Nusinersen treatment in adults with severe spinal muscular atrophy: A real-life retrospective observational cohort study.

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease due to homozygous loss-of-function of the survival motor neuron gene SMN1 with absence of the functional SMN protein. Nusinersen, a costly intrathecally administered drug approved in 2017 in Europe, induces alternative splicing of the SMN2 gene, which then produces functional SMN protein, whose amount generally increases with the number of SMN2 gene copies. METHODS: We retrospectively collected data from consecutive wheelchair-bound adults with SMA managed at a single center in 2018-2020. The following were collected at each injection, on days 1, 14, 28, 63, 183, and 303: 32-item Motor Function Measurement (MFM) total score and D2 and D3 subscores; the Canadian Occupational Performance Measure (COPM) performance and satisfaction scores; and lung function tests. The patients were divided into two groups based on whether their MFM total score was

Clinical correlations and long-term follow-up in 100 patients with sarcoglycanopathies.

BACKGROUND AND PURPOSE: To describe a large series of patients with α, ß, and γ sarcoglycanopathies (LGMD-R3, R4, and R5) and study phenotypic correlations and disease progression. METHODS: A multicentric retrospective study in four centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic, and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time-to-event analysis was performed. RESULTS: One hundred patients (54 γ-SG; 41 α-SG; 5 ß-SG) from 80 families were included. The γ-SG patients had earlier disease onset than α-SG patients (5.5 vs. 8 years; p = 0.022) and ß-SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow-up of 22.9 years, 65.3% of patients were wheelchair-bound (66.7% α-SG, 67.3% γ-SG, 40% ß-SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ-SG patients (p = 0.01). Thirty patients were ventilated and six died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time to LoA (p = 0.021 and p = 0.002). Age at onset was an independent predictor of both severity and time to LoA (p = 0.0004 and p = 0.009). The α-SG patients showed genetic heterogeneity, whereas >90% of γ-SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified. CONCLUSIONS: This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA, and should be taken into account in future clinical trials.

[Respiratory and intensive care aspects of muscular dystrophies]. / Aspects respiratoires et réanimatoires des dystrophies musculaires.

Among the various myopathies, Duchenne muscular dystrophy represents the myopathy with the most stereotypical respiratory evolution. This progressive respiratory failure is going to develop in a parallel way of motor deficit, conducting patients to mechanical ventilation at the end of their second decade. In the absence of curative therapeutics, respiratory cares like home ventilation and prevention of respiratory complications, in a systematic and organized way, allowed to decrease the morbidity and the mortality of these patients. It is not exceptional to meet patients with life expectancy of which overtakes about forty. Besides axial stabilization, cough assistance techniques and swallowing disorders management need to be associated to mechanical ventilation. Invasive techniques of ventilation as tracheostomy keep their place in this pathology even if alternative techniques allowing full day non-invasive ventilation were generalized these last years.

Be careful about abdominal discomfort in adult patients with muscular dystrophy.

Muscular dystrophies are genetic muscular disease with disability. Heart failure is a classical complication mainly in Duchenne muscular dystrophy (DMD). We report 2 cases of severe acute heart failure revealed by abdominal discomfort in a patient with DMD and in a patient with gamma-sarcoglycanopathy.

Increased incidence of Campylobacter jejuni-associated Guillain-Barré syndromes in the Greater Paris area.

The role of Campylobacter jejuni as the triggering agent of Guillain-Barré syndrome (GBS) has not been reassessed since the end of the 1990s in France. We report that the number of C. jejuni-related GBS cases increased continuously between 1996 and 2007 in the Paris region (mean annual increment: 7%, P = 0·007).

A comparison of recording modalities of P300 event-related potentials (ERP) for brain-computer interface (BCI) paradigm.

AIMS OF THE STUDY: A brain-computer interface aims at restoring communication and control in severely disabled people by identification and classification of EEG features such as event-related potentials (ERPs). The aim of this study is to compare different modalities of EEG recording for extraction of ERPs. The first comparison evaluates the performance of six disc electrodes with that of the EMOTIV headset, while the second evaluates three different electrode types (disc, needle, and large squared electrode). MATERIAL AND METHODS: Ten healthy volunteers gave informed consent and were randomized to try the traditional EEG system (six disc electrodes with gel and skin preparation) or the EMOTIV Headset first. Together with the six disc electrodes, a needle and a square electrode of larger surface were simultaneously recording near lead Cz. Each modality was evaluated over three sessions of auditory P300 separated by one hour. RESULTS: No statically significant effect was found for the electrode type, nor was the interaction between electrode type and session number. There was no statistically significant difference of performance between the EMOTIV and the six traditional EEG disc electrodes, although there was a trend showing worse performance of the EMOTIV headset. However, the modality-session interaction was highly significant (P<0.001) showing that, while the performance of the six disc electrodes stay constant over sessions, the performance of the EMOTIV headset drops dramatically between 2 and 3h of use. Finally, the evaluation of comfort by participants revealed an increasing discomfort with the EMOTIV headset starting with the second hour of use. CONCLUSION: Our study does not recommend the use of one modality over another based on performance but suggests the choice should be made on more practical considerations such as the expected length of use, the availability of skilled labor for system setup and above all, the patient comfort.

The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease.

Pompe disease is a rare autosomal recessive muscle lysosomal glycogenosis, characterised by limb-girdle muscle weakness and frequent respiratory involvement. The French Pompe registry was created in 2004 with the initial aim of studying the natural history of French patients with adult Pompe disease. Since the marketing in 2006 of enzyme replacement therapy (alglucosidase alfa, Myozyme(®)), the French Pompe registry has also been used to prospectively gather the biological and clinical follow-up data of all adult patients currently treated in France. This report describes the main clinical and molecular features, at the time of inclusion in the French registry, of 126 patients followed up in 21 hospital-based neuromuscular or metabolic centres. Sixty-five men and 61 women have been included in the registry. Median age at inclusion was 49 years, and the median age at onset of progressive limb weakness was 35 years. Fifty-five percent of the patients were walking without assistance, 24% were using a stick or a walking frame, and 21% were using a wheelchair. Forty-six percent of the patients needed ventilatory assistance, which was non-invasive in 35% of the cases. When performed, muscle biopsies showed specific features of Pompe disease in less than two-thirds of the cases, confirming the importance of acid alpha-glucosidase enzymatic assessment to establish the diagnosis. Molecular analysis detected the common c.-32-13T>G mutation, in at least one allele, in 90% of patients. The French Pompe registry is so far the largest country-based prospective study of patients with Pompe disease, and further analysis will be performed to study the impact of enzyme replacement therapy on the progression of the disease.

Strength of shock-loaded single-crystal tantalum [100] determined using in situ broadband x-ray Laue diffraction.

The strength of shock-loaded single crystal tantalum [100] has been experimentally determined using in situ broadband x-ray Laue diffraction to measure the strain state of the compressed crystal, and elastic constants calculated from first principles. The inferred strength reaches 35 GPa at a shock pressure of 181 GPa and is in excellent agreement with a multiscale strength model [N. R. Barton et al., J. Appl. Phys. 109, 073501 (2011)], which employs a hierarchy of simulation methods over a range of length scales to calculate strength from first principles.

[Heart involvement in sarcoglycanopathies]. / Cœur et sarcoglycanopathies.

Sarcoglycanopathies (SG) are autosomic recessive muscular dystrophies, secondary to mutations of the sarcoglycan complex. Clinical pictures include muscle weakness affecting mainly the proximal limb girdle musculature. We review heart involvement in this group of disease.

Development of a GIS method to localize critical source areas of diffuse nitrate pollution.

The present study aimed at developing a universal method for the localization of critical source areas (CSAs) of diffuse nitrate (NO3-) pollution in rural catchments with low data availability. Based on existing methods, land use, soil, slope, riparian buffer strips and distance to surface waters were identified as the most relevant indicator parameters for diffuse agricultural NO3- pollution. The five parameters were averaged in a GIS-overlay to localize areas with low, medium and high risk of NO3- pollution. A first application of the GIS approach to the Ic catchment in France, showed that identified CSAs were in good agreement with results from river monitoring and numerical modelling. Additionally, the GIS approach showed low sensitivity to single parameters, which makes it robust to varying data availability. As a result, the tested GIS-approach provides a promising, easy-to-use CSA identification concept, applicable for a wide range of rural catchments.

[Enzyme replacement therapy of lysosomal storage diseases]. / Thérapies enzymatiques substitutives des maladies lysosomales.

Extraction and purification of an acid ß-glucosidase from human placenta (alglucerase) for the treatment of Gaucher disease, replaced a few years later by a recombinant enzyme (imiglucérase, Cerezyme(®)), has paved the way to the development of enzyme replacement therapies (ERT) for the treatment of lysosomal storage diseases (LSD) among which Fabry disease for which the long-term efficacy of the two currently available preparations (agalsidase alfa, Replagal(®) and Fabrazyme(®)) is still being investigated. Mucopolysaccharidosis (MPS) type I (Hurler and Scheie diseases), II (Hunter syndrome) and VI (Maroteaux-Lamy disease) also benefit from ERT using laronidase (Aldurazyme(®)), idursulfase (Elaprase(®)) and galsulfase (Naglazyme(®)), respectively. ERT reduces the hepatosplenomegaly and improves the physical and respiratory capacities of MPS patients with a globally acceptable safety profile although the possibility of infusion-associated should always be kept in mind. Alglucosidase alpha (Myozyme(®)) improves the cardiomyopathy and life expectancy of infants suffering from Pompe disease and is under evaluation for the treatment of the juvenile and adult forms of the disease. CNS involvement remains a major challenge for many LSD and innovative research and approaches are needed to address the fact that recombinant enzymes do not cross the blood-brain barrier and therefore are not expected to lead to any improvement in CNS damages, except if alternative routes such as intrathecal administration would be developed. Molecular chaperones (e.g. migalastat for Fabry disease) and inhibitors of glucosylceramide synthesis (e.g. eliglustat tartrate for Gaucher disease) are currently under investigation in various clinical trials.

Efficacy and tolerance of gastrostomy feeding in Duchenne muscular dystrophy.

Undernutrition occurs often in individuals with Duchenne muscular dystrophy (DMD). Between 1997 and 2007, a gastrostomy was placed in 25 patients with DMD (median: 23 years old; range, 11-38 years) for weight loss (n=22) and/or swallowing disorders (n=13). We evaluated nutritional status using the weight-for-age (W/A) ratio, comparing the values to the reference curve for DMD patients. During the first 9 months, nutritional status improved: the W/A ratio increased and reached a plateau. The W/A ratio was 69% (range, 45-128%) at the start and increased to 87% (range, 49-164%) at the maximal follow-up of 22 months (P<0.001). However, the W/A ratio did not reach the median value for age. Complications occurred in 21 patients (84%), but caused no mortality. Our data suggest that gastrostomy is well tolerated by, and effective for improving the nutritional status of, individuals with DMD.

[Neuromuscular diseases: imaging of thoracic, digestive and urinary complications]. / Pathologies neuromusculaires: imagerie des complications thoraciques, digestives et urinaires.

Neuromuscular diseases have different characteristics. Respiratory and cardiovascular manifestations are frequent and severe. Respiratory difficulties secondary to muscle involvement and bronchial secretions worsen complications related to a frequent scoliosis. CT is a useful complement to standard radiographs in the setting of acute symptomatic deterioration and for presurgical evaluation of a scoliosis. Echocardiography is performed to determine the presence of cardiomyopathy. Gastrointestinal motility disorders are assessed with standard barium studies or CT in the acute setting. Urinary tract involvement also is possible in these patients given the increased survival and follow-up imaging may be helpful for palliative management. The imaging features of frequent manifestations will be discussed along with the imaging appearance of a few specific entities.

Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7.

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. Mutations of DOK7 have recently been described in recessive forms of CMS. Dok-7 is a cytoplasmic post-synaptic protein co-activator of the muscle-specific receptor-tyrosine kinase (MuSK) involved in neuromuscular synaptogenesis and maintenance. We report clinical, morphological and molecular data on 15 patients with mutations in DOK7. Eleven different mutations (5 novel) were identified and all patients but one were found to carry at least the common c.1124_1127dupTGCC mutation. Patients with DOK7 mutations have a particular limb-girdle pattern, without tubular aggregates but a frequent lipidosis on the muscle biopsy. Changes in pre- and post-synaptic compartments of the neuromuscular junction were also observed in muscle biopsies: terminal axons showed defective branching which resulted in a unique terminal axon contacting en passant postsynaptic cups. Clinical features, muscle biopsy findings or response to therapy were confusing in several patients. Characterization of this distinct phenotype is essential to provide clues for targeted genetic screening and to predict the therapeutic response to anticholinesterase treatments or ephedrine as has been suggested.

Tongue weakness is associated with respiratory failure in patients with severe Guillain-Barré syndrome.

OBJECTIVE: Swallowing impairment may worsen respiratory weakness and conduct to respiratory complications such as aspiration pneumonia in Guillain-Barré syndrome (GBS). We prospectively evaluate how tongue weakness could be associated to bulbar dysfunction and respiratory weakness in severe GBS patients. MEASUREMENTS AND MAIN RESULTS: Tongue strength, dysphagia and respiratory parameters were measured in 16 GBS patients at intensive care unit (ICU) admission and discharge and in seven controls. Tongue strength was decreased in the GBS patients compared with the controls. At admission, patients with dysphagia and those requiring mechanical ventilation (MV) had greater tongue weakness. All the patients with initial tongue strength <150 g required MV during ICU stay. Tongue strength correlated significantly with respiratory parameters. CONCLUSION: This study confirms the strong association between bulbar and respiratory dysfunction in GBS admitted to ICU. Tongue weakness may be present in GBS, especially during the phase of increasing paralysis, and resolves during the recovery phase. Tongue strength and indices of global and respiratory strength vary in parallel throughout the course of GBS. Further studies are needed to assess if, when used in combination with other respiratory tests, tongue strength measurement could contribute to identify patients at high risk for respiratory complications.

Complete atrioventricular block in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. It is characterized by progressive muscle wasting and weakness of variable distribution and severity. Heart is involved leading to heart failure. Conduction abnormalities are unusual. We report a case of complete atrio-ventricular block in a DMD patient.

Dehydroepiandrosterone for myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 may be associated with low circulating dehydroepiandrosterone (DHEA) levels. This study was aimed at investigating the efficacy and safety of DHEA in myotonic dystrophy type 1 patients. METHODS: This was a prospective, multicenter, randomized, double-blind, placebo-controlled trial conducted from February 2005 to January 2006 at 10 university-affiliated neuromuscular disease centers in France. Seventy-five ambulatory adults with myotonic dystrophy type 1 received an oral replacement dose (100 mg/d) or a pharmacologic dose (400 mg/d) of DHEA, or placebo. The primary endpoint was the relative change in the manual muscle testing (MMT) score from baseline to week 12. Secondary outcome measures included changes from baseline to week 12 in quantitative muscle testing and timed functional testing, respiratory and cardiac function, and quality of life. This study was registered with ClinicalTrials.gov identifier NCT00167609. RESULTS: The median (1st, 3rd quartile) relative changes in MMT score from baseline to week 12 after randomization were 3.1 (-0.9, 6.7), 1.9 (-2.7, 3.5), and 2.2 (0, 7.9), in the DHEA 100 mg, DHEA 400 mg, and placebo groups, respectively. There were no differences between placebo and combined DHEA groups (p = 0.34), placebo and DHEA 100 mg (p = 0.86), or placebo and DHEA 400 mg (p = 0.15). There were also no evidence for a difference between groups for the changes from baseline to week 12 in any secondary outcome. CONCLUSIONS: There is no evidence that a 12-week treatment with replacement or pharmacologic doses of dehydroepiandrosterone improves muscle strength in ambulatory myotonic dystrophy type 1 patients.