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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 [FFT2 ] 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. FFT2 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. ispartof: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY vol:8 issue:2 pages:359-373 ispartof: location:United States status: published

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.

Objective Our aim was to assess the role of quantitative 1H and 23Na MRI methods in providing imaging biomarkers of disease activity and severity in patients with Facioscapulohumeral muscular dystrophy (FSHD). Methods We imaged the lower leg muscles of 19 FSHD patients and 12 controls with a multimodal MRI protocol to obtain STIR-T2w images, fat fraction (FF), water T2 (wT2), water T1 (wT1), tissue sodium concentration (TSC), and intracellular-weighted sodium signal (inversion recovery (IR) and triple quantum filter (TQF) sequence). In addition, the FSHD patients underwent muscle strength testing. Results Imaging biomarkers related with water mobility (wT1 and wT2) and ion homeostasis (TSC, IR, TQF) were increased in muscles of FSHD patients. Muscle groups with FF > 10% had higher wT2, wT1, TSC, IR, and TQF values than muscles with FF 1 was increased in few muscles without fat replacement. Furthermore, few STIR-negative muscles (n = 11/76) exhibited increased wT1, TSC, IR or TQF. Increased wT1 as well as 23Na signals were also present in muscles with normal wT2. Muscle strength was related to the mean FF and all imaging biomarkers of tibialis anterior except wT2 were correlated with dorsal flexion. Conclusion The newly evaluated imaging biomarkers related with water mobility (wT1) and ion homeostasis (TSC, IR, TQF) showed different patterns compared to the established markers like FF in muscles of FSHD patients. These quantitative biomarkers could thus contain valuable complementary information for the early characterization of disease progression.

The purpose of this study was to examine exercise effects on muscle water T2 in patients with Duchenne muscular dystrophy (DMD). In 12 DMD subjects and 19 controls, lower leg muscle fat (%) was measured by Dixon and muscle water T2 and R2 (1/T2) by the tri-exponential model. Muscle water R2 was measured again at 3 hours after an ankle dorsiflexion exercise. The muscle fat fraction was higher in DMD participants than in controls (p < .001) except in the tibialis posterior muscle. Muscle water T2 was measured independent of the degree of fatty degeneration in DMD muscle. At baseline, muscle water T2 was higher in all but the extensor digitorum longus muscles of DMD participants than controls (p < .001). DMD participants had a lower muscle torque (p < .001) and exerted less power (p < .01) during exercise than controls. Nevertheless, muscle water R2 decreased (T2 increased) after exercise from baseline in DMD subjects and controls with greater changes in the target muscles of the exercise than in ankle plantarflexor muscles. Skeletal muscle water T2 is a sensitive biomarker of the disease status in DMD and of the exercise response in DMD patients and controls.

Introduction Patients with anoctamin-5 (ANO5) mutations may present not only with limb-girdle muscular dystrophy type 2L or adult-onset Miyoshi-type myopathy but also with asymptomatic hyperCKemia, exercise intolerance, or rhabdomyolysis. Materials and methods Data from 38 patients in France with ANO5 mutations with and without muscle weakness on first examination were compared. Results Twenty patients presented without muscle weakness. Median age at symptom onset or discovery of hyperCKemia was 23 years. Creatine kinase levels ranged from 200 to 40,000 U/L. Electromyography showed a myopathic pattern in 5 patients, and muscle imaging showed involvement of posterior calf muscles in 10 patients. Mild cardiac involvement was observed in 2 patients. Sixteen patients remain free of weakness after a median follow-up period of 5 years. Discussion Asymptomatic, sometimes mild hyperCKemia or exercise intolerance is a presentation of ANO5-related myopathy and may remain isolated or precede muscle weakness by many years. Muscle Nerve 56: 1096-1100, 2017.

Because respiratory failure remains a major issue in Duchenne Muscular Dystrophy patients, respiratory muscles are a key target of systemic therapies. In the Golden Retriever Muscular Dystrophy (GRMD) dogs, the disease shows strong clinical and histological similarities with the human pathology, making it a valuable model for preclinical therapeutic trials. We report here the first nuclear magnetic resonance (NMR) imaging anatomical study of the diaphragm in GRMD dogs and healthy controls. Both T1- and T2-weighted images of the diaphragm of seven healthy and thirteen GRMD dogs, from 3 to 36 months of age, were acquired on a 3 tesla NMR scanner. Abnormalities of texture and shape were revealed and consisted of increases in signal intensity on T2-weighted images and in signal heterogeneity on both T1- and T2-weighted images of the dystrophic diaphragm. These abnormalities were associated with a significant thickening of the muscle and we identified a clear 8-mm-threshold distinguishing clinically preserved GRMD dogs from those more severely affected. In this study, we demonstrated the feasibility of NMR imaging of the diaphragm and depicted several anatomical and mesoscopic anomalies in the dystrophic diaphragm. NMR imaging of the diaphragm shows a promise as an outcome measure in preclinical trials using GRMD dogs.

International audience; Nemaline myopathies are clinically and genetically heterogeneous muscle diseases characterized by the presence of nemaline bodies (rods) in muscle fibers. Mutations in the KLHL40 (kelch-like family member 40) gene (NEM 8) are common cause of severe/lethal nemaline myopathy. We report an 8-year-old girl born to consanguineous Moroccan parents, who presented with hypotonia and poor sucking at birth, delayed motor development, and further mild difficulties in walking and fatigability. A muscle biopsy revealed the presence of nemaline bodies. KLHL40 gene Sanger sequencing disclosed a never before reported pathogenic homozygous mutation which resulted in absent KLHL40 protein expression in the muscle. This further expands the phenotypical spectrum of KLHL40 related nemaline myopathy.

Autosomal dominant pathogenic variants in the filamin C gene (FLNC) have been associated with myofibrillar myopathies, distal myopathies, and isolated cardiomyopathies. Mutations in different functional domains of FLNC can cause various clinical phenotypes. A novel heterozygous missense variant c.608G>A, p.(Cys203Tyr) in the actin binding domain of FLCN was found to cause an upper limb distal myopathy (MIM #614065). The muscle MRI findings are similar to those observed in FLNC-myofibrillar myopathy (MIM #609524). However, the muscle biopsy revealed >20% of muscle fibers with nemaline bodies, in addition to numerous ring fibers and a predominance of type 1 fibers. Overall, this case shows some unique and rare aspects of FLNC-myopathy constituting a new morphologic phenotype of FLNC-related myopathies.

ObjectiveWe studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchenne muscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction (FF) to age on loss of ambulation (LoA).MethodsVL FFs were determined on longitudinal Dixon MRI scans from 2 natural history studies in Leiden University Medical Center (LUMC) and Cincinnati Children's Hospital Medical Center (CCHMC). CCHMC included ambulant patients, while LUMC included a mixed ambulant and nonambulant population. We fitted longitudinal VL FF values to a sigmoidal curve using a mixed model with random slope to predict individual trajectories. The additive value of VL FF over age to predict LoA was calculated from a Cox model, yielding a hazard ratio.ResultsEighty-nine MRIs of 19 LUMC and 15 CCHMC patients were included. At similar age, 6-minute walking test distances were smaller and VL FFs were correspondingly higher in LUMC compared to CCHMC patients. Hazard ratio of a percent-point increase in VL FF for the time to LoA was 1.15 for LUMC (95% confidence interval [CI] 1.05–1.26;p= 0.003) and 0.96 for CCHMC (95% CI 0.84–1.10;p= 0.569).ConclusionsThe hazard ratio of 1.15 corresponds to a 4.11-fold increase of the instantaneous risk of LoA in patients with a 10% higher VL FF at any age. Although results should be confirmed in a larger cohort with prospective determination of the clinical endpoint, this added predictive value of VL FF to age on LoA supports the use of qMRI FF as an endpoint or stratification tool in clinical trials.

The Jain COS Consortium., Practice of sports during childhood or adolescence correlates with an earlier onset and more rapidly progressing phenotype in dysferlinopathies. To determine if this correlation relates to greater muscle pathology that persists into adulthood, we investigated the effect of exercise on the degree of muscle fatty replacement measured using muscle MRI. We reviewed pelvic, thigh and leg T1W MRI scans from 160 patients with genetically confirmed dysferlinopathy from the Jain Foundation International clinical outcomes study in dysferlinopathy. Two independent assessors used the Lamminen-Mercuri visual scale to score degree of fat replacement in each muscle. Exercise intensity for each individual was defined as no activity, minimal, moderate, or intensive activity by using metabolic equivalents and patient reported frequency of sports undertaken between the ages of 10 and 18. We used ANCOVA and linear modeling to compare the mean Lamminen-Mercuri score for the pelvis, thigh, and leg between exercise groups, controlling for age at assessment and symptom duration. Intensive exercisers showed greater fatty replacement in the muscles of the pelvis than moderate exercisers, but no significant differences of the thigh or leg. Within the pelvis, Psoas was the muscle most strongly associated with this exercise effect. In patients with a short symptom duration of, The estimated $4 million USD needed to fund this study was provided by the Jain Foundation. VS was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1.

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.

Muscle imaging is increasingly important in the management of neuromuscular diseases, and techniques are becoming ever more sophisticated. Three new studies demonstrate the advances being made in diagnostic and quantitative muscle imaging, including the incorporation of artificial intelligence for image analysis.

International audience; 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.

Myofibrillar myopathies (MFM) have been described in the mid-1990s as a group of diseases sharing common histological features, including an abnormal accumulation of intrasarcoplasmic proteins, the presence of vacuoles and a disorganization of the intermyofibrillar network beginning at the Z-disk. The boundaries of this concept are still uncertain, and whereas six genes (DES, CRYAB, LDB3/ZASP, MYOT, FLNC and BAG3) are now classically considered as responsible for MFM, other entities such as FHL1 myopathy or Hereditary Myopathy with Early Respiratory Failure linked to mutations of titin can now as well be included in this group. The diagnosis of MFM is not always easy; as histological lesions can be focal, and muscle biopsy may be disappointing; this has led to a growing importance of muscle imaging, and the selectivity of muscle involvement has now been described in several disorders. Due to the rarity of these myopathies, if some clinical patterns (such as distal myopathy associated with cardiomyopathy due to desmin mutations) are now well known, surprises remain possible and should lead to systematic testing of the known genes in case of a typical histological presentation. In this paper, we aim at reviewing the data acquired on the six main genes listed above as well as presenting the experience from two French reference centres, Paris and Marseilles.

In recent years, MRI has proven its usefulness for the diagnostic workup of patients with musculo-skeletal diseases, and also shown great promise as a non-invasive, quantitative outcome measure in clinical studies. The characterization of patterns of fatty degenerative lesions, which now plays an important part in the diagnosis of some diseases, is typically performed by the radiologist on routine T1-weighted images. We propose to rationalize acquisitions and reduce patients' time in the scanner by allowing radiologists to perform the qualitative grading of the muscles on images derived from fat/water acquisitions. These maps are color-coded, where the different colors correspond to classes of fatty infiltration degree. This allows a quick visual assessment of the muscles, equivalent to the standard method. Using the weighted Kappa agreement test, the agreement between the proposed method and the traditional one, as well as the reproducibility of the results with two raters, was measured on twenty patients suffering from various neuromuscular pathologies. The presented comparisons show that the use of color coded fat fraction maps is statistically equivalent to using the traditional T1-weighted images when performing visual assessment of degenerative lesions with fatty infiltrations in patients with neuromuscular disorders.

Introduction: Acid α-glucosidase deficiency, that is, Pompe disease, is a glycogenosis for which enzyme replacement therapy (ERT) is available. It is not known whether patients diagnosed at an asymptomatic stage should be treated to prevent progression of the disease. Methods: We investigated 7 patients with asymptomatic Pompe disease identified from the French Pompe registry. Results: The patients had a mean age of 45 (range 24–75) years, a median follow-up duration of 2 (range 1–22) years, and normal clinical examination, pulmonary function tests (PFTs), and echocardiography. All presented with at least 1 subclinical abnormality, including hyperCKemia, vacuolar myopathy, and muscle MRI abnormalities, suggesting that subclinical myopathy was present in all cases. Conclusions: Asymptomatic Pompe disease may remain clinically silent for decades, and affected patients should be monitored closely for overt myopathy using clinical examination, PFTs, and muscle MRI to determine when to start ERT. Muscle Nerve 51: 884–889, 2015

Background and objectiveDysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests.MethodsWe present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed.ResultsIn 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment.ConclusionsThe information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials.Clinical trial registrationNCT01676077.

Objective Mutations in one of the 3 genes encoding collagen VI (COLVI) are responsible for a group of heterogeneous phenotypes of which Bethlem myopathy (BM) represents the milder end of the spectrum. Genotype-phenotype correlations and long-term follow-up description in BM remain scarce. Methods We retrospectively evaluated the long-term clinical evolution, and genotype-phenotype correlations in 35 genetically identified BM patients (23 index cases). Results Nineteen patients showed a typical clinical picture with contractures, proximal weakness and slow disease progression while 11 presented a more severe evolution. Five patients showed an atypical presentation, namely a limb girdle muscle weakness in 2 and a congenital myopathy pattern with either no contractures, or only limited to ankles, in 3 of them. Pathogenic COL6A1-3 mutations were mostly missense or in frame exon-skipping resulting in substitutions or deletions. Twenty one different mutations were identified including 12novel ones. The mode of inheritance was, autosomal dominant in 83% of the index patients (including 17% (N=4) with a de novo mutation), recessive in 13%, and undetermined in one patient. Skipping of exon 14 of COL6A1 was found in 35% of index cases and was mostly associated with a severe clinical evolution. Missense mutations were detected in 39% of index cases and associated with milder forms of the disease. Conclusions Long-term follow-up identified important phenotypic variability in this cohort of 35 BM patients. However, worsening of the functional disability appeared typically after the age of 40 in 47% of our patients, and was frequently associated with COL6A1 exon 14 skipping.

Contains fulltext : 182328.pdf (Publisher’s version ) (Closed access) X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.

Limb girdle muscular dystrophy type 2L (LGMD2L) is an adult-onset slowly progressive muscular dystrophy associated with recessive mutations in the ANO5 gene. We analysed the muscle MRI pattern in a cohort of 25 LGMD2L patients in order to understand the extent and progression of muscle pathology in LGM2L and assess if muscle MRI might help in the diagnostic work-up of these patients. Our results showed a homogeneous pattern of muscle pathology on muscle MRI, with a predominant involvement of the posterior compartment muscles in both the thighs and calves. The muscles of the anterior compartments in the leg together with the sartorius and gracilis muscles were best preserved, which partially overlaps with patterns observed for other recessive LGMDs. Muscle MRI therefore does not appear to be as useful in the diagnostic work up of LGMD2L as for other neuromuscular diseases, such as Bethlem myopathy or myofibrillar myopathy. 2012 Published by Elsevier B.V.

The Golden Retriever Muscular Dystrophy (GRMD) dog is the closest animal counterpart of Duchenne muscular dystrophy in humans and has, for this reason, increasingly been used in preclinical therapeutic trials for this disease. The aim of this study was to describe the abnormalities in canine dystrophic muscle non-invasively, quantitatively, thoroughly and serially by means of NMR imaging. Thoracic and pelvic limbs of five healthy and five GRMD dogs were imaged in a 3T NMR scanner at 2, 4, 6 and 9months of age. Standard and fat-saturated T 1 -, T 2 - and proton-density-weighted images were acquired. A measurement of T 1 and a two-hour kinetic study of muscle enhancement after gadolinium-chelate injection were also performed. Ten out of the 15 indices evaluated differed between healthy and GRMD dogs. The maximal relative enhancement after gadolinium injection and the proton-density-weighted/ T 2 -weighted signal ratio were the most discriminating indices. Inter-muscle heterogeneity was found to vary significantly for most of the indices. The body of data that has been acquired here will help in designing and interpreting preclinical trials using dystrophin-deficient dogs.

Background: We wished to identify noninvasive in vivo biomarkers of brain energy deficit in Huntington disease. Methods: We studied 15 early affected patients (mean motor United Huntington Disease Rating Scale, 18 ± 9) and 15 age- and sex-matched controls. We coupled 31phosphorus nuclear magnetic resonance spectroscopy with activation of the occipital cortex in order to measure the relative concentrations of adenosine triphosphate, phosphocreatine, and inorganic phosphate before, during, and after visual stimulation. Results: In controls, we observed an 11% increase in the inorganic phosphate/phosphocreatine ratio (P = .024) and a 13% increase in the inorganic phosphate/adenosine triphosphate ratio (P = .016) during brain activation, reflecting increased adenosine diphosphate concentrations. Subsequently, controls had a return to baseline levels during recovery (P = .012 and .022, respectively). In contrast, both ratios were unchanged in patients during and after visual stimulation. Conclusions: 31Phosphorus nuclear magnetic resonance spectroscopy could provide functional biomarkers of brain energy deficit to monitor therapeutic efficacy in Huntington disease. © 2012 Movement Disorder Society

To describe muscle involvement on whole-body MRI scans in adult patients at different stages of late-onset Pompe disease. Twenty patients aged 37 to 75 were examined. Five were bedridden and required ventilatory support. Axial and coronal T1 turbo-spin-echo sequences were performed on 1.5T or 3T systems. MRI was scored for 47 muscles using Mercuri's classification. Whole-body scans were obtained with a mean in-room time of 29 min. Muscle changes consisted of internal bright signals of fatty replacement without severe retraction of the muscles' corpus. Findings were consistent with previous descriptions of spine extensors and pelvic girdle, but also provided new information on recurrent muscle changes particularly in the tongue and subscapularis muscle. Moreover thigh involvement was more heterogeneous than previously described, in terms of distribution across muscles as well as with respect to the overall clinical presentation. Whole-body MRI provides a very evocative description of muscle involvement in Pompe disease in adults.

Objective: To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy. Methods: The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments. Results: There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies. Conclusions: These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.

Recent years have seen tremendous progress towards therapy of many previously incurable neuromuscular diseases. This new context has acted as a driving force for the development of novel non-invasive outcome measures. These can be organized in three main categories: functional tools, fluid biomarkers and imagery. In the latest category, nuclear magnetic resonance imaging (NMRI) offers a considerable range of possibilities for the characterization of skeletal muscle composition, function and metabolism. Nowadays, three NMR outcome measures are frequently integrated in clinical research protocols. They are: 1/ the muscle cross sectional area or volume, 2/ the percentage of intramuscular fat and 3/ the muscle water T2, which quantity muscle trophicity, chronic fatty degenerative changes and oedema (or more broadly, "disease activity"), respectively. A fourth biomarker, the contractile tissue volume is easily derived from the first two ones. The fat fraction maps most often acquired with Dixon sequences have proven their capability to detect small changes in muscle composition and have repeatedly shown superior sensitivity over standard functional evaluation. This outcome measure will more than likely be the first of the series to be validated as an endpoint by regulatory agencies. The versatility of contrast generated by NMR has opened many additional possibilities for characterization of the skeletal muscle and will result in the proposal of more NMR biomarkers. Ultra-short TE (UTE) sequences, late gadolinium enhancement and NMR elastography are being investigated as candidates to evaluate skeletal muscle interstitial fibrosis. Many options exist to measure muscle perfusion and oxygenation by NMR. Diffusion NMR as well as texture analysis algorithms could generate complementary information on muscle organization at microscopic and mesoscopic scales, respectively. 31P NMR spectroscopy is the reference technique to assess muscle energetics non-invasively during and after exercise. In dystrophic muscle, 31P NMR spectrum at rest is profoundly perturbed, and several resonances inform on cell membrane integrity. Considerable efforts are being directed towards acceleration of image acquisitions using a variety of approaches, from the extraction of fat content and water T2 maps from one single acquisition to partial matrices acquisition schemes. Spectacular decreases in examination time are expected in the near future. They will reinforce the attractiveness of NMR outcome measures and will further facilitate their integration in clinical research trials.

The Golden Retriever Muscular Dystrophy dog lacks dystrophin. Disease progression in this model shares many similarities with the Duchenne muscular dystrophy, both from anatomico pathological and clinical standpoints. The model is increasingly used in pre-clinical trials but needs to be further investigated, particularly with reference to the evaluation of therapies. The aim of this study was to identify quantitative indices that would help characterize the dystrophic dog non-invasively using NMR imaging. Two-month-old dystrophic dogs and healthy control animals were scanned at 4T. Standard T2- and T1-weighted images, fat-saturated T1-weighted images pre- and post-gadolinium chelate injection were acquired and kinetics of muscle enhancement were studied over a 2-h period. Several indices were found to be abnormally high in dystrophic dogs: the T2-weighted/T1-weighted signal ratio, T2-weighted image heterogeneity and maximal signal enhancement post-gadolinium. These may be proposed to evaluate muscle structural alterations non-invasively in this disease.

International audience; Duchenne muscular dystrophy (DMD) is an X-linked inherited muscle-wasting disease primarily affecting young boys with a prevalence of 1:5000. The disease is caused by loss-of-function mutations in the gene encoding for the Dystrophin protein and is characterised by systemic, progressive, irreversible and severe loss of muscle function. Among vector systems that allow efficient in vivo gene transfer, recombinant Adeno Associated Virus vectors (rAAV) hold great promise and result in particular in very efficient transduction of skeletal and cardiac muscles.

Gene and cell therapies convey high hopes for treatment of skeletal and heart muscle diseases. In the experimental protocols under development as well as in the first clinical trials, longitudinal control by an atraumatic procedure is needed. Nuclear magnetic resonance (NMR), via its two modalities, imaging or spectroscopy, should play a major role both for in vivo animal and human studies, because of the great number of parameters that can be measured, sequentially or simultaneously, and because of its aptitude to monitor several steps of protocols, in particular to detect physiological modifications induced by therapies. We review here the many possible applications of nuclear magnetic resonance in gene/cell therapies where muscle is the target organ, with emphasis on the application of nuclear magnetic resonance to functional studies.