Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous diseases caused by mutations affecting neuromuscular transmission. Even if the first symptoms mainly occur during childhood, adult neurologists must confront this challenging diagnosis and manage these patients throughout their adulthood. However, long-term follow-up data from large cohorts of CMS patients are lacking and the long-term prognosis of these patients is largely unknown. We report the clinical features, diagnostic difficulties, and long-term prognosis of a French nationwide cohort of 235 adult patients with genetically confirmed CMS followed in 23 specialized neuromuscular centres. Data were retrospectively analysed. Of the 235 patients, 123 were female (52.3%). The diagnosis was made in adulthood in 139 patients, 110 of whom presented their first symptoms before the age of 18. Mean follow-up time between first symptoms and last visit was 34 years (SD = 15.1). Pathogenic variants were found in 19 disease-related genes. CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%). Genotypes were clustered into four groups according to the initial presentation: ocular group (CHRNE-LE, CHRND, FCCMS), distal group (SCCMS), limb-girdle group (RAPSN, COLQ, DOK7, GMPPB, GFPT1), and a variable-phenotype group (MUSK, AGRN). The phenotypical features of CMS did not change throughout life. Only four genotypes had a proportion of patients requiring intensive care unit (ICU) admission that exceeded 20%: RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%). In RAPSN and MUSK patients most ICU admissions occurred before age 18 years and in DOK7 and AGRN patients at or after 18 years of age. Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another in the same patient throughout life, particularly in AGRN, DOK7 and COLQ. At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation; 36.3% of DOK7 patients, 25% of GMPPB patients and 20% of GFPT1 patients were wheelchair-bound; most of the patients who were both wheelchair-bound and ventilated were DOK7 patients. Six patients died in this cohort. The positive impact of therapy was striking, even in severely affected patients. In conclusion, even if motor and/or respiratory deterioration could occur in patients with initially moderate disease, particularly in DOK7, SCCMS and GFPT1 patients, the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit. CHRNE patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved.

Hypersensitivity infusion-associated reactions induced by enzyme replacement therapy in a cohort of patients with late-onset Pompe disease: An experience from the French Pompe Registry.

BACKGROUND AND OBJECTIVES: Pompe disease is a rare hereditary glycogen storage disorder due to lysosomal acid alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) is the only available treatment. Infusion-associated reactions (IAR) are challenging since there are no guidelines for ERT rechallenge after a drug hypersensitivity reaction (DHR) in Pompe disease. The objective of the present study was to describe IAR and their management in late-onset Pompe disease (LOPD) patients in France, and to discuss the various possibilities of ERT rechallenge. METHODS: An exhaustive screening of LOPD patients receiving ERT between 2006 and 2020 from the 31-participating hospital-based or reference centers was performed. The patients who had presented at least one hypersensitivity IAR (=DHR) episode were included. Demographic characteristics of the patients, IAR onset and timing, were retrospectively collected from the French Pompe Registry. RESULTS: Fifteen patients among 115 treated LOPD patients in France presented at least 1 IAR; 80.0% were women. Twenty-nine IAR were reported; 18 (62.1%) IAR were Grade I reactions, 10 (34.5%) IAR were Grade II, and 1 (3.4%) IAR was Grade III. IgE-mediated hypersensitivity was found in 2/15 patients (13.3%). The median [IQR] time from ERT introduction to the first IAR was 15.0 months [11.0-24.0]. ERT was safely and effectively re-introduced either with premedication alone, or in combination with either modified regimen or desensitization protocol, in all 9 rechallenged patients; including in patients with IgE-mediated hypersensitivity, in the patient with the Grade III reaction, as well as in patients with very high anti-GAA titer. DISCUSSION: Based on the results herein and previous reports, we discuss premedication and modified regimen for Grade I reactions, and desensitization in Grade II and III reactions. In conclusion, ERT-induced IAR can be safely and effectively managed with a modified regimen or desensitization protocol in LOPD patients.

Determinants of diaphragm inspiratory motion, diaphragm thickening, and its performance for predicting respiratory restrictive pattern in Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Respiratory status is a key determinant of prognosis in patients with Duchenne muscular dystrophy (DMD). We aimed to evaluate the determinants of diaphragm ultrasound and its performance in predicting restrictive respiratory patterns in DMD. METHODS: This was a retrospective study of DMD patients followed in our center and admitted for an annual checkup from 2015 to 2018. We included DMD patients who underwent diaphragm ultrasound and pulmonary functional tests. RESULTS: This study included 74 patients with DMD. The right diaphragm thickening fraction (TF) was significantly associated with age (P = .001), Walton score (P = .012), inspiratory capacity (IC) (P = .004), upright forced vital capacity (FVC) (P < .0001), supine FVC (P = .038), and maximal inspiratory pressure (MIP) (P = .002). Right diaphragm excursion was significantly associated with age (P < .0001), steroid use (P = .008), history of spinal fusion (P < .0001), body mass index (BMI) (P = .002), Walton score (P < .0001), IC (P < .0001), upright FVC (P < .0001), supine FVC (P < .0001), and MIP (P < .0001). A right diaphragm TF >28% and a right diaphragm excursion>25.4 mm were associated with an FVC >50% with, respectively, an area under the curve (AUC) of 0.95 (P = .001) and 0.93 (P < .001). A left diaphragm TF >26.8% and a left diaphragm excursion >21.5 mm were associated with an FVC >50% with, respectively, an AUC of 0.95 (P = .011) and 0.97 (P < .001). DISCUSSION: Diaphragm excursion and diaphragm TF can predict restrictive pulmonary insufficiency in DMD.

Association between prophylactic angiotensin-converting enzyme inhibitors and overall survival in Duchenne muscular dystrophy-analysis of registry data.

AIMS: To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD). METHODS AND RESULTS: We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). We estimated the association between the prophylactic prescription of ACEi and event-free survival in 668 patients aged 8 to 13 years, with normal left ventricular function, using (i) a Cox model with intervention as a time-dependent covariate, (ii) a propensity-based analysis comparing ACEi treatment vs. no treatment, and (iii) a set of sensitivity analyses. The study outcomes were overall survival and hospitalizations for heart failure (HF) or acute respiratory failure. Among the 668 patients included in the DMD Heart Registry, 576 (mean age 6.1 ± 2.8 years) were eligible for this study, of whom 390 were treated with ACEi prophylactically. Death occurred in 53 patients (13.5%) who were and 60 patients (32.3%) who were not treated prophylactically with ACEi, respectively. In a Cox model with intervention as a time-dependent variable, the hazard ratio (HR) associated with ACEi treatment was 0.49 [95% confidence interval (CI) 0.34-0.72] and 0.47 (95% CI 0.31-0.17) for overall mortality after adjustment for baseline variables. In the propensity-based analysis, 278 patients were included in the treatment group and 834 in the control group, with 18.5% and 30.4% 12-year estimated probability of death, respectively. ACEi were associated with a lower risk of death (HR 0.39; 95% CI 0.17-0.92) and hospitalization for HF (HR 0.16; 95% CI 0.04-0.62). All other sensitivity analyses yielded similar results. CONCLUSION: Prophylactic ACEi treatment in DMD was associated with a significantly higher overall survival and lower rates of hospitalization for HF.

Deep phenotyping of an international series of patients with late-onset dysferlinopathy.

BACKGROUND: To describe the clinical, pathological, and molecular characteristics of late-onset (LO) dysferlinopathy patients. METHODS: Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30 years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS). Patients with early-onset (EO) dysferlinopathy (<30 years) were randomly selected from the COS study as a control group, and the North Star Assessment for Dysferlinopathy (NSAD) and Activity Limitation (ACTIVLIM) scores were used to assess functionality. Muscle biopsies obtained from 11 LO and 11 EO patients were revisited. RESULTS: Forty-eight patients with LO dysferlinopathy were included (28 females). Median age at onset of symptoms was 37 (range 30-57) years and most patients showed a limb-girdle (n = 26) or distal (n = 10) phenotype. However, compared with EO dysferlinopathy patients (n = 48), LO patients more frequently showed atypical phenotypes (7 vs. 1; p = 0.014), including camptocormia, lower creatine kinase levels (2855 vs. 4394 U/L; p = 0.01), and higher NSAD (p = 0.008) and ACTIVLIM scores (p = 0.016). Loss of ambulation in LO patients tended to occur later (23 ± 4.4 years after disease onset vs. 16.3 ± 6.8 years; p = 0.064). Muscle biopsy of LO patients more frequently showed an atypical pattern (unspecific myopathic changes) as well as significantly less necrosis regeneration and inflammation. Although LO patients more frequently showed missense variants (39.8% vs. 23.9%; p = 0.021), no differences in dysferlin protein expression were found on Western blot. CONCLUSIONS: Late-onset dysferlinopathy patients show a higher frequency of atypical presentations, are less severely affected, and show milder dystrophic changes in muscle biopsy.

Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients.

Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.

Quantitative Muscle MRI Depicts Increased Muscle Mass after a Behavioral Change in Myotonic Dystrophy Type 1.

Background Patients with myotonic dystrophy type 1 (DM1) increased their physical activity and exercise capacity following a behavioral intervention. However, it is unknown what is altered in muscles of patients with DM1 as a result of this intervention. The increased exercise capacity suggests that decelerated fat infiltration or increased muscle cross-sectional area (CSA) could be involved. Purpose To assess the effect of this activity-stimulating behavioral intervention on the lower extremity muscles of patients with DM1 with longitudinal quantitative muscle MRI. Materials and Methods In this prospective trial, participants with DM1 were randomized to a behavioral intervention (n = 14) or continued regular care (standard care; n = 13); no age-matched pairing was performed. Participants underwent MRI of the lower extremities at baseline and 10-month follow-up (January 2015 to March 2016). Fat fraction (FF), muscle CSA, and muscle water T2 (T2water) as markers for fat infiltration, muscle mass, and alteration in tissue water distribution (edema), respectively, were assessed with a chemical shift-encoded Dixon sequence and multiecho spin-echo sequence. Longitudinal within-group and between-group changes were assessed with paired-samples t tests and multivariable regression models. Results A total of 27 patients with DM1 (15 men) were evaluated. Patient age was comparable between groups (intervention, 45 years ± 13 [standard deviation]; standard care, 5 years ± 12; P = .96). Muscle CSA increased 5.9 cm2 ± 7.8 in the intervention group during the 10-month follow-up (P = .03) and decreased 3.6 cm2 ± 7.2 in the standard care group (P = .13). After 10 months, the mean difference between the groups was 9.5 cm2 (P = .01). This effect was stronger in muscles with baseline FF below the mean ± standard deviation of unaffected volunteers (-0.4 cm2 ± 0.15; P < .001). FF increased 0.9% ± 1.0 in the intervention group (P = .02) and 1.2% ± 1.2 for standard care (P = .02), with no between-group difference (P = .56). T2water did not change significantly in either group (intervention, P = .08; standard care, P = .88). Conclusion A behavioral intervention targeting physical activity increased lower extremity muscle cross-sectional area in patients with myotonic dystrophy, preferentially in healthy-appearing muscle. © RSNA, 2020 Online supplemental material is available for this article.

Brody myopathy demonstrates a pseudo-increment on repetitive nerve stimulation.

INTRODUCTION: Brody myopathy (BM) is a recessive condition caused by mutations in the ATP2A1 gene and usually induces impaired muscle relaxation during and after exercise. Diagnosis relies on needle electromyography showing electrical silence, muscle biopsy with decreased sarcoplasmic reticulum calcium adenosine triphosphatase activity, and genetic analysis. Electrodiagnostic functional analyses are useful in the diagnosis of channelopathies, and thus may be impaired in BM. METHODS: We performed exercise tests and repetitive nerve stimulation (RNS; 10 supramaximal stimuli at 3 Hz) in 10 patients with BM. RESULTS: All participants showed incremental responses on RNS. Compound muscle action potential amplitude was increased and duration was decreased, especially in the ulnar nerve (+30.2 ± 7.1% and - 30.3 ± 2.8%, respectively; both P < .001). DISCUSSION: Easily accessible, this sign, referred to as the Arzel sign, could prove to be a very useful tool in BM diagnosis and in broadening its phenotype.

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

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

Unusual association of a unique CAG interruption in 5' of DM1 CTG repeats with intergenerational contractions and low somatic mosaicism.

Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder associated with high variability of symptoms and anticipation. DM1 is caused by an unstable CTG repeat expansion that usually increases in successive generations and tissues. DM1 family pedigrees have shown that ∼90% and 10% of transmissions result in expansions and contractions of the CTG repeat, respectively. To date, the mechanisms of CTG repeat contraction remain poorly documented in DM1. In this report, we identified two new DM1 families with apparent contractions and no worsening of DM1 symptoms in two and three successive maternal transmissions. A new and unique CAG interruption was found in 5' of the CTG expansion in one family, whereas multiple 5' CCG interruptions were detected in the second family. We showed that these interruptions are associated with maternal intergenerational contractions and low somatic mosaicism in blood. By specific triplet-prime PCR, we observed that CTG repeat changes (contractions/expansions) occur preferentially in 3' of the interruptions for both families.

Muscle ischaemia associated with NXP2 autoantibodies: a severe subtype of juvenile dermatomyositis.

Objectives: Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM. The aim of our study was to explore without a priori hypotheses whether MSAs are associated with distinct clinical-pathological changes and severity in a monocentric JDM cohort. Methods: Clinical, biological and histological findings from 23 JDM patients were assessed. Twenty-six histopathological parameters were subjected to multivariate analysis. Results: Autoantibodies included anti-NXP2 (9/23), anti-TIF1γ (4/23), anti-MDA5 (2/23), no MSAs (8/23). Multivariate analysis yielded two histopathological clusters. Cluster 1 (n = 11) showed a more severe and ischaemic pattern than cluster 2 (n = 12) assessed by: total score severity ⩾ 20 (100.0% vs 25.0%); visual analogic score ⩾6 (100.0% vs 25.0%); the vascular domain score >1 (100.0% vs 41.7%); microinfarcts (100% vs 58.3%); ischaemic myofibrillary loss (focal punched-out vacuoles) (90.9 vs 25%); and obvious capillary loss (81.8% vs 16.7). Compared with cluster 2, patients in cluster 1 had strikingly more often anti-NXP2 antibodies (7/11 vs 2/12), more pronounced muscle weakness, more gastrointestinal involvement and required more aggressive treatment. Furthermore, patients with anti-NXP2 antibodies, mostly assigned in the first cluster, also displayed more severe muscular disease, requiring more aggressive treatment and having a lower remission rate during the follow-up period. Conclusion: Marked muscle ischaemic involvement and the presence of anti-NXP2 autoantibodies are associated with more severe forms of JDM.

The quality of life in genetic neuromuscular disease questionnaire: Rasch validation of the French version.

INTRODUCTION: Slowly progressive, genetic neuromuscular diseases (gNMDs) often lead to important motor deficiencies and functional limitations. The Quality of Life in Genetic Neuromuscular Disease Questionnaire (QoL-gNMD) is a new health-related quality-of-life questionnaire developed for these patients. The purpose of the present study was to validate the French version of the QoL-gNMD and to calibrate its measurement system. METHODS: Both the QoL-gNMD and a validated generic questionnaire (WHOQOL-BREF) were administered to patients. Validation was performed using item response theory. The partial credit model (Rasch) was used to calibrate each domain. RESULTS: Three hundred fifteen adult patients were included. All 3 domains showed adequate psychometric properties (internal consistency: person separation index >0.77; repeatability: test-retest intraclass correlation coefficient >0.75, scalability coefficient >0.38) and fitted the partial credit model. The QoL-gNMD also demonstrated adequate concurrent validity with the WHOQOL-BREF. DISCUSSION: The QoL-gNMD showed adequate psychometric properties and can be used in clinical settings. Although not anchor-based, the minimum detectable change tables help in interpreting score change. Muscle Nerve 56: 1085-1091, 2017.

Construction of a Quality of Life Questionnaire for slowly progressive neuromuscular disease.

PURPOSE: To build a questionnaire to assess health-related quality of life (HRQL) in patients suffering from slowly progressive neuromuscular disease (NMD) using item response theory (IRT). METHODS: A pool of 64 items and a validated questionnaire (WHOQOL-BREF) were administered to 159 patients recruited in eight NMD referral centers. Exploratory statistical analysis included methods derived from both IRT and classical test theory. RESULTS: We constructed a questionnaire named QoL-NMD which is composed of two general items and 24 items classified in three domains: (1) "Impact of Physical Symptoms," (2) "Self-perception" and (3) "Activities and Social Participation." Each domain has good psychometric properties (Cronbach's alpha > 0.77, test-retest ICC > 0.81, Loevinger's H > 0.41) and meets IRT assumptions. Comparison with the WHOQOL-BREF enabled assessing similarities and discrepancies with a generic questionnaire. CONCLUSION: This study enabled the development of a new HRQL questionnaire specifically designed for slowly progressive NMD patients. The QoL-NMD is short enough to be used in clinical practice (26 items). The next steps will be to validate QoL-NMD by re-assessing psychometrics in an independent sample of patients and calibrate the IRT scoring system.

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.

Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour.

Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology.

Expert opinion on mexiletine treatment in adult patients with myotonic dystrophy.

In France, mexiletine - a class I antiarrhythmic drug - can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with myotonic dystrophy under a compassionate use programme. Mexiletine is used according to its summary of product characteristics, which describes its use for myotonia treatment in adult patients with non-dystrophic myotonia, a different neuromuscular condition without cardiac involvement. A cardiac assessment is required prior to initiation and throughout treatment due to potential proarrhythmic effects. The presence of conduction system disease, the most common cardiac manifestation of myotonic dystrophy, mandates repeated cardiac evaluations in patients with this condition, and becomes even more important when they are given mexiletine. A group of experts, including three neurologists and five cardiologists from French neuromuscular reference centres, were involved in a task force to develop a treatment algorithm to guide mexiletine use in myotonic dystrophy. The recommendations are based on data from a literature review of the safety of mexiletine-treated patients with myotonic dystrophy, the compassionate use protocol for mexiletine and the personal clinical experience of the experts. The main conclusion of the expert group is that, although existing safety data in mexiletine-treated patients with myotonic dystrophy are reassuring, cardiac assessments should be reinforced in such patients compared with mexiletine-treated patients with non-dystrophic myotonia. This expert opinion to guide mexiletine treatment in patients with myotonic dystrophy should help to reduce the risk of severe adverse events and facilitate interactions between specialists involved in the routine care of patients with myotonic dystrophy.

EURO-NMD registry: federated FAIR infrastructure, innovative technologies and concepts of a patient-centred registry for rare neuromuscular disorders.

BACKGROUND: The EURO-NMD Registry collects data from all neuromuscular patients seen at EURO-NMD's expert centres. In-kind contributions from three patient organisations have ensured that the registry is patient-centred, meaningful, and impactful. The consenting process covers other uses, such as research, cohort finding and trial readiness. RESULTS: The registry has three-layered datasets, with European Commission-mandated data elements (EU-CDEs), a set of cross-neuromuscular data elements (NMD-CDEs) and a dataset of disease-specific data elements that function modularly (DS-DEs). The registry captures clinical, neuromuscular imaging, neuromuscular histopathology, biological and genetic data and patient-reported outcomes in a computer-interpretable format using selected ontologies and classifications. The EURO-NMD registry is connected to the EURO-NMD Registry Hub through an interoperability layer. The Hub provides an entry point to other neuromuscular registries that follow the FAIR data stewardship principles and enable GDPR-compliant information exchange. Four national or disease-specific patient registries are interoperable with the EURO-NMD Registry, allowing for federated analysis across these different resources. CONCLUSIONS: Collectively, the Registry Hub brings together data that are currently siloed and fragmented to improve healthcare and advance research for neuromuscular diseases.

Neutral lipid storage disease with myopathy: a whole-body nuclear MRI and metabolic study.

Neutral lipid storage disease with myopathy (NLSDM) is caused by a mutation in the gene encoding adipose triglyceride lipase (ATGL), and is characterized by the presence of numerous triglyceride-containing cytoplasmic droplets in type I muscle fibers. Major clinical manifestations concern the heart and skeletal muscle, and some patients also present diabetes mellitus. We report the clinical, metabolic, and whole-body nuclear magnetic resonance imaging findings of three patients with NLSDM. Muscle MRI study was consistent with previous descriptions, and allowed to show a common pattern of fatty replacement. Muscle changes predominated in the paravertebral muscles, both compartments of legs, and posterior compartment of the thighs. A more variable distribution of muscle involvement was observed on upper limbs, with marked asymmetry in one patient, and alterations predominating on supra and infra spinatus, biceps brachialis and anterior compartment of arms. Cardiac NMR studies revealed anomalies despite normal echocardiography in two patients. Endocrine studies showed low leptin and adiponectine levels, a moderate increase in insulin levels at fasting state, and even greater increase after oral glucose tolerance test in one patient. Two patients had elevated triglycerides and low cholesterol-HDL. Based on these analyses, regular control of cardiometabolic risks appear mandatory in the clinical follow-up of these subjects.