients with severe muscle wasting and fatty degeneration. S shows promises for non-invasive, fast, and accessible estimation and follow-up of lean regional skeletal muscle volume for transversal and longitudinal studies.
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http://dx.doi.org/10.1002/jcsm.12656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890267PMC
February 2021

Natural history of Type 2 and 3 spinal muscular atrophy: 2-year NatHis-SMA study.

Ann Clin Transl Neurol 2021 02 24;8(2):359-373. Epub 2020 Dec 24.

Institute of Myology, GH Pitié Salpêtrière, Paris, France.

Objective: To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials.

Methods: Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease-modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo ), quantitative magnetic resonance imaging (fat fraction [FF ] mapping and contractile cross-sectional area [C-CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels.

Results: MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FF increased over 12 and 24 months, although not with statistical significance. A significant increase in C-CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months.

Interpretation: These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months.
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http://dx.doi.org/10.1002/acn3.51281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886049PMC
February 2021

Ultrasound shear wave elastography for assessing diaphragm function in mechanically ventilated patients: a breath-by-breath analysis.

Crit Care 2020 11 27;24(1):669. Epub 2020 Nov 27.

Sorbonne Université, INSERM, UMRS1158 Neurophysiologie respiratoire expérimentale et clinique, Paris, France.

Background: Diaphragm dysfunction is highly prevalent in mechanically ventilated patients. Recent work showed that changes in diaphragm shear modulus (ΔSMdi) assessed using ultrasound shear wave elastography (SWE) are strongly related to changes in Pdi (ΔPdi) in healthy subjects. The aims of this study were to investigate the relationship between ΔSMdi and ΔPdi in mechanically ventilated patients, and whether ΔSMdi is responsive to change in respiratory load when varying the ventilator settings.

Methods: A prospective, monocentric study was conducted in a 15-bed ICU. Patients were included if they met the readiness-to-wean criteria. Pdi was continuously monitored using a double-balloon feeding catheter orally introduced. The zone of apposition of the right hemidiaphragm was imaged using a linear transducer (SL10-2, Aixplorer, Supersonic Imagine, France). Ultrasound recordings were performed under various pressure support settings and during a spontaneous breathing trial (SBT). A breath-by-breath analysis was performed, allowing the direct comparison between ΔPdi and ΔSMdi. Pearson's correlation coefficients (r) were used to investigate within-individual relationships between variables, and repeated measure correlations (R) were used for determining overall relationships between variables. Linear mixed models were used to compare breathing indices across the conditions of ventilation.

Results: Thirty patients were included and 930 respiratory cycles were analyzed. Twenty-five were considered for the analysis. A significant correlation was found between ΔPdi and ΔSMdi (R = 0.45, 95% CIs [0.35 0.54], p < 0.001). Individual correlation displays a significant correlation in 8 patients out of 25 (r = 0.55-0.86, all p < 0.05, versus r = - 0.43-0.52, all p > 0.06). Changing the condition of ventilation similarly affected ΔPdi and ΔSMdi. Patients in which ΔPdi-ΔSMdi correlation was non-significant had a faster respiratory rate as compared to that of patient with a significant ΔPdi-ΔSMdi relationship (median (Q1-Q3), 25 (18-33) vs. 21 (15-26) breaths.min, respectively).

Conclusions: We demonstrate that ultrasound SWE may be a promising surrogate to Pdi in mechanically ventilated patients. Respiratory rate appears to negatively impact SMdi measurement. Technological developments are needed to generalize this method in tachypneic patients.

Trial Registration: NCT03832231 .
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http://dx.doi.org/10.1186/s13054-020-03338-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695240PMC
November 2020

Ultrafast ultrasound coupled with cervical magnetic stimulation for non-invasive and non-volitional assessment of diaphragm contractility.

J Physiol 2020 12 20;598(24):5627-5638. Epub 2020 Oct 20.

Laboratoire de Physiologie et Evaluation Neuromusculaire, Institut de Myologie, Paris, France.

Key Points: Twitch transdiaphragmatic pressure elicited by cervical magnetic stimulation of the phrenic nerves is a fully non-volitional method for assessing diaphragm contractility in humans, yet it requires invasive procedures such as oesophageal and gastric catheter balloons.  Ultrafast ultrasound enables a very high frame rate allowing the capture of transient events, such as muscle contraction elicited by nerve stimulation (twitch). Whether indices derived from ultrafast ultrasound can be used as an alternative to the invasive measurement of twitch transdiaphragmatic pressure is unknown.  Our findings demonstrate that maximal diaphragm tissue velocity assessed using ultrafast ultrasound following cervical magnetic stimulation is reliable, sensitive to change in cervical magnetic stimulation intensity, and correlates to twitch transdiaphragmatic pressure.  This approach provides a novel fully non-invasive and non-volitional tool for the assessment of diaphragm contractility in humans.

Abstract: Measuring twitch transdiaphragmatic pressure (P ) elicited by cervical magnetic stimulation (CMS) is considered as a reference method for the standardized evaluation of diaphragm function. Yet, the measurement of P requires invasive oesophageal and gastric catheter-balloons. Ultrafast ultrasound is a non-invasive imaging technique enabling frame rates high enough to capture transient events such as evoked muscle contractions. This study investigated relationships between indices derived from ultrafast ultrasound and P , and how these indices might be used to estimate P . CMS was performed in 13 healthy volunteers from 30% to 100% of maximal stimulator intensity in units of 10% in a randomized order. P was measured and the right hemidiaphragm was imaged using a custom ultrafast ultrasound sequence with 1 kHz framerate. Maximal diaphragm axial velocity (V , ) and diaphragm thickening fraction (TF ) were computed. Intra-session reliability was assessed. Repeated-measures correlation (R) and Spearman correlation coefficients (ρ) were used to assess relationships between variables. Intra-session reliability was strong for P and V and moderate for TF . V correlated with P in all subjects (0.64 < ρ < 1.00, R = 0.75; all P < 0.05). TF correlated with P in eight subjects only (0.85 < ρ < 0.93, R = 0.69; all P < 0.05). Coupling ultrafast ultrasound and CMS shows promise for the non-invasive and fully non-volitional assessment of diaphragm contractility. This approach opens up the prospect of both diagnosis and follow-up of diaphragm contractility in clinical populations.
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http://dx.doi.org/10.1113/JP280457DOI Listing
December 2020

Relationship between change in physical activity and in clinical status in patients with idiopathic inflammatory myopathy: A prospective cohort study.

Semin Arthritis Rheum 2020 10 30;50(5):1140-1149. Epub 2020 Jun 30.

Department of Internal Medicine and Clinical Immunology and Inflammation-Immunopathology-Biotherapy Department (I2B), Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, East Paris Neuromuscular Diseases Reference Center, Inserm U974, Sorbonne Université, Paris 6, Paris, France; Institute of Myology, Neuromuscular Investigation Center, Pitié-Salpêtrière University Hospital, Paris, France.

Objective: This study aimed to investigate the relationship between changes in clinical status on daily life physical activity (PA) in patients with idiopathic inflammatory myopathy (IIM).

Methods: Patients with dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM) or overlap myositis (OM) who presented either a new-onset or relapsing IIM, stable disease on maintenance therapy or were undergoing immunosuppressant tapering were included. Patients were evaluated at inclusion (V0), and at two follow-up visits (V1, 94±12 days from V0; V2, 96±17 days from V1). The American College of Rheumatology/European League against Rheumatism (ACR/EULAR) response criteria was recorded. PA assessed using 14-days raw accelerometry data gathered using a wrist-worn accelerometer after each visit (mean daily Euclidean norm minus 1 g (ENMO) was computed).

Results: Fifty-five patients (16 OM, 27 IMNM and 12 DM) were included. At baseline, 67% of patients had an ENMO Z-score less than 1. At inclusion, ENMO mainly correlated with health assessment questionnaire score (HAQ, ρ=-0.51, p<0.01), manual muscle testing 8 (MMT8, ρ=0.42, p<0.01), creatinine level (ρ=0.41, p<0.01), and SF-36 physical functioning score (ρ=0.38, p<0.002). At follow-up, ENMO changes mainly correlated with changes in MMT8, HAQ, SF-36 fatigue, and depression score (all ρ>0.43, all p<0.001). Level of agreement between ACR/EULAR response criteria and changes in PA was 15, 45, and 90% for minimal (n = 13), moderate (n = 20), and major (n = 10) improvements, respectively.

Conclusion: Baseline PA levels and change in PA correlated with muscle strength and function, yet changes in PA were also influenced by psychological status. Only patients with major improvements on the ACR/EULAR criteria had significant increase in PA. Accelerometer may serve as an objective tool to define a clinically relevant real-life outcome.
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http://dx.doi.org/10.1016/j.semarthrit.2020.06.014DOI Listing
October 2020

Long-term benefit of enzyme replacement therapy with alglucosidase alfa in adults with Pompe disease: Prospective analysis from the French Pompe Registry.

J Inherit Metab Dis 2020 11 27;43(6):1219-1231. Epub 2020 Jul 27.

Centre de référence des maladies neuromusculaires Nord-Est-Ile de France, Service de Neurologie, CHU Raymond Poincaré, AP-HP, Garches, France.

Despite a wide clinical spectrum, the adult form of Pompe disease is the most common one, and represents more than 90% of diagnosed patients in France. Since the marketing of enzyme replacement therapy (alglucosidase alfa, Myozyme), all reports to date in adults demonstrated an improvement of the walking distance, and a trend toward stabilization of respiratory function, but the majority of these studies were less than 5 years of duration. We report here the findings from 158 treated patients included in the French Pompe Registry, who underwent regular clinical assessments based on commonly used standardized tests (6-minute walking test, MFM scale, sitting vital capacity, MIP and MEP). For longitudinal analyses, the linear mixed effects models were used to assess trends in primary endpoints over time under ERT. A two-phase model better described the changes in distance traveled in the 6-minute walk test and MFM. 6MWT showed an initial significant increase (1.4% ± 0.5/year) followed by a progressive decline (-2.3%/year), with a cut-off point at 2.2 years. A similar pattern was observed in total MFM score (6.6% ± 2.3/year followed by a - 1.1%/year decline after 0.5 years). A single-phase decline with a slope of -0.9 ± 0.1%/year (P < .001) was observed for FVC, and MEP remained stable over the all duration of follow-up. This study provides further evidence that ERT improves walking abilities and likely stabilizes respiratory function in adult patients with Pompe disease, with a ceiling effect for the 6MWT in the first 3 years of treatment.
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http://dx.doi.org/10.1002/jimd.12272DOI Listing
November 2020

Determinants of Performance in the Timed Up-and-Go and Six-Minute Walk Tests in Young and Old Healthy Adults.

J Clin Med 2020 May 21;9(5). Epub 2020 May 21.

Musculoskeletal Science and Sports Medicine, School of Healthcare Science, Manchester Metropolitan University, Manchester M1 5GD, UK.

The aim of this study was to assess associations between performance in the timed up-and-go (TUG) and six-minute walk distance (6MWD) with physiological characteristics in young and old healthy adults. Thereto, we determined TUG, 6MWD, normalised jump power, centre of pressure displacement during 1-leg standing, forced expiratory volume in 1 s, percentage of age-predicted maximal heart rate (HR%) and height in 419 healthy young (men: 23.5 ± 2.8 years, women: 23.2 ± 2.9 years) and old (men: 74.6 ± 3.2 years, women: 74.1 ± 3.2 years) adults. Normalised jump power explained 8% and 19% of TUG in young ( = 0.025) and older men ( < 0.001), respectively. When fat mass percentage and age were added to normalised jump power, 30% of TUG was explained in older men (R = 0.30, < 0.001 to 0.106). Appendicular lean muscle mass percentage (ALM%) and age were the best determinants of TUG for older women (R = 0.16, < 0.001 to 0.01). HR% explained 17-39% of 6MWD across all groups (R = 0.17 to 39, < 0.001). In conclusion, in men, jump power was a key determinant for TUG, while in old women only it was the ALM%. As HR% was the most important determinant of 6MWD, motivational bias needs to be considered in the interpretation of this test.
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http://dx.doi.org/10.3390/jcm9051561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290512PMC
May 2020

Normalized grip strength is a sensitive outcome measure through all stages of Duchenne muscular dystrophy.

J Neurol 2020 Jul 21;267(7):2022-2028. Epub 2020 Mar 21.

Centre de Référence Des Maladies Neuromusculaires, CHU de Liège, Liège, Belgium.

Objective: The main aim was to explore the changes in hand-grip strength in patients with Duchenne muscular dystrophy (DMD) aged 5-29 years. Secondary aims were to test the effect of mutation, ambulatory status and glucocorticoid use on grip strength and its changes over time and to compute the number of subjects needed for a clinical trial to stabilize grip strength.

Methods: The analysis was performed on data collected during five international natural history studies on a cohort of DMD patients. Two hundred and two patients with genetically proven DMD were pooled from five different natural history studies. Excepting 13 patients with only one visit, the mean duration of follow-up was 2.2 ± 1.6 years. A total of 977 measurement points were collected. Grip strength was measured on the dominant side with a high precision dynamometer. The analysis was performed using absolute values and normalized values expressed in percentage of predicted values for age.

Results: For absolute values, grip strength typically increased in ambulatory boys and decreased in non-ambulatory patients. However, when normalized, grip strength was already reduced at age 5 years and thereafter continued to fall away from normal values. The weaker the patients, the less strength they are prone to lose over again.

Interpretation: Grip strength constitutes a sensitive and continuous outcome measure that can be used across all stages of DMD. Its measurement is easy to standardized, can be used in ambulatory and non-ambulatory patients and does not present any floor or ceiling effect. It is thus attractive as an outcome measure in therapeutic trials.
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http://dx.doi.org/10.1007/s00415-020-09800-9DOI Listing
July 2020

Routine monitoring of isometric knee extension strength in patients with muscle impairments using a new portable device: cross-validation against a standard isokinetic dynamometer.

Physiol Meas 2020 02 5;41(1):015003. Epub 2020 Feb 5.

Institute of Myology, Neuromuscular Investigation Center, Pitié-Salpêtrière University Hospital, Paris, France. Author to whom any correspondence should be addressed.

Objective: Muscle strength is a critical clinical hallmark in both health and disease. The current study introduces a novel portable device prototype (MyoQuad) for assessing and monitoring maximal voluntary isometric knee extension torque (MVIT).

Approach: Fifty-six patients with inclusion body myositis were studied. Knee extension weakness is a key feature in this inflammatory muscle disease. Cross-validation with an isokinetic dynamometer (Biodex System 3 Pro) was performed. Between-day reproducibility and ability to monitor changes in muscle strength over time compared to the gold standard method as a reference, were also investigated.

Main Results: The measurement was feasible even in the weakest patients. Agreement between methods was excellent (standard error of measurement (SEM) was 3.8 Nm and intra-class correlation coefficient (ICC) was 0.973). Least significant difference (LSD) was 4.9 and 5.3 Nm for the MyoQuad and the Biodex, respectively Measurements using the MyoQuad exhibited excellent between-day reproducibility (SEM was 2.4 Nm and ICC was 0.989 versus 2.6 Nm and 0.988 using the Biodex). Changes in MVIT at 6 and 12 months were similar between methods (timepoint  ×  method interaction was not significant; all p   >  0.19); strength changes classified according to LSD at 6 and 12 months were consistent between methods (>70% consistent classification)).

Significance: The measurement of MVIT using the MyoQuad offers a cost-effective, portable and immediate alternative for the routine measurement of maximal voluntary isometric strength of the quadriceps. The MyoQuad offers a comfort and stability that cannot be provided by standard hand-held dynamometers. These results support quantitative muscle strength assessment using fixed yet flexible dynamometry within clinical routine and multicenter trials.
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http://dx.doi.org/10.1088/1361-6579/ab6b49DOI Listing
February 2020

An embryonic CaVβ1 isoform promotes muscle mass maintenance via GDF5 signaling in adult mouse.

Sci Transl Med 2019 11;11(517)

Sorbonne Université, Centre de Recherche en Myologie, UM76, INSERM U974, Institut de Myologie, F-75013, Paris, France.

Deciphering the mechanisms that govern skeletal muscle plasticity is essential to understand its pathophysiological processes, including age-related sarcopenia. The voltage-gated calcium channel CaV1.1 has a central role in excitation-contraction coupling (ECC), raising the possibility that it may also initiate the adaptive response to changes during muscle activity. Here, we revealed the existence of a gene transcription switch of the CaV1.1 β subunit (CaVβ1) that is dependent on the innervation state of the muscle in mice. In a mouse model of sciatic denervation, we showed increased expression of an embryonic isoform of the subunit that we called CaVβ1E. CaVβ1E boosts downstream growth differentiation factor 5 (GDF5) signaling to counteract muscle loss after denervation in mice. We further reported that aged mouse muscle expressed lower quantity of CaVβ1E compared with young muscle, displaying an altered GDF5-dependent response to denervation. Conversely, CaVβ1E overexpression improved mass wasting in aging muscle in mice by increasing GDF5 expression. We also identified the human CaVβ1E analogous and show a correlation between CaVβ1E expression in human muscles and age-related muscle mass decline. These results suggest that strategies targeting CaVβ1E or GDF5 might be effective in reducing muscle mass loss in aging.
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http://dx.doi.org/10.1126/scitranslmed.aaw1131DOI Listing
November 2019

Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease.

Neurology 2019 11 16;93(19):e1756-e1767. Epub 2019 Oct 16.

From the Departments of Neurology (L.H., E.B., P.A.v.D., N.A.M.E.v.d.B.) and Pediatrics (M.E.K., A.T.v.d.P.), Center for Lysosomal and Metabolic Diseases Erasmus MC, and Department of Biostatistics (D.R.), University Medical Center Rotterdam, Netherlands; Institute of Myology (J.-Y.H., B.P., N.T., A.C.), Pitié-Salpêtrière Hospital, Paris; Department of Neurology (P.L.), Nord/Est/Ile de France Neuromuscular Center, Raymond Poincaré Teaching Hospital, AP-HP, Garches; and INSERM U1179 (P.L.), END-ICAP, Université Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.

Objective: To determine the effects of 10 years of enzyme replacement therapy (ERT) in adult patients with Pompe disease, focusing on individual variability in treatment response.

Methods: In this prospective, multicenter cohort study, we studied 30 patients from the Netherlands and France who had started ERT during the only randomized placebo-controlled clinical trial with ERT in late-onset Pompe disease (NCT00158600) or its extension (NCT00455195) in 2005 to 2008. Main outcomes were walking ability (6-minute walk test [6MWT]), muscle strength (manual muscle testing using Medical Research Council [MRC] grading), and pulmonary function (forced vital capacity [FVC] in the upright and supine positions), assessed at 3- to 6-month intervals before and after the start of ERT. Data were analyzed with linear mixed-effects models for repeated measurements.

Results: Median follow-up duration on ERT was 9.8 years (interquartile range [IQR] 8.3-10.2 years). At the group level, baseline 6MWT was 49% of predicted (IQR 41%-60%) and had deteriorated by 22.2 percentage points (pp) at the 10-year treatment point ( < 0.001). Baseline FVC upright was 54% of predicted (IQR 47%-68%) and decreased by 11 pp over 10 years ( < 0.001). Effects of ERT on MRC sum score and FVC supine were similar. At the individual level, 93% of patients had initial benefit of ERT. Depending on the outcome measured, 35% to 63% of patients had a secondary decline after ≈3 to 5 years. Still, at 10 years of ERT, 52% had equal or better 6MWT and/or FVC upright compared to baseline.

Conclusions: The majority of patients with Pompe disease benefit from long-term ERT, but many patients experience some secondary decline after ≈3 to 5 years. Individual variation, however, is considerable.

Classification Of Evidence: This study provides Class IV evidence that for the majority of adults with Pompe disease, long-term ERT positively affects, or slows deterioration in, muscle strength, walking ability, and/or pulmonary function.
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http://dx.doi.org/10.1212/WNL.0000000000008441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946483PMC
November 2019

Quantitative nuclear magnetic resonance imaging detects subclinical changes over 1 year in skeletal muscle of GNE myopathy.

J Neurol 2020 Jan 15;267(1):228-238. Epub 2019 Oct 15.

I-Motion-Pediatric Clinical Trials Department, Hôpital Armand Trousseau, Bâtiment Lemariey-Porte 20 * 2ème étage, 26 Avenue du Dr Arnold Netter, 75012, Paris, France.

Background And Objective: To identify the most responsive and sensitive clinical outcome measures in GNE myopathy.

Methods: ClinBio-GNE is a natural history study in GNE myopathy. Patients were assessed prospectively by clinical, functional and quantitative nuclear magnetic resonance imaging (qNMRI) evaluations. Strength and functional tests included Myogrip, Myopinch, MoviPlate and Brooke assessments for upper limb and the 6-min walk distance for lower limb. qNMRI was performed for determining the degree of fatty infiltration and trophicity in leg, thigh, forearm and hand skeletal muscles. Ten GNE myopathy patients were included. Three patients were non-ambulant. Age and gender-matched healthy subjects were used as controls.

Results: Fatty infiltration and contractile cross-sectional area changed inversely and significantly in lower distal limbs and in proximal lower and distal upper limbs over 1 year. qNMRI indices and functional assessment results were strongly correlated.

Conclusions: Even in a limited number of patients, qNMRI could detect a significant change over a 1-year period in GNE myopathy, which suggests that qNMRI could constitute a surrogate endpoint in this slowly progressive disease. Quantitative NMRI outcome measures can monitor intramuscular fat accumulation with high responsiveness. Longer follow-up should improve our understanding of GNE myopathy evolution and also lead to the identification of non-invasive outcome measures with the highest discriminant power for upcoming clinical trials.
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http://dx.doi.org/10.1007/s00415-019-09569-6DOI Listing
January 2020

Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints.

Ann Clin Transl Neurol 2019 Jun 16;6(6):1033-1045. Epub 2019 May 16.

The John Walton Muscular Dystrophy Research Centre Institute of Genetic Medicine Newcastle University Newcastle Hospitals NHS Foundation Trust Central Parkway Newcastle Upon Tyne United Kingdom NE1 4EP.

Objective: Limb girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive muscle disease for which there is currently no causative treatment. The development of putative therapies requires sensitive outcome measures for clinical trials in this slowly progressing condition. This study extends functional assessments and MRI muscle fat fraction measurements in an LGMD R9 cohort across 6 years.

Methods: Twenty-three participants with LGMD R9, previously assessed over a 1-year period, were re-enrolled at 6 years. Standardized functional assessments were performed including: myometry, timed tests, and spirometry testing. Quantitative MRI was used to measure fat fraction in lower limb skeletal muscle groups.

Results: At 6 years, all 14 muscle groups assessed demonstrated significant increases in fat fraction, compared to eight groups in the 1-year follow-up study. In direct contrast to the 1-year follow-up, the 6-min walk test, 10-m walk or run, timed up and go, stair ascend, stair descend and chair rise demonstrated significant decline. Among the functional tests, only FVC significantly declined over both the 1- and 6-year studies.

Interpretation: These results further support fat fraction measurements as a primary outcome measure alongside functional assessments. The most appropriate individual muscles are the vastus lateralis, gracilis, sartorius, and gastrocnemii. Using composite groups of lower leg muscles, thigh muscles, or triceps surae, yielded high standardized response means (SRMs). Over 6 years, quantitative fat fraction assessment demonstrated higher SRM values than seen in functional tests suggesting greater responsiveness to disease progression.
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http://dx.doi.org/10.1002/acn3.774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562036PMC
June 2019

Hyperammonaemia following exercise may also reveal PGK1 deficiency.

J Clin Pathol 2019 Jun 27;72(6):452. Epub 2019 Mar 27.

Paris-Est Neuromuscular Center, Institute of Myology, University Hospital Pitié Salpêtrière, Paris, France.

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http://dx.doi.org/10.1136/jclinpath-2019-205750DOI Listing
June 2019

X-linked myotubular myopathy: A prospective international natural history study.

Neurology 2019 04 22;92(16):e1852-e1867. Epub 2019 Mar 22.

From I-Motion (M.A., C.L., T.G., E.G., V.C., L.S.), Institute of Myology, Paris, France; Paediatric Neurology and Neuromuscular Center (U.S., A.G.), University of Essen, Germany; Unit of Neuromuscular and Neurodegenerative Disorders (A. D'Amico), Department of Neurosciences, Bambino Gesu Children's Research Hospital IRCCS, Rome, Italy; Division of Neurology and Program for Genetics and Genome Biology (J.J.D.), Hospital for Sick Children, Toronto, Canada; Boston Children's Hospital (B.T.D.), MA; Centre de Référence Neuromusculaire (A. Daron), CHR La Citadelle, Liège, Belgium; UCI Pediatrica (A.H.), Hospital Puerta del Mar, Cadiz, Spain; Centre de Référence Maladies Neuromusculaires Adulte (C.d.L.), Hôpital de la Croix-Rousse, Hospices Civils de Lyon; Service de Réanimation Polyvalente (J.-M.A.), Hôpital Sainte Musse, Toulon; Centre de Référence des Maladies Neuromusculaires d'Ile de France-Nord et Est (M.M.), Hôpital Armand Trousseau, Paris; Service de Neuropédiatrie Hôpital Roger Salengro (J.-M.C.), CHRU, Lille; Service de Rééducation Pédiatrique "L'Escale" (C.V., S.F.), Hôpital Mère Enfant, CHU-Lyon, France; CeRCa (R.B.), Hôpital Pierre-Zobda-Quitman, CHU de Martinique, Fort-de-France, Martinique; Laboratoire Diagnostic Génétique (V.B.), Nouvel Hôpital Civil, Strasbourg; Genethon (A.B.-B.), UMR S951 Inserm, Univ Evry, Université Paris Saclay, Evry; Neuromuscular Investigation Center (J.-Y.H.), Institute of Myology, Paris, France; and Valerion Therapeutics (H.L.), Concord, MA.

Objectives: Because X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disease caused by mutations in the gene with a large phenotypic heterogeneity, to ensure clinical trial readiness, it was mandatory to better quantify disease burden and determine best outcome measures.

Methods: We designed an international prospective and longitudinal natural history study in patients with XLMTM and assessed muscle strength and motor and respiratory functions over the first year of follow-up. The humoral immunity against adeno-associated virus serotype 8 was also monitored.

Results: Forty-five male patients aged 3.5 months to 56.8 years were enrolled between May 2014 and May 2017. Thirteen patients had a mild phenotype (no ventilation support), 7 had an intermediate phenotype (ventilation support less than 12 hours a day), and 25 had a severe phenotype (ventilation support 12 or more hours a day). Most strength and motor function assessments could be performed even in very weak patients. Motor Function Measure 32 total score, grip and pinch strengths, and forced vital capacity, forced expiratory volume in the first second of exhalation, and peak cough flow measures discriminated the 3 groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients showed that the Motor Function Measure 32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti-adeno-associated virus type 8 neutralizing activity was detected in 26% with 2 patients having an inhibitory titer >1:10.

Conclusions: Our data confirm that XLMTM is slowly progressive for male survivors regardless of their phenotype and provide outcome validation and natural history data that can support clinical development in this population.

Clinicaltrialsgov Identifier: NCT02057705.
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http://dx.doi.org/10.1212/WNL.0000000000007319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550499PMC
April 2019

Diaphragm shear modulus reflects transdiaphragmatic pressure during isovolumetric inspiratory efforts and ventilation against inspiratory loading.

J Appl Physiol (1985) 2019 03 7;126(3):699-707. Epub 2019 Feb 7.

Service de Pneumologie, Médecine Intensive et Réanimation (Département "R3S"), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Assistance Publique-Hôpitaux de Paris, Paris , France.

The reference method for the assessment of diaphragm function relies on the measurement of transdiaphragmatic pressure (Pdi). Local muscle stiffness measured using ultrafast shear wave elastography (SWE) provides reliable estimates of muscle force in locomotor muscles. This study aimed at investigating whether SWE could be used as a surrogate of Pdi to evaluate diaphragm function. Fifteen healthy volunteers underwent a randomized stepwise inspiratory loading protocol of 0-60% of maximal isovolumetric inspiratory pressure during closed-airways maneuvers and 0-50% during ventilation against an external inspiratory threshold load. During all tasks, Pdi was measured and SWE was used to assess shear modulus of the right hemidiaphragm (SMdi) at the zone of apposition. Pearson correlation coefficients ( r) and repeated-measures correlation coefficients ( R) were computed to determine within-individual and overall relationships between Pdi and SMdi, respectively. During closed-airways maneuvers, mean Pdi correlated to mean SMdi in all participants [ r ranged from 0.77 to 0.96, all P < 0.01; R = 0.82, 95% confidence intervals (0.76, 0.86), P < 0.01]. During ventilation against inspiratory threshold loading, Pdi swing correlated to maximal SMdi in all participants [ r ranged from 0.40 to 0.90, all P < 0.01; R = 0.70, 95% confidence intervals (0.66, 0.73), P < 0.001]. Changes in diaphragm stiffness as assessed by SWE reflect changes in transdiaphragmatic pressure. SWE provides a new opportunity for direct and noninvasive assessment of diaphragm function. NEW & NOTEWORTHY Accurate and specific estimation of diaphragm effort is critical for evaluating and monitoring diaphragm dysfunction. The measurement of transdiaphragmatic pressure requires the use of invasive gastric and esophageal probes. In the present work, we demonstrate that changes in diaphragm stiffness assessed with ultrasound shear wave elastography reflect changes in transdiaphragmatic pressure, therefore offering a new noninvasive method for gauging diaphragm effort.
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http://dx.doi.org/10.1152/japplphysiol.01060.2018DOI Listing
March 2019

Assessment of disease progression in dysferlinopathy: A 1-year cohort study.

Neurology 2019 Jan 9. Epub 2019 Jan 9.

From the John Walton Muscular Dystrophy Research Centre (U.M., M.K.J., A.G.M., R.F.-T., M.E., K.B., R.M.L., H.H., H.L., K.B., V.S.), Newcastle University and Newcastle Hospitals NHS Foundation Trust, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Central Parkway, Newcastle Upon Tyne, UK; Center for Translational Science (M.J., J.F., A. Cnaan), Division of Biostatistics and Study Methodology, Cooperative International Neuromuscular Research Group (T.D., B.D.), and Department of Neurology (D.X.B.-G.), Children's National Health System; Pediatrics, Epidemiology and Biostatistics (M.J., A. Cnaan), George Washington University, Washington, DC; Neuromuscular Area (R.F.-T.), Biodonostia Health Research Institute, Neurology Service, Donostia University Hospital, Donostia-San Sebastian, Spain; Jain Foundation (L.E.R., P.M.), Seattle, WA; Magnetic Resonance Centre (A.M.B.), Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK; AIM & CEA NMR Laboratory (P.G.C.), Institute of Myology, Pitié-Salpêtrière University Hospital, 47-83, Paris, France; Research Institute at Nationwide Children's Hospital (L.P.L., L.A., K.M.B., J.R.M.), The Ohio State University, Columbus; Institute for Neuroscience and Muscle Research (K.R., M. Hutchence, K.J.J.), Children's Hospital at Westmead, University of Sydney, Australia; Lucile Salter Packard Children's Hospital at Stanford (T.D.), 24349, Neurology, Palo Alto, CA; Physical Medicine and Rehabilitation (E.M.-M., I.P.-H.), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Neuroscience Institute (S.H., M.S., E.B., S. Sparks), Carolinas Neuromuscular/ALS-MDA Center, Carolinas HealthCare System, Charlotte, NC; Department of Physical Rehabilitation (A.A., C. Sakamoto, T.T., H.Y.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; Institut de Myologie (A. Canal, G.O., V.D., J.-Y.H., T.S.), AP-HP, GH Pitié-Salpêtrière, Paris, France; Neurorehabilitation Unit (J.B.M.), Rehabilitation Hospital Universitario Virgen del Rocío Sevilla; Neurophysiotherapy Department (N.S.-A.P.), Hospital Universitario Virgen del Rocío, Seville, Spain; Friedrich-Baur-Institute (S. Thiele, S.K., O.S.-K. M.C.W.), Department of Neurology, Ludwig-Maximilians-University of Munich, Germany; Department of Neurology (C. Siener, J.S., J.M.F., M. Harms, A.P.), Washington University School of Medicine, St. Louis, MO; Centre de Reference des Maladies Neuromusculaires PACA Réunion Rhone Alpes (B.V., E.S.-C.), Hopital de la Timone, Aix-Marseille Université, France; ELAN-PHYSIO (J.P., E.M.), Praxis für Physiotherapie Maron; Charite Muscle Research Unit (U.G., S. Spuler), Experimental and Clinical Research Center, a joint cooperation of the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany; Department of Neurology and Neurological Sciences (C.T.R., J.W.D.), Stanford University School of Medicine, CA; NIH (D.X.B.-G.), Bethesda, MD; Neuromuscular Unit (C.P.), Department of Neurology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla, Spain; Department of Neurology (S. Takeda, M.M.-Y.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; Centro de Investigación Biomédica en Red en Enfermedades Raras (J.D.-M.); Neuromuscular Disorders Unit (J.D.-M.), Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; and Department of Neuroscience (L.B., C. Semplicini, E.P.), University of Padova, Italy.

Objective: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.

Methods: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis.

Results: The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint.

Conclusion: Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.

Clinicaltrialsgov Identifier: NCT01676077.
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http://dx.doi.org/10.1212/WNL.0000000000006858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369904PMC
January 2019

The spinal and cerebral profile of adult spinal-muscular atrophy: A multimodal imaging study.

Neuroimage Clin 2019 28;21:101618. Epub 2018 Nov 28.

Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France; APHP, Département de Neurologie, Hôpital Pitié-Salpêtrière, Centre référent SLA, Paris, France; Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute Ulster University, C-TRIC, Altnagelvin Hospital, Derry, Londonderry, United Kingdom. Electronic address:

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging.

Methods: Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations.

Results: In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level.

Conclusions: Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation.
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http://dx.doi.org/10.1016/j.nicl.2018.101618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413472PMC
December 2019

The motor unit number index (MUNIX) profile of patients with adult spinal muscular atrophy.

Clin Neurophysiol 2018 11 13;129(11):2333-2340. Epub 2018 Sep 13.

Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France; APHP, Département de Neurologie, Hôpital Pitié-Salpêtrière, Centre référent SLA, Paris, France; Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute Ulster University, C-TRIC, Altnagelvin Hospital, Derry/Londonderry, United Kingdom. Electronic address:

Objective: Objective of this study is the comprehensive characterisation of motor unit (MU) loss in type III and IV Spinal Muscular Atrophy (SMA) using motor unit number index (MUNIX), and evaluation of compensatory mechanisms based on MU size indices (MUSIX).

Methods: Nineteen type III and IV SMA patients and 16 gender- and age-matched healthy controls were recruited. Neuromuscular performance was evaluated by muscle strength testing and functional scales. Compound motor action potential (CMAP), MUNIX and MUSIX were studied in the abductor pollicis brevis (APB), abductor digiti minimi (ADM), deltoid, tibialis anterior and trapezius muscles. A composite MUNIX score was also calculated.

Results: SMA patients exhibited significantly reduced MUNIX values (p < 0.05) in all muscles, while MUSIX was increased, suggesting active re-innervation. Significant correlations were identified between MUNIX/MUSIX and muscle strength. Similarly, composite MUNIX scores correlated with disability scores. Interestingly, in SMA patients MUNIX was much lower in the ADM than in the ABP, a pattern which is distinctly different from that observed in Amyotrophic Lateral Sclerosis.

Conclusions: MUNIX is a sensitive measure of MU loss in adult forms of SMA and correlates with disability.

Significance: MUNIX evaluation is a promising candidate biomarker for longitudinal studies and pharmacological trials in adult SMA patients.
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http://dx.doi.org/10.1016/j.clinph.2018.08.025DOI Listing
November 2018

Report of the third outcome measures in myotonic dystrophy type 1 (OMMYD-3) international workshop Paris, France, June 8, 2015.

J Neuromuscul Dis 2018 ;5(4):523-537

Functional Area Occupational Therapy & Physiotherapy, Allied Health Professionals Function, Karolinska University Hospital, Stockholm, Sweden.

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http://dx.doi.org/10.3233/JND-180329DOI Listing
January 2019

Marathons and myasthenia gravis: a case report.

BMC Neurol 2018 Sep 18;18(1):145. Epub 2018 Sep 18.

Institute of Myology, GH Pitié-Salpêtrière (AP-HP), Bd de l'Hôpital, 75651, Paris Cedex 13, France.

Background: The cardinal symptoms of auto-immune myasthenia gravis are fatigue and weakness. Endurance events such as marathon running would seem incompatible with this chronic disease. Many patients stop sport altogether. There is limited literature of patients with auto-immune myasthenia gravis undergoing regular endurance exercise.

Case Presentation: We report the case of a 36-year-old female who began long-distance running whilst experiencing initial symptoms of myasthenia gravis. She was diagnosed with auto-immune myasthenia gravis and whilst advised to stop all sport, her way of fighting and living with this chronic and unpredictable disease was to continue running to maintain a healthy body and mind. Despite suffering from ocular, bulbar and localized limb fatigability, she managed to complete multiple marathons and achieve disease stability with cholinesterase inhibitors.

Conclusions: Marathon and half-marathon running lead to distinct changes in mediators of inflammation in an exercise-dose-dependent manner. Despite symptoms of weakness and fatigue in certain muscles in myasthenia gravis, physical exertion remains possible and may not worsen symptoms as demonstrated in this case and recent studies. The immunomodulatory role of exercise could be considered in this case however this hypothesis remains to be confirmed in future studies with quantitative data.
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http://dx.doi.org/10.1186/s12883-018-1150-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142625PMC
September 2018

Improved mobility with metformin in patients with myotonic dystrophy type 1: a randomized controlled trial.

Brain 2018 10;141(10):2855-2865

INSERM U861, I-Stem, Corbeil-Essonnes 91100 France.

Metformin, the well-known anti-diabetic drug, has been shown recently to improve the grip test performance of the DMSXL mouse model of myotonic dystrophy type 1. The drug may have positively affected muscle function via several molecular mechanisms, on RNA splicing, autophagia, insulin sensitivity or glycogen synthesis. Myotonic dystrophy remains essentially an unmet medical need. Since metformin benefits from a good toxicity profile, we investigated its potential for improving mobility in patients. Forty ambulatory adult patients were recruited consecutively at the neuromuscular reference centre of Henri-Mondor Hospital. Participants and investigators were all blinded to treatment until the end of the trial. Oral metformin or placebo was provided three times daily, with a dose-escalation period over 4 weeks up to 3 g/day, followed by 48 weeks at maximum dose. The primary outcome was the change in the distance walked during the 6-minute walk test, from baseline to the end of the study. Concomitant changes in muscle strength and effect on myotonia, gait variables, biological parameters and quality of life were explored. Patients randomized into two arms eventually revealed similar results in all physical measures and in the mean 6-minute walk test at baseline. For the 23/40 patients who fully completed the 1-year study, differences between the groups were statistically significant, with the treated group (n = 9) gaining a distance of 32.9 ± 32.7 m, while the placebo group (n = 14) gained 3.7 ± 32.4 m (P < 0.05). This improvement in mobility was associated with an increase in total mechanical power (P = 0.01), due to a concomitant increase in the cranial and antero-posterior directions suggesting an effect of the treatment on gait. Subanalysis revealed positive effects of metformin treatment on the 6-minute walk test at the first intermediate evaluation (after 16 weeks of treatment), quantitatively similar to those recorded at 1 year. In contrast, except for the expected limited weight loss associated to metformin treatment, there was no change in any of the other secondary endpoints, including myotonia and muscle strength. Patients in the treated group had a higher incidence of mild-to-moderate adverse effects, mostly gastrointestinal dysfunctions that required symptomatic treatment. Although results were statistically significant only for the per protocol population of patients and not in the intent-to-treat analysis, metformin at the maximal tolerated dose provided a promising effect on the mobility and gait abilities of myotonic patients. These encouraging results obtained in a small-scale monocentric phase II study call for replication in a well-powered multicentre phase III trial.
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http://dx.doi.org/10.1093/brain/awy231DOI Listing
October 2018
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