Cannabis for the treatment of amyotrophic lateral sclerosis: What is the patients' view?

Cannabis may have therapeutic benefits to relieve symptoms of amyotrophic lateral sclerosis (ALS) thanks to its pleiotropic pharmacological activity. This study is the first to present a large questionnaire-based survey about the "real-life" situation regarding cannabis use in the medical context in ALS patients in France. There were 129 respondents and 28 reported the use of cannabis (21.7%) to relieve symptoms of ALS. Participants mostly reported the use of cannabidiol (CBD) oil and cannabis weed and declared benefits both on motor (rigidity, cramps, fasciculations) and non-motor (sleep quality, pain, emotional state, quality of life, depression) symptoms and only eight reported minor adverse reactions (drowsiness, euphoria and dry mouth). Even if cannabis is mostly used outside medical pathways and could expose patients to complications (street and uncontrolled drugs, drug-drug interactions, adverse effects…), most of the participants reported "rational" consumption (legal cannabinoids, with only few combustion and adverse reactions). Despite some limitations, this study highlights the need for further research on the potential benefits of cannabis use for the management of ALS motor and non-motor symptoms. Indeed, there is an urgent need and call for and from patients to know more about cannabis and secure its use in a medical context.

Care management in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disease characterized by progressive weakness of voluntary muscles of movement as well as those for swallowing, speech and respiration. In the absence of curative treatment, care can improve quality of life, prolong survival, and support ALS patients and their families, and also help them to anticipate and prepare for the end of life. Multidisciplinary management in tertiary centers is recommended in close collaboration with general practitioners, home carers and a dedicated health network. Patients' follow-up deals mainly with motor impairment and physical disability, adaptation, nutrition and respiratory function. Involvement of palliative care as part of the multidisciplinary team management offers patients the possibility of discussing their end of life issues. This review summarizes the different aspects of ALS care, from delivering the diagnosis to the end of life, and the organization of its management.

Revisiting the spectrum of lower motor neuron diseases with snake eyes appearance on magnetic resonance imaging.

BACKGROUND AND PURPOSE: The 'snake eyes' sign refers to bilateral hyperintensities of the anterior horns on axial spinal cord imaging. Based on sporadic reports, it has been associated with a range of lower motor neuron (LMN) syndromes, such as spondylotic amyotrophy and Hirayama disease, as well as spinal cord infarction. The objective of our study was to comprehensively characterize the full diagnostic spectrum of LMN syndromes with this radiological clue and discuss potential aetiological factors. METHODS: A large patient cohort with snake eyes sign and upper limb LMN degeneration was recruited from three French neuromuscular units. Patients underwent detailed electrophysiological, radiological, clinical and anamnestic profiling. RESULTS: Twenty-nine patients were ascertained and followed up for 9.5 ± 8.6 years. The majority of the patients were male (86.2%) with a mean age of 37.3 ± 14.4 years. Symptoms were bilateral in most cases (86.2%). Patients with predominantly proximal and distal deficits were equally represented (44.8% and 55.2%, respectively). A history of preceding trauma or intense physical activity was confirmed in 58.6% of the cases; 27.6% of the patients were given an initial clinical diagnosis of amyotrophic lateral sclerosis (ALS), and 51.7% were originally suspected to have multifocal motor neuropathy. None of the patients developed ALS on longitudinal follow-up. CONCLUSION: The snake eyes sign on magnetic resonance imaging is associated with a wide spectrum of neurological conditions and is more common in young men with a history of strenuous activity or antecedent trauma. The recognition of this syndrome is crucial as many of these patients are initially misdiagnosed with ALS.

[Electrodiagnostic criteria for early diagnosis of bulbar-onset ALS: a comparison of El Escorial, revised El Escorial and Awaji algorithm]. / Apport de l'électromyogramme dans le diagnostic précoce des SLA à début bulbaire: comparaison des critères d'El Escorial, d'El Escorial modifiés et d'Awaji.

INTRODUCTION: Diagnosis of bulbar ALS is difficult at the early stage of the disease. According to guidelines, early diagnosis is better in view to optimize the management of affected patients. To improve the sensitivity without losing specificity of the prior criteria, the Board of Awaji has proposed modified electrodiagnostic criteria for ALS. The aim of this study was to evaluate the contribution of needle electromyography in early diagnosis of bulbar ALS by comparing the El Escorial criteria (EEC), Revised El Escorial Criteria (R-EEC) and Awaji algorithm (AA). METHODS: In a retrospective study, we analysed clinical and electrophysiological data of 46 patients followed in our center for a bulbar-onset ALS seen for the first time between January 2007 and February 2011. All these patients had bulbar-onset ALS probable or certain at the last follow-up. All data were collected during the first clinical examination and the first electrophysiological study. RESULTS: Mean age of the population was 69 (37-90years, sex ratio: 0.91). Using the EEC, 9 patients were diagnosed as definite or probable ALS at the first consultation. Applying the R-EEC, 13 patients were diagnosed as definite or probable ALS and using the AA, 23 patients were diagnosed as definite or probable ALS. The sensitivity of the EEC was 19.5%, the R-EEC was 28.2% and for AA was 49.98%. CONCLUSION: AA are more sensitive in early diagnosis of bulbar ALS compared to R-EEC with the contribution of ENMG and when fasciculations are considered as evidence of spontaneous activity. Such an approach can contribute to accelerate an optimal management of the disease. AA are a breakthrough in the diagnosis of ALS especially in the bulbar-onset forms.

[Efficacy of autologous peripheral blood stem cell transplantation (auto-PBSCT) on the neuropathic manifestations in POEMS syndrome]. / Efficacité à moyen terme de l'autogreffe de cellules souches hématopoïétiques périphériques sur la polyneuropathie du syndrome POEMS: expérience chez 5 cas.

INTRODUCTION: POEMS syndrome (polyneuropathy, organomegaly, endocrynopathy, M-protein, and skin changes) is a rare multisystem disease associated with plasma cell dyscrasia. The efficacy of autologous peripheral blood stem cell transplantation (auto-PBSCT) reported in case series has been mainly based on hematologic criteria and clinical recovery of peripheral neuropathy dysfunctions but has not been specifically evaluated. This retrospective study aimed to analyze the efficacy of auto-PBSCT on disability and electrophysiological patterns in patients with POEMS syndrome. METHODS: Five patients presenting with POEMS syndrome received auto-PBSCT. Disability was evaluated before treatment and at 6 and 12 months using the Overall Neuropathy Limitation Scale (ONLS) and MRC sumscore of 28 muscles. Nerve conduction studies were performed before and one year after treatment, on median, ulnar, fibular and tibial nerves. RESULTS: Mean age was 60.6 years (49-70). Disease duration between first symptoms and auto-PBSCT was 15.4 months (2-33). Before auto-PBSCT, mean ONLS score was 4.2 (1-10) and mean MRC sumscore 115.8/140 (74-140). At M6, mean ONLS score decreased and mean MRC sumscore increased; both were improved in all patients at M12: mean ONLS score 3 (range 0-8) at M6 and 2.2 (range 0-7) at M12; mean MRC sumscore 118/140 (77-140) at M6 and 122.4/140 (80-140) at M12. Significant recovery in electrophysiological patterns was observed in all patients on ulnar and median nerves: before-after treatment differences were observed for motor conduction velocities (34.41 vs. 45.47 m/s; P<0.001), distal CMAP amplitudes (5.04 vs. 5.96 mV; P=0.004), and sensory conduction velocities (43.20 vs. 49.20 m/s; P=0.001). Distal CMAP amplitude remained low in fibular and tibial nerves (0.41 vs. 0.17 mV). CONCLUSIONS: Clinical and electrophysiological improvement is obvious in POEMS syndrome peripheral neuropathy within one year after treatment with auto-PBSCT, undoubtedly resulting from extensive remyelinisation and axonal regeneration. Further studies are required to examine long-term outcome in patients with POEMS syndrome given auto-PBSCT.

Quantitative brainstem and spinal MRI in amyotrophic lateral sclerosis: implications for predicting noninvasive ventilation needs.

BACKGROUND: Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation (NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis. METHODS: Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period. RESULTS: Both the clinical model (R2 = 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures' volumes model (R2 = 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (R2 = 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (R2 = 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes. CONCLUSIONS: Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.

[Facioscapulohumeral muscular dystrophy type 2]. / Dystrophie musculaire facio-scapulo-humérale de type 2.

INTRODUCTION: In recent years, the advances of knowledge in clinical, genetic and epigenetic features of facioscapulohumeral muscular dystrophy (FSHD) allowed the identification of two forms of FSHD, the classical autosomal dominant FSHD type 1, and FSHD type 2 characterized by an identical clinical phenotype but associated with a different (epi)genetic defect. STATE OF THE ART: In the large majority of FSHD1 patients, the identification of D4Z4 pathogenic contraction on a permissive chromosome 4 is sufficient for diagnosis, while FSHD2 diagnosis is complicated by the fact that the genetic defect associated with this disease is not known yet and a complete D4Z4 genotype and a D4Z4 specific methylation test are required. Indeed, FSHD2 patients display a non-contracted D4Z4 allele on chromosomes 4, at least one permissive chromosome 4QA and a profound hypomethylation of both chromosomes 4 and 10. A common pathophysiological pathway has been hypothesized for FSHD1 and FSHD2 in order to explain the identical clinical phenotype and the highly similar epigenetic changes found in patients affected by these diseases. According to this hypothesis, chromatin relaxation - due to pathogenic D4Z4 contraction in FSHD1 patients, and to important hypomethylation of this locus in FSHD2 patients - would allow the last D4Z4 unit to encode for a toxic DUX4 transcript. This transcript would be stable only when encoded from a permissive chromosome 4 carrying a polyadenylation signal immediately distal to the last D4Z4 unit on chromosome 4. PERSPECTIVES: Since, to express clinical phenotype, FSHD2 patients have to carry both 4QA chromosome and hypomethylated D4Z4 on chromosomes 4 and 10, digenic transmission has been hypothesized for this disease. The identification of the gene(s) and the exact epigenetic pathway underlining this disease will be mandatory to increase the rate of diagnosis for FSHD2 patients and to confirm the hypothesis of a common FSHD1 and FSHD2 pathophysiological pathway involving DUX4 gene. CONCLUSIONS: The identification, among patients carrying a FSHD phenotype, of FSHD2, a new disease with distinct (epi)genetic features but having a common pathophysiological pathway with FSHD1, suggests the possibility of developping new therapeutic strategies suitable for both diseases.

[Subjectivity, decision and neurodegenerative diseases: reflexions on the role of the clinical psychologist in medical decision making]. / Subjectivité, décision et maladies neurodégénératives: réflexions sur la place du psychologue clinicien dans le processus décisionnel.

Should a patient be forced to accept a treatment, especially when suffering from a neurodegenerative disease? We argue that physicians, nurses and care givers should instead accept his or her choice in accordance with the principle that every patient is an autonomous person able to make a choice, even in case of declined cognition. Beside the legal obligation, we suggest a theoretical approach and focus on the practical impacts of the patient's decision. Our objective is to promote the value of ethical doubt and attentive listening to individual opinions, so as to improve the quality of the medical staff's work and reduce patients' distress when affected by fatal diseases.

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.

[Phenotypic heterogeneity and phenotype-genotype correlations in dystrophinopathies: Contribution of genetic and clinical databases]. / Variabilité phénotypique et corrélations génotype-phénotype des dystrophinopathies : contribution des banques de données.

The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD database. The collection of 70,000 clinical data for 600 patients with an average longitudinal follow-up of 12years enabled clarification of the natural history of Duchenne and Becker muscular dystrophies and clinical presentations in symptomatic females. We were able to specify the phenotypic heterogeneity of motor, orthopedic and respiratory involvements (severe, standard and intermediary form), of the cardiac disorder (severe, standard or absent cardiomyopathy, absence of correlation between motor and cardiac involvements), and of brain function (mental deficiency in the patients with Becker muscular dystrophy, psychopathological disorders in dystrophinopathies). Phenotypic variability did not correlate with a specific mutational spectrum. We propose a model of phenotypic analysis based on the presence or not of muscular and cardiac involvements (described by age at onset and rate of progression) and brain involvement (described by the type and the severity of the cognitive impairment and of the psychological disorders). The methodology developed for the DMD gene can be generalized and used for other databases dedicated to genetic diseases. Application of this model of phenotypic analysis for each patient and further development of the database should contribute substantially to clinical research providing useful tools for future clinical trials.

The effect of tibialis anterior weakness on foot drop and toe clearance in patients with facioscapulohumeral dystrophy.

BACKGROUND: Facioscapulohumeral dystrophy is a genetic disease characterized by progressive muscle weakness leading to a complex combination of postural instability, foot drop during swing and compensatory strategies during gait that have been related to an increased risk of falling. The aim is to assess the effect of tibialis anterior muscle weakness on foot drop and minimum toe clearance of patients with facioscapulohumeral dystrophy during gait. METHODS: Eight patients allocated to a subgroup depending on the severity of tibialis anterior muscle weakness, assessed by manual muscle testing (i.e., severe and mild weakness), and eight matched control participants underwent gait analysis at self-selected walking speeds. FINDINGS: Walking speed, for all facioscapulohumeral dystrophy patients, and step length, for patients with severe weakness only, were significantly decreased compared to control participants. Minimum toe clearance was similar across all groups, but its variability was increased only for patients with severe weakness. A greater foot drop was systematically observed for patients with severe weakness during swing and only in late swing for patients with mild weakness. Individual strategies to compensate for foot drop remain unclear and may depend on other muscle impairment variability. INTERPRETATION: Although all patients were able to control the average height of their foot trajectory during swing, patients with severe tibialis anterior muscle weakness exhibited increased foot drop and minimum toe clearance variability. Manual muscle testing is a simple, cheap and effective method to assess tibialis anterior muscle weakness and seems promising to identify facioscapulohumeral dystrophy patients with an increased risk of tripping.

Comparison of spinal magnetic resonance imaging and classical clinical factors in predicting motor capacity in amyotrophic lateral sclerosis.

BACKGROUND: Motor capacity is crucial in amyotrophic lateral sclerosis (ALS) clinical trial design and patient care. However, few studies have explored the potential of multimodal MRI to predict motor capacity in ALS. This study aims to evaluate the predictive value of cervical spinal cord MRI parameters for motor capacity in ALS compared to clinical prognostic factors. METHODS: Spinal multimodal MRI was performed shortly after diagnosis in 41 ALS patients and 12 healthy participants as part of a prospective multicenter cohort study, the PULSE study (NCT00002013-A00969-36). Motor capacity was assessed using ALSFRS-R scores. Multiple stepwise linear regression models were constructed to predict motor capacity at 3 and 6 months from diagnosis, based on clinical variables, structural MRI measurements, including spinal cord cross-sectional area (CSA), anterior-posterior, and left-to-right cross-section diameters at vertebral levels from C1 to T4, and diffusion parameters in the lateral corticospinal tracts (LCSTs) and dorsal columns. RESULTS: Structural MRI measurements were significantly correlated with the ALSFRS-R score and its sub-scores. And as early as 3 months from diagnosis, structural MRI measurements fit the best multiple linear regression model to predict the total ALSFRS-R (R2 = 0.70, p value = 0.0001) and arm sub-score (R2 = 0.69, p value = 0.0002), and combined with DTI metric in the LCST and clinical factors fit the best multiple linear regression model to predict leg sub-score (R2 = 0.73, p value = 0.0002). CONCLUSIONS: Spinal multimodal MRI could be promising as a tool to enhance prognostic accuracy and serve as a motor function proxy in ALS.

[Improvement of severe and intravenous immunoglobulin-dependent multifocal motor neuropathy with conduction block after long-term rituximab]. / Amélioration d'un cas de neuropathie motrice multifocale avec blocs de conduction sévère, dépendant des immunoglobulines intraveineuses, après adjonction de rituximab au long cours.

INTRODUCTION: Some patients suffering from multifocal motor neuropathy with conduction blocks (MMNCB) are still disabled after treatment with intravenous immunoglobulin (IVIg). CASE REPORT: We report the benefits of a combination of rituximab (RTX) and IVIg in the case of a 72-year-old man with MMNCB. DISCUSSION: Despite an IVIg treatment, the patient had severe motor weakness of the four limbs which limited daily living activity. Azathioprine, mycophenolate mofetyl and cyclophosphamid did not improve the patient's status. Adjunction of rituximab to IVIg therapy increased muscle strength measured on MRC sum score and reduced disability evaluated on ONLS (Overall Neuropathy Limitation Scale) score in the long term (37 months). In spite of the improvement of his neurological status, the patient remained dependent on IVIg. CONCLUSION: RTX could be proposed as a long-term complementary treatment for some severe cases of IVIg-dependent NMMBC. These results must be confirmed in a randomized controlled study.

[Retinal involvement and genetic myopathy]. / Atteinte rétinienne et myopathies génétiques.

INTRODUCTION: In genetic diseases, association between retinal and muscular involvement is uncommon, quite specific and frequently allows the diagnosis. In this context, three types of retinal involvement have been described: retinitis pigmentosa (RP), pattern retinal dystrophy (PRD) and exudative retinitis resembling Coats disease (CD). STATE OF THE ART: The association between RP, PRD and muscle weakness is highly evocative of a mitochondrial disorder. Extra ocular muscles may be affected, but limb girdle or distal weakness can also be present in association or not with symptoms and signs of multisystemic involvement. In a large number of patients suffering from facioscapulohumeral muscular dystrophy (FSHD), retinal vessels telangectasia can be found at the fundoscopic examination. This finding, which corresponds to a developmental abnormality of peripheral retinal blood vessels, is not progressive and remains clinically asymptomatic. Nevertheless, a few patients with FSHD can develop an exsudative retinopathy resembling Coats disease with the risk of the major complication, recurrent retinal detachments. PERSPECTIVES AND CONCLUSIONS: Considering the diagnostic interest and the deleterious consequences that may follow retinal involvement, close collaboration between the neurologist and ophthalmologist is needed in order to establish the diagnosis, detect complications early, and set up appropriate therapies.

[Validity of the motor function measurement scale when routinely used in the follow-up of adult outpatients in a neuromuscular center]. / Analyse de validité de la "Mesure de la fonction motrice" (MFM) en pratique de consultation adulte d'un centre de référence pour maladies neuromusculaires.

INTRODUCTION: The Motor Function Measure (MFM) is widely used to assess severity and progression of neuromuscular diseases. Validity was established in a group of patients aged 6-60 years with suspected or confirmed diagnosis of neuromuscular diseases, Duchenne Muscular Dystrophy being the most frequent diagnosis in the population tested. OBJECTIVES: Our aim was to check the validity of the MFM in a hospital department specialized in neuromuscular diseases in the follow-up of adult out-patients presenting a myopathy, such population being very different from the MFM validation group in terms of age and sub-groups of myopathy. METHODS: One hundred patients were randomly selected in the Reference Center for Neuromuscular Diseases of Nice (France) between 2005 and 2007. Were collected: the MFM score, manual muscular testing (MMT) of lower and upper limb, face and spine, Brooke and Vignos scores. MFM and its three dimensions D1 (standing position and transfers), D2 (axial and proximal limb motor function) and D3 (distal motor function) were compared to the other scores with the Spearman Correlation Coefficient and the Principal Component Analysis. RESULTS: Patients were aged 18-78 years. The most frequent diagnoses were Steinert's Muscular Dystrophy (DM1) and Facio-ScapuloHumeral Dystrophy (FSHD) (30% and 29%). MFM was significantly correlated to all other scores except for Face MMT. However, Face MMT was correlated to D1 and D2 in DM1 patients and to D2 in FSHD patients. DISCUSSION: Our results confirm the validity of the MFM in adult patients with muscular diseases. However, the MFM global score and its three dimensions D1, D2 and D3 are variously correlated with the facial and axial muscle testing. Therefore, we recommend using separately the three dimensions D1, D2, D3 (rather than the global score) and, if more accuracy is required, the facial and axial muscle testing.

Mechanisms underlying Andersen's syndrome pathology in skeletal muscle are revealed in human myotubes.

Andersen's syndrome is a rare disorder that has been defined with a triad: periodic paralysis, cardiac arrhythmia, and development anomalies. Muscle weakness has been reported in two-thirds of the patients. KCNJ2 remains the only gene linked to Andersen's syndrome; this gene encodes for the alpha-subunit of the strong inward-rectifier K+ channel Kir2.1. Several studies have shown that Andersen's syndrome mutations lead to a loss of function of the K+ channel activity in vitro. However, ex vivo studies on isolated patient muscle tissue have not been reported. We have performed muscle biopsies of controls and patients presenting with clinically and genetically defined Andersen's syndrome disorder. Myoblasts were cultured and characterized morphologically and functionally using the whole cell patch-clamp technique. No morphological difference was observed between Andersen's syndrome and control myoblasts at each passage of the cell culture. Cellular proliferation and viability were quantified in parallel with direct cell counts and showed no difference between control and Andersen's syndrome patients. Moreover, our data show no significant difference in myoblast fusion index among Andersen's syndrome and control patients. Current recordings carried out on myotubes revealed the absence of an inwardly rectifying Ba2+-sensitive current in affected patient cells. One consequence of the Ik1 current loss in Andersen's syndrome myotubes is a shift of the resting membrane potential toward depolarizing potentials. Our data describe for the first time the functional consequences of Andersen's syndrome mutations ex vivo and provide clues to the K+ channel pathophysiology in skeletal muscle.

Alteration of expression of muscle specific isoforms of the fragile X related protein 1 (FXR1P) in facioscapulohumeral muscular dystrophy patients.

BACKGROUND: The Fragile X Mental retardation-Related 1 (FXR1) gene belongs to the fragile X related family, that also includes the Fragile X Mental Retardation (FMR1) gene involved in fragile X syndrome, the most common form of inherited mental retardation. While the absence of FMRP impairs cognitive functions, inactivation of FXR1 has been reported to have drastic effects in mouse and xenopus myogenesis. Seven alternatively spliced FXR1 mRNA variants have been identified, three of them being muscle specific. Interestingly, they encode FXR1P isoforms displaying selective RNA binding properties. METHODS AND RESULTS: Since facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy characterised by altered splicing of mRNAs encoding muscle specific proteins, we have studied the splicing pattern of FXR1 mRNA in myoblasts and myotubes of FSHD patients. We show here that FSHD myoblasts display an abnormal pattern of expression of FXR1P isoforms. Moreover, we provide evidence that this altered pattern of expression is due to a specific reduced stability of muscle specific FXR1 mRNA variants, leading to a reduced expression of FXR1P muscle specific isoforms. CONCLUSION: Our data suggest that the molecular basis of FSHD not only involves splicing alterations, as previously proposed, but may also involve a deregulation of mRNA stability. In addition, since FXR1P is an RNA binding protein likely to regulate the metabolism of muscle specific mRNAs during myogenesis, its altered expression in FSHD myoblasts may contribute to the physiopathology of this disease.

Periodic salbutamol in facioscapulohumeral muscular dystrophy: a randomized controlled trial.

OBJECTIVE: To evaluate the effects on muscle strength of salbutamol administered for 6 months using a periodic regimen in patients presenting with facioscapulohumeral muscular dystrophy (FSHD). DESIGN: Placebo-controlled double-blind randomized study. SETTING: Three clinical centers involved in neuromuscular disorders. PARTICIPANTS: Ambulatory patients (N=112), 56 per group, with genetically confirmed FSHD, age 18 to 60 years. INTERVENTIONS: Salbutamol (sustained released formulation) administered orally at a daily dose of 16 mg using a periodic dosage regimen (3 wks on, 1 wk off). MAIN OUTCOME MEASURES: Muscle strength was assessed with quantitative muscle testing (QMT), manual muscle testing (MMT), and timed motor tests. Patients were evaluated at baseline, and 3 and 6 months later. Plasma drug assays were carried out at each visit. RESULTS: There was no significant change with periodic use of salbutamol in the total composite QMT z-score, MMT score, or timed motor tests. Salbutamol was well tolerated. Lack of efficacy did not seem to be related to plasma concentrations, which were within the expected range. CONCLUSIONS: Results from this study and previous controlled trials preclude at present the use of salbutamol as routine treatment for FSHD, even if we cannot exclude improvement from anabolic effects with a longer duration of treatment.

[Epidemiology of amyotrophic lateral sclerosis]. / Epidémiologie de la SLA.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. Loss of pyramidal and anterior horn motor neurons leads to progressive limb weakness, disability, dysarthria, dysphagia and respiratory insufficiency with a progressive fatal course. The incidence of ALS ranges between 1.5 to 2.5 for 100,000 per year. Although there are familial cases of ALS, about 90% are sporadic and of unknown etiology. Several exogenous risk factors have been documented. However, no convincing evidence has demonstrated in a reproducible manner an association between an environmental or lifestyle risk factor and ALS. Disease duration varies considerably, ranging from a few months to 10-15 years with a mean survival of about 36 months. Prognostic factors such as age, site of disease onset, nutritional, functional and respiratory status at the diagnosis or delay between beginning of the disease and diagnosis have been reported but they appear to be insufficient to explain prognostic variability. These last 15 years, development of supportive care for ALS patients and management in ALS centers may have contributed to improve survival. Finally, ALS centres, and particularly French ALS centres, have developed databases to improve our knowledge of ALS, phenotypic characterization, more accurate phenotype-genotype correlations and thus contribute to new therapeutics developments.

[Anti-MAG paraproteinemic demyelinating polyneuropathy: a clinical, biological, electrophysiological and anatomopathological descriptive study of a 13-patients' cohort]. / Les polyneuropathies avec IgM monoclonale anti-MAG : étude descriptive clinique, biologique, électrophysiologique et anatomopathologique d'une cohorte de 13 patients.

INTRODUCTION: Polyneuropathies associated with IgM paraproteinemia and anti-myelin associated glycoprotein (MAG) antibodies (MAG-PN) have to be differentiated from chronic inflammatory demyelinating polyneuropathies. METHODS: In a retrospective study, we have analyzed clinical, electrophysiological, biological and pathological data from MAG-PN patients. RESULTS: Seven male and six female patients were followed in the department for a mean 2 years (0.5-6.5 years). Mean age at diagnosis was 61 years (44.5-85.5 years). Patients had symmetrical bilateral paresthesia (11/13) and hypoesthesia (11/13) prominent in the lower limbs. Nine patients developed gait ataxia and four patients had moderate distal weakness in the lower limbs. Mean Overall Neuropathy Limitation Scale was 2.3 (0-5). Nerve conduction study showed demyelinating features though delayed distal motor latency on median (206 % of normal value) and ulnar nerves (150% of normal value). Seven out of thirteen patients had at least two nerves with terminal latency index below 0.25. IgM paraproteinemia was of undetermined significance in ten cases and three patients had non-Hodgkin lymphoma. IgM deposits and widening of the peripheral myelin were observed in 5/7 sural nerve biopsies. Anti-MAG antibodies were detected in the sera of all patients using enzyme-linked immunosorbent assay and in 8/12 patients using western blot analysis. CONCLUSIONS: MAG-PN have distinctive clinical, electrophysiological and pathological features. It is a chronic, slowly progressive, predominantly sensory and ataxic neuropathy. Disability is usually moderate. Electrophysiological study shows distal demyelinating process and is highly suggestive of MAG-PN in more than one half of our patients. Several techniques may detect anti-MAG antibodies, they have to be associated to improve sensitivity and specificity of the test.