N-acetyl cysteine alleviates oxidative stress and protects mice from dilated cardiomyopathy caused by mutations in nuclear A-type lamins gene.

Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is an anatomic and pathologic condition associated with muscular and electrical dysfunction of the heart, often leading to heart failure-related disability. There is currently no specific therapy available for patients that target the molecular pathophysiology of LMNA cardiomyopathy. We showed here an increase in oxidative stress levels in the hearts of mice carrying LMNA mutation, associated with a decrease of the key cellular antioxidant glutathione (GHS). Oral administration of N-acetyl cysteine, a GHS precursor, led to a marked improvement of GHS content, a decrease in oxidative stress markers including protein carbonyls and an improvement of left ventricular structure and function in a model of LMNA cardiomyopathy. Collectively, our novel results provide therapeutic insights into LMNA cardiomyopathy.

Whole-Body Muscle Magnetic Resonance Imaging in Glycogen-Storage Disease Type III.

INTRODUCTION: The main objective of this study was to describe muscle involvement on whole-body magnetic resonance imaging scans in adults at different stages of glycogen-storage disease type III (GSDIII). METHODS: Fifteen patients, 16-59 years of age, were examined on a 3-T system. The examinations consisted of coronal and axial T1-weighted images or fat images with a Dixon technique, and were scored for 47 muscles using Mercuri's classification. Muscle changes consisted of internal bright signals of fatty replacement. RESULTS: Distribution across muscles showed predominant signal alteration in the lower limbs and postural muscles. This finding is consistent with the overall clinical presentation of GSDIII and the results of heatmap scores. Review of the MRI scans provided new information regarding recurrent muscle changes, particularly in the soleus, gastrocnemius medial head, and thoracic extensor muscles. DISCUSSION: Whole-body muscle imaging provides clinically relevant information regarding muscle involvement in GSDIII. A severity score may contribute to improved patient management. Muscle Nerve, 2019.

Long term longitudinal study of muscle function in patients with glycogen storage disease type IIIa.

Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by mutations in the AGL gene coding for the glycogen debranching enzyme. Current therapy is based on dietary adaptations but new preclinical therapies are emerging. The identification of outcome measures which are sensitive to disease progression becomes critical to assess the efficacy of new treatments in upcoming clinical trials. In order to prepare future longitudinal studies or therapeutic trials with large cohorts, information about disease progression is required. In this study we present preliminary longitudinal data of Motor Function Measure (MFM), timed tests, Purdue pegboard test, and handgrip strength collected over 5 to 9years of follow-up in 13 patients with GSDIII aged between 13 and 56years old. Follow-up for nine of the 13 patients was up to 9years. Similarly to our previous cross-sectional retrospective study, handgrip strength significantly decreased with age in patients older than 37years. MFM scores started to decline after the age of 35. The Purdue pegboard score also significantly reduced with increasing age (from 13years of age) but with large inter-visit variations. The time to stand up from a chair or to climb 4 stairs increased dramatically in some but not all patients older than 30years old. In conclusion, this preliminary longitudinal study suggests that MFM and handgrip strength are the most sensitive muscle function outcome measures in GSDIII patients from the end of their third decade. Sensitive muscle outcome measures remain to be identified in younger GSDIII patients but is challenging as muscle symptoms remain discrete and often present as accumulated fatigue.

Heterozygous LmnadelK32 mice develop dilated cardiomyopathy through a combined pathomechanism of haploinsufficiency and peptide toxicity.

Dilated cardiomyopathy (DCM) associates left ventricular (LV) dilatation and systolic dysfunction and is a major cause of heart failure and cardiac transplantation. LMNA gene encodes lamins A/C, proteins of the nuclear envelope. LMNA mutations cause DCM with conduction and/or rhythm defects. The pathomechanisms linking mutations to DCM remain to be elucidated. We investigated the phenotype and associated pathomechanisms of heterozygous Lmna(ΔK32/+) (Het) knock-in mice, which carry a human mutation. Het mice developed a cardiac-specific phenotype. Two phases, with two different pathomechanisms, could be observed that lead to the development of cardiac dysfunction, DCM and death between 35 and 70 weeks of age. In young Het hearts, there was a clear reduction in lamin A/C level, mainly due to the degradation of toxic ΔK32-lamin. As a side effect, lamin A/C haploinsufficiency probably triggers the cardiac remodelling. In older hearts, when DCM has developed, the lamin A/C level was normalized and associated with increased toxic ΔK32-lamin expression. Crossing our mice with the Ub(G76V)-GFP ubiquitin-proteasome system (UPS) reporter mice revealed a heart-specific UPS impairment in Het. While UPS impairment itself has a clear deleterious effect on engineered heart tissue's force of contraction, it also leads to the nuclear aggregation of viral-mediated expression of ΔK32-lamin. In conclusion, Het mice are the first knock-in Lmna model with cardiac-specific phenotype at the heterozygous state. Altogether, our data provide evidence that Het cardiomyocytes have to deal with major dilemma: mutant lamin A/C degradation or normalization of lamin level to fight the deleterious effect of lamin haploinsufficiency, both leading to DCM.

Wrist flexion and extension torques measured by highly sensitive dynamometer in healthy subjects from 5 to 80 years.

BACKGROUND: Wrist movements become impaired with disease progression in various neuromuscular disorders. With the development of new therapies, thorough measurement of muscle strength is crucial to document natural disease progression and to assess treatment efficacy. We developed a new dynamometer enabling wrist flexion and extension torque measurement with high sensitivity. The aims of the present study were to collect norms for healthy children and adults, to compute predictive equations, to assess the reliability of the measurements and to test the feasibility of using the device in patients with a neuromuscular disease. METHODS: The peak isometric torque of wrist flexion and extension was measured with the MyoWrist dynamometer in 345 healthy subjects aged between 5 and 80 years old and in 9 patients with limb girdle muscle dystrophy type 2 C (LGMD2C) aged between 16 and 38 years old. RESULTS: Predictive equations are proposed for the wrist flexion and extension strength in children and adults. Intra-rater and inter-rater reliability was good with ICCs higher than 0.9 for both wrist flexion and extension. However, retest values were significantly higher by 4% than test results. The dynamometer was applied with no difficulty to patients with LGMD2C and was sensitive enough to detect strength as weak as 0.82 N.m. From our models, we quantified the mean strength of wrist extension in LGMD2C patients to 39 ± 17% of their predicted values. CONCLUSIONS: The MyoWrist dynamometer provides reliable and sensitive measurement of both wrist flexion and extension torques. However, a training session is recommended before starting a study as a small but significant learning effect was observed. Strength deficit can be quantified from predictive equations that were computed from norms of healthy children and adults.

Molecular, physiological, and motor performance defects in DMSXL mice carrying >1,000 CTG repeats from the human DM1 locus.

Myotonic dystrophy type 1 (DM1) is caused by an unstable CTG repeat expansion in the 3'UTR of the DM protein kinase (DMPK) gene. DMPK transcripts carrying CUG expansions form nuclear foci and affect splicing regulation of various RNA transcripts. Furthermore, bidirectional transcription over the DMPK gene and non-conventional RNA translation of repeated transcripts have been described in DM1. It is clear now that this disease may involve multiple pathogenic pathways including changes in gene expression, RNA stability and splicing regulation, protein translation, and micro-RNA metabolism. We previously generated transgenic mice with 45-kb of the DM1 locus and >300 CTG repeats (DM300 mice). After successive breeding and a high level of CTG repeat instability, we obtained transgenic mice carrying >1,000 CTG (DMSXL mice). Here we described for the first time the expression pattern of the DMPK sense transcripts in DMSXL and human tissues. Interestingly, we also demonstrate that DMPK antisense transcripts are expressed in various DMSXL and human tissues, and that both sense and antisense transcripts accumulate in independent nuclear foci that do not co-localize together. Molecular features of DM1-associated RNA toxicity in DMSXL mice (such as foci accumulation and mild missplicing), were associated with high mortality, growth retardation, and muscle defects (abnormal histopathology, reduced muscle strength, and lower motor performances). We have found that lower levels of IGFBP-3 may contribute to DMSXL growth retardation, while increased proteasome activity may affect muscle function. These data demonstrate that the human DM1 locus carrying very large expansions induced a variety of molecular and physiological defects in transgenic mice, reflecting DM1 to a certain extent. As a result, DMSXL mice provide an animal tool to decipher various aspects of the disease mechanisms. In addition, these mice can be used to test the preclinical impact of systemic therapeutic strategies on molecular and physiological phenotypes.

DelK32-lamin A/C has abnormal location and induces incomplete tissue maturation and severe metabolic defects leading to premature death.

The LMNA gene encodes lamin A/C intermediate filaments that polymerize beneath the nuclear membrane, and are also found in the nucleoplasm in an uncharacterized assembly state. They are thought to have structural functions and regulatory roles in signaling pathways via interaction with transcription factors. Mutations in LMNA have been involved in numerous inherited human diseases, including severe congenital muscular dystrophy (L-CMD). We created the Lmna(ΔK32) knock-in mouse harboring a L-CMD mutation. Lmna(ΔK32/ΔK32) mice exhibited striated muscle maturation delay and metabolic defects, including reduced adipose tissue and hypoglycemia leading to premature death. The level of mutant proteins was markedly lower in Lmna(ΔK32/ΔK32), and while wild-type lamin A/C proteins were progressively relocated from nucleoplasmic foci to the nuclear rim during embryonic development, mutant proteins were maintained in nucleoplasmic foci. In the liver and during adipocyte differentiation, expression of ΔK32-lamin A/C altered sterol regulatory element binding protein 1 (SREBP-1) transcriptional activities. Taken together, our results suggest that lamin A/C relocation at the nuclear lamina seems important for tissue maturation potentially by releasing its inhibitory function on transcriptional factors, including but not restricted to SREBP-1. And importantly, L-CMD patients should be investigated for putative metabolic disorders.

Relationship Between Hand Strength and Function in Duchenne Muscular Dystrophy and Spinal Muscular Atrophy: Implications for Clinical Trials.

Background: Measurement of muscle strength and motor function is recommended in clinical trials of neuromuscular diseases, but the loss of hand strength at which motor function is impacted is not documented. Objectives: To establish the relationship between hand strength and function, and to determine the strength threshold that differentiates normal and abnormal hand function in individuals with Duchenne Muscular Dystrophy (DMD) or Spinal Muscular Atrophy (SMA). Methods: Maximal handgrip and key pinch strength were measured with the MyoGrip and MyoPinch dynamometers, respectively. Hand function was assessed using the MoviPlate, the Motor Function Measure items for distal upper limb (MFM-D3-UL) and the Cochin Hand Function Scale (CHFS). Results: Data from 168 participants (91 DMD and 77 SMA, age 6-31 years) were analyzed. Relationships between strength and function were significant (P < 0.001). Hand function was generally preserved when strength was above the strength threshold determined by Receiver-Operating Characteristic (ROC) analysis: For MFM-D3-UL, the calculated handgrip strength thresholds were 41 and 13% of the predicted strength for a healthy subject (% pred) and the key pinch strength thresholds were 42 and 26% pred for DMD and SMA, respectively. For the MoviPlate, handgrip strength thresholds were 11 and 8% pred and key pinch strength thresholds were 21 and 11% pred for DMD and SMA, respectively. For participants with sub-threshold strength, hand function scores decreased with decreasing strength. At equal % pred strength, individuals with SMA had better functional scores than those with DMD. Conclusions: Hand function is strength-dependent for most motor tasks. It declines only when strength falls below a disease-specific threshold. Therefore, therapies capable of maintaining strength above this threshold should preserve hand function.

Development of the Performance of the Upper Limb module for Duchenne muscular dystrophy.

AIM: An international Clinical Outcomes Group consisting of clinicians, scientists, patient advocacy groups, and industries identified a need for a scale to measure motor performance of the upper limb. We report the steps leading to the development of the Performance of the Upper Limb (PUL), a tool specifically designed for assessing upper limb function in ambulant and non-ambulant patients with Duchenne muscular dystrophy (DMD). METHOD: The development of the PUL followed a number of steps, from the systematic review and a preliminary study exploring the suitability of the existing measures, to the application of a pilot version in a multicentric setting, with Rasch analysis of the preliminary results, leading to a revised pro forma. RESULTS: The PUL was specifically designed for DMD, with a conceptual framework reflecting the progression of weakness and natural history of functional decline in DMD. Modern psychometric methods were used to create a scale with robust internal reliability, validity, and hierarchical scalability; males with DMD and their families were involved iteratively throughout the process of the clinician-reported outcome assessment tool development to establish clinical meaningfulness and relevance of individual PUL items to activities of daily living. INTERPRETATION: The module was developed using innovative approaches and will be useful for designing clinical trials.

French recommendations for the management of glycogen storage disease type III.

The aim of the Protocole National De Diagnostic et de Soins/French National Protocol for Diagnosis and Healthcare (PNDS) is to provide advice for health professionals on the optimum care provision and pathway for patients with glycogen storage disease type III (GSD III).The protocol aims at providing tools that make the diagnosis, defining the severity and different damages of the disease by detailing tests and explorations required for monitoring and diagnosis, better understanding the different aspects of the treatment, defining the modalities and organisation of the monitoring. This is a practical tool, to which health care professionals can refer. PNDS cannot, however, predict all specific cases, comorbidities, therapeutic particularities or hospital care protocols, and does not seek to serve as a substitute for the individual responsibility of the physician in front of his/her patient.

Stature is an essential predictor of muscle strength in children.

BACKGROUND: Children with growth retardation or short stature generally present with lower strength than children of the same chronological age. The aim of the study was to establish if strength was dependent on variables related to stature in a population of healthy children and to propose practical predictive models for the muscle functions tested. A secondary aim was to test for any learning effects concerning strength measured at two successive visits by children. METHODS: Hand grip, elbow flexion and extension, and knee flexion and extension were measured by fixed dynamometry in 96 healthy subjects (47 girls and 49 boys, aged from 5 to 17 years). RESULTS: For the present paediatric population, muscle strength was highly dependent on height. Predictive models are proposed for the muscle functions tested. No learning effect between the first and the second visit was detected for any of the muscle functions tested. CONCLUSIONS: This work shows that strength measurements using fixed dynamometry are reliable in children when using appropriate standardization of operating procedures. It underlines the particular relationship between body stature and muscle strength. Predictive equations may help with assessing the neuromuscular involvement in children suffering from various disorders, particularly those affecting their stature.

Upper limb disease evolution in exon 53 skipping eligible patients with Duchenne muscular dystrophy.

OBJECTIVE: To understand the natural disease upper limb progression over 3 years of ambulatory and non-ambulatory patients with Duchenne muscular dystrophy (DMD) using functional assessments and quantitative magnetic resonance imaging (MRI) and to exploratively identify prognostic factors. METHODS: Forty boys with DMD (22 non-ambulatory and 18 ambulatory) with deletions in dystrophin that make them eligible for exon 53-skipping therapy were included. Clinical assessments, including Brooke score, motor function measure (MFM), hand grip and key pinch strength, and upper limb distal coordination and endurance (MoviPlate), were performed every 6 months and quantitative MRI of fat fraction (FF) and lean muscle cross sectional area (flexor and extensor muscles) were performed yearly. RESULTS: In the whole population, there were strong nonlinear correlations between outcome measures. In non-ambulatory patients, annual changes over the course of 3 years were detected with high sensitivity standard response mean (|SRM| ≥0.8) for quantitative MRI-based FF, hand grip and key pinch, and MFM. Boys who presented with a FF<20% and a grip strength >27% were able to bring a glass to their mouth and retained this ability in the following 3 years. Ambulatory patients with grip strength >35% of predicted value and FF <10% retained ambulation 3 years later. INTERPRETATION: We demonstrate that continuous decline in upper limb strength, function, and MRI measured muscle structure can be reliably measured in ambulatory and non-ambulatory boys with DMD with high SRM and strong correlations between outcomes. Our results suggest that a combination of grip strength and FF can be used to predict important motor milestones.

The non-muscle ADF/cofilin-1 controls sarcomeric actin filament integrity and force production in striated muscle laminopathies.

Cofilins are important for the regulation of the actin cytoskeleton, sarcomere organization, and force production. The role of cofilin-1, the non-muscle-specific isoform, in muscle function remains unclear. Mutations in LMNA encoding A-type lamins, intermediate filament proteins of the nuclear envelope, cause autosomal Emery-Dreifuss muscular dystrophy (EDMD). Here, we report increased cofilin-1 expression in LMNA mutant muscle cells caused by the inability of proteasome degradation, suggesting a protective role by ERK1/2. It is known that phosphorylated ERK1/2 directly binds to and catalyzes phosphorylation of the actin-depolymerizing factor cofilin-1 on Thr25. In vivo ectopic expression of cofilin-1, as well as its phosphorylated form on Thr25, impairs sarcomere structure and force generation. These findings present a mechanism that provides insight into the molecular pathogenesis of muscular dystrophies caused by LMNA mutations.

Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy.

Mutations in LMNA, which encodes nuclear Lamins A and C cause diseases affecting various organs, including the heart. We have determined the effects of an Lmna H222P mutation on signaling pathways involved in the development of cardiomyopathy in a knockin mouse model of autosomal dominant Emery-Dreifuss muscular dystrophy. Analysis of genome-wide expression profiles in hearts using Affymetrix GeneChips showed statistically significant differences in expression of genes in the MAPK pathways at the incipience of the development of clinical disease. Using real-time PCR, we showed that activation of MAPK pathways preceded clinical signs or detectable molecular markers of cardiomyopathy. In heart tissue and isolated cardiomyocytes, there was activation of MAPK cascades and downstream targets, implicated previously in the pathogenesis of cardiomyopathy. Expression of H222P Lamin A in cultured cells activated MAPKs and downstream target genes. Activation of MAPK signaling by mutant A-type lamins could be a cornerstone in the development of heart disease in autosomal dominant Emery-Dreifuss muscular dystrophy.

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

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.

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

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.

Cross-sectional retrospective study of muscle function in patients with glycogen storage disease type III.

Glycogen storage disease type III is an inherited metabolic disorder characterized by liver and muscle impairment. This study aimed to identify promising muscle function measures for future studies on natural disease progression and therapeutic trials. The age-effect on the manual muscle testing (MMT), the hand-held dynamometry (HHD), the motor function measure (MFM) and the Purdue pegboard test was evaluated by regression analysis in a cross-sectional retrospective single site study. In patients aged between 13 and 56 years old, the Purdue pegboard test and dynamometry of key pinch and knee extension strength were age-sensitive with annual losses of 1.49, 1.10 and 0.70% of the predicted values (%pred), respectively. The MFM score and handgrip strength were also age-sensitive but only in patients older than 29 and 37 years old with annual losses of 1.42 and 1.84%pred, respectively. Muscle strength assessed by MMT and elbow extension measured by HHD demonstrated an annual loss of less than 0.50%pred and are thus unlikely to be promising outcome measures for future clinical trials. In conclusion, our results identified age-sensitive outcomes from retrospective data and may serve for future longitudinal studies in which an estimation of the minimal number of subjects is provided.

Relationship between muscle impairments, postural stability, and gait parameters assessed with lower-trunk accelerometry in myotonic dystrophy type 1.

This study evaluated gait using lower-trunk accelerometry and investigated relationships between gait abnormalities, postural instability, handgrip myotonia, and weakness in lower-limb and axial muscle groups commonly affected in myotonic dystrophy type 1 (DM1). Twenty-two patients (11 men, 11 women; age = 42 years (range: 26-51)) with DM1 and twenty healthy controls (9 men, 11 women; age = 44 years (range: 24-50)) participated in this study. Gait analysis using lower-trunk accelerometry was performed at self-selected walking pace. Postural stability was measured via center of pressure displacement analysis using a force platform during eyes-closed normal stance. Handgrip myotonia was quantified using force-relaxation curve modeling. Patients displayed lower walking speed, stride frequency, stride length, gait regularity, and gait symmetry. Strength of ankle plantar flexors, ankle dorsal flexors and neck flexors correlated with interstride regularity in the vertical direction (ρ = 0.57, ρ = 0.59, and ρ = 0.44, respectively; all P < 0.05). Knee extension strength correlated with gait symmetry in the anteroposterior direction (ρ = 0.45, P < 0.05). Center of pressure velocity was greater in patients and correlated with neck flexion and ankle plantar flexion weakness (ρ = -0.51 and ρ = -0.62, respectively; both P < 0.05), and with interstride regularity in the vertical direction (ρ = -0.58, P < 0.05). No correlation was found between handgrip myotonia and any other variable studied. Lower-trunk accelerometry allows the characterization of gait pattern abnormalities in patients with DM1. Further studies are required to determine the relevance of systematic gait analysis using lower-trunk accelerometry for patient follow-up and intervention planning.

Longitudinal functional and NMR assessment of upper limbs in Duchenne muscular dystrophy.

OBJECTIVE: To explore the value of nuclear magnetic resonance (NMR) and functional assessments for follow-up of ambulatory and nonambulatory patients with Duchenne muscular dystrophy (DMD). METHODS: Twenty-five 53-skippable patients with DMD were included in this study; 15 were nonambulatory at baseline. All patients underwent clinical and functional assessments every 6 months using the Motor Function Measure (MFM), hand grip and key pinch strength, MoviPlate, and NMR spectroscopy and imaging studies. RESULTS: Upper limb distal strength decreased in nonambulatory patients over the period of 1 year; ambulatory patients showed improvement during the same period. The same applied for several NMRS indices, such as phosphocreatine/adenosine triphosphate, which decreased in older patients but increased in younger ambulatory patients. Fat infiltration in the upper limbs increased linearly with age. Almost all NMR and functional assessment results correlated. CONCLUSIONS: Our results underscore complementarity of functional and NMR assessments in patients with DMD. Sensitivity to change of various indices may differ according to disease stage.

Upper limb strength and function changes during a one-year follow-up in non-ambulant patients with Duchenne Muscular Dystrophy: an observational multicenter trial.

INTRODUCTION: Upper limb evaluation of patients with Duchenne Muscular Dystrophy is crucially important to evaluations of efficacy of new treatments in non-ambulant patients. In patients who have lost ambulation, there are few validated and informative outcome measures. In addition, longitudinal data demonstrating sensitivity to clinical evolution of outcome measures over short-term periods are lacking. PATIENTS AND METHODS: We report here the results of a one-year multicenter study using specifically designed tools to assess grip, pinch strength, and hand function in wheelchair-bound patients. Our study assessed 53 non-ambulant patients with Duchenne muscular dystrophy aged 17.1 ± 4.8 years (range: 9 - 28.1 years). The average Brooke functional score of these patients was 4.6 ± 1.1. The average forced vital capacity was 44.5% predicted and 19 patients used non-invasive ventilation. Patients were assessed at baseline, 6 months, and one year using the Motor Function Measure and innovative devices (namely the MyoSet composed of MyoGrip, MyoPinch, and MoviPlate). RESULTS: Our study confirmed preliminary data previously reported regarding feasibility of use and of reliability of the MyoSet and the correlation at baseline between distal strength and clinical outcomes such as FVC, Brooke score, age, and duration since loss of ambulation. A significant correlation was observed between the distal upper limb strength and clinical variables. The sensitive dynamometers (MyoGrip and MyoPinch) and MoviPlate captured a 12-month change in non-ambulant Duchenne muscular dystrophy patients of all ages. TRIAL REGISTRATION: ClinicalTrials.gov NCT00993161 NCT00993161.