Epidemiology of myasthenia gravis in France: A retrospective claims database study (STAMINA).

BACKGROUND: The objectives of this observational study were to report the incidence and prevalence of myasthenia gravis (MG) in France, describe patients' characteristics and treatment patterns, and estimate mortality. METHODS: A historical cohort analysis was performed using the French National Health Data System (SNDS) database between 2008 and 2020. Patients with MG were identified based on ICD-10 codes during hospitalization and/or long-term disease (ALD) status, which leads to a 100% reimbursement for healthcare expenses related to MG. The study population was matched to a control group based on age, sex and region of residence. RESULTS: The overall incidence of MG was estimated at 2.5/100,000 in 2019 and the overall prevalence at 34.2/100,000. The mean age was 58.3 years for incident patients and 58.6 for prevalent patients. Among patients with MG, 57.1% were women. In the first year after identification of MG, acetylcholinesterase inhibitors were the most commonly used treatments (87.0%). Corticosteroids were delivered to 58.3% of patients, intravenous immunoglobulin to 34.4%, and azathioprine to 29.9%. Additionally, 8% of patients underwent thymectomy. The proportions of patients with exacerbations and crises were 59.7% and 13.5% respectively in the first year after MG identification. All-cause mortality was significantly higher in patients with MG compared to matched controls (HR=1.82 (95% CI [1.74;1.90], P<0.0001)). CONCLUSION: In this study, the incidence and prevalence of MG estimated in France were found to be higher than previously reported. Most exacerbations and crises occurred within the first year after MG identification. MG was associated with increased mortality compared to a control population matched on age, gender, and geographical region.

The new horizons for treatment of Late-Onset Pompe Disease (LOPD).

Late-onset Pompe disease (LOPD) is a genetic myopathy causing skeletal muscle weakness and severe respiratory impairment, due to the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) leading to lysosomal glycogen accumulation along with other complex pathophysiological processes. A major step for treatment of Pompe disease was reached in 2006 with the marketing of alglucosidase alfa, a first enzyme replacement therapy (ERT) that showed a significant motor and respiratory benefit. However, efficacy of alglucosidase alfa is limited in LOPD with a loss of efficacy over time, promoting research on new treatments. Next-generation ERT are new enzymes biochemically modified to increase the uptake of exogenous enzyme by target tissues, and the benefit of two recombinant enzymes (avalglucosidase alfa and cipaglucosidase alfa) has been recently studied in large phase III clinical trials, the latest combined with miglustat. Several innovative therapies, based on GAA gene transfer, antisense oligonucleotides or inhibition of glycogen synthesis with substrate reduction therapy, are currently under study, but are still at an early stage of development. Overall, active research for new treatments raises hope for LOPD patients but challenges remain for the clinician with the need for reliable efficacy assessment tools, long-term registry data, and evidence-based recommendations for the best use of these new molecules recently available or under development.

Gene therapy review: Duchenne muscular dystrophy case study.

Gene therapy, i.e., any therapeutic approach involving the use of genetic material as a drug and more largely altering the transcription or translation of one or more genes, covers a wide range of innovative methods for treating diseases, including neurological disorders. Although they share common principles, the numerous gene therapy approaches differ greatly in their mechanisms of action. They also differ in their maturity for some are already used in clinical practice while others have never been used in humans. The aim of this review is to present the whole range of gene therapy techniques through the example of Duchenne muscular dystrophy (DMD). DMD is a severe myopathy caused by mutations in the dystrophin gene leading to the lack of functional dystrophin protein. It is a disease known to all neurologists and in which almost all gene therapy methods were applied. Here we discuss the mechanisms of gene transfer techniques with or without viral vectors, DNA editing with or without matrix repair and those acting at the RNA level (RNA editing, exon skipping and STOP-codon readthrough). For each method, we present the results obtained in DMD with a particular focus on clinical data. This review aims also to outline the advantages, limitations and risks of gene therapy related to the approach used.

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

Bariatric surgery related proximal myopathy: A partially reversible complication.

Deficiency neuropathies and rhabdomyolysis have previously been reported after bariatric surgery (BS) but never myopathies. We report cases of five patients with morbid obesity who developed within 2 to 4 months of a BS, proximal myopathy following significant and rapid weight loss worsened by postoperative gastrointestinal complications. Muscle weakness concerned lower limbs in particular in quadriceps and less frequently in upper limbs and diaphragm, sometimes mimicked a Guillain-Barré syndrome. Muscle biopsy performed in 1 patient, revealed selective atrophy of type 2 fibers. Weakness slowly decreased with refeeding with vitamins supplementation. We enlarge here the clinical pattern of post-BS complications.

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.

Guidance for the care of neuromuscular patients during the COVID-19 pandemic outbreak from the French Rare Health Care for Neuromuscular Diseases Network.

In France, the epidemic phase of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in February 2020 and resulted in the implementation of emergency measures and a degradation in the organization of neuromuscular reference centers. In this special context, the French Rare Health Care for Neuromuscular Diseases Network (FILNEMUS) has established guidance in an attempt to homogenize the management of neuromuscular (NM) patients within the French territory. Hospitalization should be reserved for emergencies, the conduct of treatments that cannot be postponed, check-ups for which the diagnostic delay may result in a loss of survival chance, and cardiorespiratory assessments for which the delay could be detrimental to the patient. A national strategy was adopted during a period of 1 to 2months concerning treatments usually administered in hospitalization. NM patients treated with steroid/immunosuppressants for a dysimmune pathology should continue all of their treatments in the absence of any manifestations suggestive of COVID-19. A frequently asked questions (FAQ) sheet has been compiled and updated on the FILNEMUS website. Various support systems for self-rehabilitation and guided exercises have been also provided on the website. In the context of NM diseases, particular attention must be paid to two experimental COVID-19 treatments, hydroxycholoroquine and azithromycin: risk of exacerbation of myasthenia gravis and QT prolongation in patients with pre-existing cardiac involvement. The unfavorable emergency context related to COVID-19 may specially affect the potential for intensive care admission (ICU) for people with NMD. In order to preserve the fairest medical decision, a multidisciplinary working group has listed the neuromuscular diseases with a good prognosis, usually eligible for resuscitation admission in ICU and, for other NM conditions, the positive criteria suggesting a good prognosis. Adaptation of the use of noninvasive ventilation (NIV) make it possible to limit nebulization and continue using NIV in ventilator-dependent patients.

Sensory neuronopathy as a major clinical feature of mitochondrial trifunctional protein deficiency in adults.

INTRODUCTION: Mitochondrial trifunctional protein deficiency (MTPD) is a long-chain fatty acid oxidation disorder characterized by co-existence of rhabdomyolysis episodes and peripheral neuropathy. Two phenotypes are described: generalized mitochondrial trifunctional protein deficiency (gMTPD) and isolated long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency (iLCHADD) that is always associated with the c.1528G>C mutation. Peripheral neuropathy of MTPD is commonly described in children as axonal, length-dependent and sensorimotor. OBJECTIVES: To report clinical and electrophysiological features of four independent adult MTPD patients with peripheral neuropathy. RESULTS: Onset of the disease was characterized in all patients by rhabdomyolysis episodes occurring during childhood preceded by severe hypoglycemic episodes in three patients. Peripheral nerve involvement manifesting as sensory ataxia appeared later, during adolescence or adulthood. In all cases, electroneuromyogram showed no length-dependent sensory potentials decrease characteristic of sensory neuronopathy ("ganglionopathy"). All patients harbored at least one c.1528G>C mutation. DISCUSSION: We describe MTPD as a newly hereditary etiology of sensory neuronopathy in adults, specifically in patients with c.1528G>C mutation. MTPD should be screened for by performing plasma acylcarnitines in patients with chronic sensory neuronopathy and additional suggestive features such as exercise intolerance or retinopathy.

Scapular dyskinesis in myotonic dystrophy type 1: clinical characteristics and genetic investigations.

OBJECTIVE: To study scapular winging or other forms of scapular dyskinesis (condition of alteration of the normal position and motion of the scapula) in myotonic dystrophy type 1 (DM1), which is generally considered to be a distal myopathy, we performed an observational cohort study. METHODS: We performed a prospective cohort study on the clinical features and progression over time of 33 patients with DM1 and pronounced, mostly asymmetric scapular winging or other forms of scapular dyskinesis. We also explored if scapular dyskinesis in DM1 has the same genetic background as in facioscapulohumeral muscular dystrophy type 1 (FSHD1). RESULTS: The cohort included patients with congenital (n = 3), infantile (n = 6) and adult-onset DM1 (n = 24). Scapular girdle examination showed moderate shoulder girdle weakness (mean MRC 3) and atrophy of trapezius, infraspinatus, and rhomboid major, seemingly similar as in FSHD1. Shoulder abduction and forward flexion were limited (50-70°). In five patients, scapular dyskinesis was the initial disease symptom; in the others it appeared 1-24 years after disease onset. Follow-up data were available in 29 patients (mean 8 years) and showed mild to severe increase of scapular dyskinesis over time. In only three patients, DM1 coexisted with a FSHD mutation. In all other patients, FSHD was genetically excluded. DM2 was genetically excluded in nine patients. The clinical features of the patients with both DM1 and FSHD1 mutations were similar to those with DM1 only. CONCLUSION: Scapular dyskinesis can be considered to be part of DM1 in a small proportion of patients. In spite of the clinical overlap, FSHD can explain scapular dyskinesis only in a small minority. This study is expected to improve the recognition of shoulder girdle involvement in DM1, which will contribute to the management of these patients.

Dilated cardiomyopathy and limb-girdle muscular dystrophy-dystroglycanopathy due to novel pathogenic variants in the DPM3 gene.

Deficiency of Dolichol-P-mannose synthase subunit 3 (DPM3) affects the N-glycosylation and O-mannosylation pathways that are respectively involved in congenital disorders of glycosylation (CDG) and alpha-dystroglycanopathies. Herein, we describe novel pathogenic variants in the DPM3 gene in two unrelated male patients. They developed dilated cardiomyopathy in their late teens, limb-girdle muscular dystrophy - one patient in childhood and the other in adulthood. In both patients, next generation sequencing found in the DPM3 gene a heterozygous deletion and a heterozygous pathogenic missense mutation in exon 2 (c.41T>C, p.Leu14Pro). Electrophoresis of serum transferrin found an abnormal N-glycosylation profile suggestive of CDG type 1 (decreased tetrasialotransferrin, increased disialo- and asialotransferrin). Only two cases of DPM3 gene mutations with limb-girdle muscular dystrophy-dystroglycanopathy have been reported previously. The present study highlights several aspects related to DPM3 gene mutations such as mild to moderately severe limb-girdle muscular dystrophy, dilated cardiomyopathy, and abnormal N-glycosylation profile suggestive of CDG type 1.

Life-threatening lactic acidosis occurring in adults with mitochondrial disorders.

Although relatively common in children, severe acute lactic acidosis is rare in adults with mitochondrial myopathies. We report here three cases, aged 27, 32 and 32 years, who developed life-threatening metabolic crisis with severe lactic acidosis, requiring hospitalisation in intensive care unit. Plasma lactates were elevated 10 to 15 fold normal values, necessitating extra-renal dialysis. By contrast CK levels were moderately increased (3 to 5N). No triggering factor was identified, but retrospectively all patients reported long-lasting mild muscle fatigability and weakness before their acute metabolic crisis. All of them recovered after prolonged intensive care but resting lactate levels remained elevated. Muscle biopsy showed ragged-red and COX-negative fibers in two patients and mild lipidosis in the third one. Heteroplasmic pathogenic point mutations were detected in MT-TL1 (m.3280G>A;m.3258C>T) and MT-TK (m.8363A>G). Life-threatening lactic acidosis may thus be a major inaugural clinical manifestation in adults with mitochondrial myopathies. Prolonged intensive care may lead to a dramatic and sustained improvement and is mandatory in such cases.

Myopathy with MTCYB mutation mimicking Multiple Acyl-CoA Dehydrogenase Deficiency.

We describe two patients with mitochondrial DNA mutations in the gene encoding cytochrome b (m.15579A>G, p.Tyr278Cys and m.15045G>A p.Arg100Gln), which presented as a pure myopathic form (exercise intolerance), with an onset in childhood. Diagnosis was delayed, because acylcarnitine profile showed an increase in medium and long-chain acylcarnitines, suggestive of multiple acyl-CoA dehydrogenase deficiency, riboflavin transporter deficiency or FAD metabolism disorder. Implication of cytochrome b in fatty acid oxidation, and physiopathology of the mutations are discussed.

Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome.

OBJECTIVES: Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available. MATERIAL & METHODS: We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands. RESULTS: Twenty-two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility. CONCLUSION: Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.

[A complex case of diabetes due to LMNA mutation]. / Un diabète particulièrement compliqué.

INTRODUCTION: Laminopathies (diseases related to A/C mutations of lamines) are rare genetic diseases with an extensive phenotypic spectrum, including lipodystrophic syndromes-characterized by a selective loss of adipose tissue-of which the partial Dunnigan family type is the most frequent. CASE REPORT: We report on a 55-year-old woman with diabetes and long-term disabling myalgia. Her cushingoid morphotype, associated with cutaneous lipo-atrophy and muscle hypertrophy in addition to a genetic heritage, led us to the diagnosis of complex partial familial lipodystrophy heterozygous LMNA_c.82C>T, p.Arg28Trp mutation. CONCLUSION: Familial partial lipodystrophic syndromes may have varied phenotypes, mainly cardio-metabolic, which could mimic a particularly severe type 2 diabetes. The diagnostic work-up of this disease has to include a careful investigation of gait troubles and paroxysmal conduction that could lead to sudden death, as well as a genetic examination. In some cases, recombinant leptin can be proposed.

European consensus for starting and stopping enzyme replacement therapy in adult patients with Pompe disease: a 10-year experience.

BACKGROUND AND PURPOSE: Pompe disease is a rare inheritable muscle disorder for which enzyme replacement therapy (ERT) has been available since 2006. Uniform criteria for starting and stopping ERT in adult patients were developed and reported here. METHODS: Three consensus meetings were organized through the European Pompe Consortium, a network of experts from 11 European countries in the field of Pompe disease. A systematic review of the literature was undertaken to determine the effectiveness of ERT in adult patients on a range of clinical outcome measures and quality of life. A narrative synthesis is presented. RESULTS: Consensus was reached on how the diagnosis of Pompe disease should be confirmed, when treatment should be started, reasons for stopping treatment and the use of ERT during pregnancy. This was based on expert opinion and supported by the literature. One clinical trial and 43 observational studies, covering a total of 586 individual adult patients, provided evidence of a beneficial effect of ERT at group level. At individual patient level, the response to treatment varied, but factors associated with a patient's response to ERT were not described in many studies. Eleven observational studies focused on more severely affected patients, suggesting that ERT can also be beneficial in these patients. There are no studies on the effects of ERT in pre-symptomatic patients. CONCLUSIONS: This is the first European consensus recommendation for starting and stopping ERT in adult patients with Pompe disease, based on the extensive experience of experts from different countries.

Prediction of long-term prognosis by heteroplasmy levels of the m.3243A>G mutation in patients with the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome.

BACKGROUND AND PURPOSE: Our aim was to determine the prognostic value of urine and blood heteroplasmy in patients with the m.3243A>G mutation. METHODS: Adults with the m.3243A>G mutation referred to our institution between January 2000 and May 2014 were retrospectively included. The relationship between their baseline clinical characteristics, their mutation load in urine and blood, and major adverse events (MAEs) during follow-up, defined as medical complications requiring a hospitalization or complicated by death, was studied. RESULTS: Of the 43 patients (age 45.6 ± 13.3 years) included in the study, 36 patients were symptomatic, including nine with evidence of focal brain involvement, and seven were asymptomatic. Over a 5.5 ± 4.0 year mean follow-up duration, 14 patients (33%) developed MAEs. Patients with MAEs had a higher mutation load than others in urine (60.1% ± 13.8% vs. 40.6% ± 26.2%, P = 0.01) and in blood (26.9% ± 18.4% vs. 16.0% ± 12.1%, P = 0.03). Optimal cutoff values for the prediction of MAEs were 45% for urine and 35% for blood. In multivariate analysis, mutation load in urine ≥45% [odds ratio 25.3; 95% confidence interval (CI) 1.1-567.8; P = 0.04], left ventricular hypertrophy (odds ratio 16.7; 95% CI 1.3- 222.5; P = 0.03) and seizures (odds ratio 48.3; 95% CI 2.5-933; P = 0.01) were associated with MAEs. CONCLUSIONS: Patients with the m.3243A>G mutation are at high risk of MAEs, which can be independently predicted by mutation load in urine ≥45%, a personal history of seizures, and left ventricular hypertrophy.

What have we learned about glycogenosis in recent years?

The field of glycogenosis has been greatly expanded over the past few years with the discovery of new metabolic diseases that have allowed new metabolic pathways to be deciphered. Described here are the clinical and pathological features of four recently described muscle glycogenoses caused by GYS1, GYG1, RBCK1 and PGM1 gene mutations. The initial steps of glycogen synthesis are involved in deficiencies of glycogenin-1 (GYG1) and muscle glycogen synthase (GYS1). Phosphoglucomutase deficiency disrupts two metabolic pathways: the connection between galactose and glycogen on the one hand, and glucose metabolism on the other. However, the metabolic consequences of mutations in the ubiquitin ligase gene RBCK1 are still poorly understood.