Aims
The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the ...description of the recurrent variants, c.643_663del21 p.(Ser215_Gly221del) and c.598_612del15 p.(Phe200_Leu204del), associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies.
Methods
Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance.
Results
We identified a novel dominantly inherited CAPN3 variant, c.1333G>A p.(Gly445Arg) in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice.
Conclusions
We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in‐frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well‐documented CAPN3 missense variant, c.1333G>A p.(Gly445Arg). In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re‐assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.
Dear Editor, Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy and Pulmonary Fibrosis (POIKTMP MIM 615704) is a recently described autosomal dominant disorder due to missense ...mutations in the FAM111B gene. Key features are early-onset poikiloderma, muscle contractures in particular of the triceps surae, diffuse progressive fatty myopathy, pulmonary fibrosis in adulthood and exocrine pancreatic insufficiency. Dermatological manifestations seem to be constant and early however, a precise description is lacking.
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.
•We found a higher incidence and prevalence of MG are higher than previously reported in most European countries.•AChEIs are the most common treatment and more aggressive treatments (thymectomy, ...IVIg, azathioprine, plasma exchange, mycophenolate mofetil, cyclophosphamide, and rituximab) are mainly used the first year of the disease history.•Despite the availability of several treatments, patients with MG still experience exacerbations and crises and have an excess mortality compared to controls without MG, regardless of comorbidities.
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.
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.
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)).
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.
A retrospective analysis was performed to document the clinical and electrophysiological features of Guillain-Barré syndrome (GBS) subtypes using different diagnostic criteria.
One hundred GBS ...patients were included. Clinical and laboratory features were analyzed, and patients were classified according to four sets of diagnostic criteria. Electrodiagnostic criteria were also analyzed.
A total of 69 patients met Asbury and Cornblath's criteria, 96 met Van der Meché’s criteria, 99 met Wakerley's diagnostic classification and 86 met level 1 or 2 of the Brighton criteria. Rates of GBS subtypes were: 69% classic GBS; 8% Miller–Fisher syndrome; 12% paraparetic GBS; 2% pharyngeal–cervical–brachial GBS; and 9% unclassified. Those for electrodiagnostic subtypes were 52% demyelinating and 9% axonal according to Hadden's criteria vs 41% demyelinating and 41% axonal as per Rajabally's criteria.
In this study of case distribution within the GBS spectrum of a retrospective cohort of French patients, the application of new diagnostic criteria enabled accurate diagnoses and classifications of the different subtypes, and also increased the recognition of axonal GBS.
Growing numbers of indications for intravenous immunoglobulins (IVIg) in recent years has resulted in an increase in the consumption of these products. A lack of raw material has led to IVIg ...shortage. The objective of this work was to evaluate the impact of this situation on patient care in one French referral centre considering practice modifications and clinical impact.
All patients treated with IVIg for chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and myasthenia gravis from October 2017 to October 2018 were included.
Out of 142 patients, 111 (78%) had a modification of their IVIg treatment. We noted that 75 (68%) patients had a delay in IVIg treatment, 41 (37%) patients had a decrease in IVIg doses and 31 (28%) experienced IVIg treatment interruption. Thirty percent of patients for whom IVIg treatment was discontinued were switched to other treatments mainly plasma exchange (16%) or corticosteroids (13%). Switches to plasma exchange or corticosteroids were carried out in order to save immunoglobulins for patients who had no other alternatives. Fifty-eight (52%) patients presented a deterioration of their clinical score after IVIg treatment changes including 31 (28%) patients who had a moderate or a clinically significant deterioration. Concerning practice modifications, we noted a substantial though not significant decrease in median IVIg dose for myasthenia gravis and a significant increase in the delay between IVIg courses for chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy (P=0.011 and P=0.018 respectively).
Our study showed a rather important number of changes in IVIg treatment related to IVIg shortage during the period considered. These changes had a negative impact on the clinical status of some patients.
Facioscapulohumeral muscular dystrophy (FSHD), an inherited and progressive muscle disorder, is among the most common hereditary muscle disorders. From a clinical vantage point, FSHD is characterized ...by weakness of the facial, shoulder (often with scapular winging), arm (including biceps and triceps) and abdominal muscles. Forearm muscles are usually spared and weakness is usually asymmetrical. Over the past few decades, muscle magnetic resonance imaging (MRI) has become established as a reliable and accurate noninvasive tool for the diagnosis and assessment of progression in neuromuscular diseases, showing specific patterns of muscle involvement for a number of myopathies. More recently, MRI has been used to noninvasively identify quantitative biomarkers, allowing evaluation of the natural progression of disease and assessment of therapeutic interventions. In the present review, the intention was to present the most significant MRI developments related to diagnosis and pattern recognition in FSHD and to discuss its capacity to provide outcome measures.
Intravenous immunoglobulins (IVIg) are commonly used for treatment of dysimmune diseases, but they are known to promote thrombotic events. The medical records of patients who received IVIg infusions ...to treat neuromuscular disorders were retrospectively studied during two periods: the on-demand period (May 2013–January 2015), when patients received anticoagulant prophylaxis based on personal thrombotic risk factors, and the systematic period (May 2015–January 2017), when patients received systematic anticoagulant prophylaxis. Of the 334 total patients included, 19/153 received anticoagulant prophylaxis in the on-demand period, and 181 were treated in the systematic period. In the on-demand period, thrombosis occurred in three patients (1.96%) as one central retinal artery occlusion, one pulmonary embolism, and one brachiocephalic vein thrombosis. In the systematic period, thrombosis occurred in two patients (1.1%), both as pulmonary embolisms. There was no statistical difference in thrombosis incidence between the periods (P=0.66). The only factor associated with thrombosis was splenectomy (20% versus 0.3% in patients without thrombosis, P=0.03). There were no adverse events due to thromboprophylaxis by low-molecular-weight heparin in either period. Systematic thromboprophylaxis did not significantly reduce the incidence of thrombosis versus thromboprophylaxis based on personal thrombotic risk.
Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disease, characterized by an autosomal dominant mode of inheritance, facial involvement, and selectivity and asymmetry of muscle ...involvement. In general, FSHD typically presents before age 20 years. Usually, FSHD muscle involvement starts in the face and then progresses to the shoulder girdle, the humeral muscles and the abdominal muscles, and then the anterolateral compartment of the leg. Disease severity is highly variable and progression is very slow. About 20% of FSHD patients become wheelchair-bound. Lifespan is not shortened. The diagnosis of FSHD is based on a genetic test by which a deletion of 3.3kb DNA repeats (named D4Z4 and mapping to the subtelomeric region of chromosome 4q35) is identified. The progressive pattern of FSHD requires that the severity of symptoms as well as their physical, social and psychological impact be evaluated on a regular basis. A yearly assessment is recommended. Multidisciplinary management of FSHD — consisting of a combination of genetic counselling, functional assessment, an assessment by a physical therapist, prescription of symptomatic therapies and prevention of known complications of this disease — is required. Prescription of physical therapy sessions and orthopedic appliances are to be adapted to the patient's deficiencies and contractures.
La dystrophie musculaire facioscapulohumérale (DMFSH) est une affection musculaire d’hérédité autosomique dominante caractérisée par l’atteinte faciale, la sélectivité et l’asymétrie de l’atteinte musculaire. L’âge de début est généralement inférieur à 20ans. L’atteinte musculaire débute habituellement par la face, puis progresse à la ceinture scapulaire, aux muscles huméraux, puis évolue vers les muscles abdominaux et la loge antéroexterne de la jambe. La gravité de la maladie est très variable. L’évolution est lentement progressive. Environ 20 % des patients requièrent l’utilisation d’un fauteuil roulant. L’espérance de vie n’est pas écourtée. La DMFSH est diagnostiquée par un test génétique qui identifie la délétion de copies d’un motif répété de l’ADN de 3,3kb, D4Z4, située dans la région subtélomérique du chromosome 4q35. Le caractère évolutif de la DMFSH nécessite une évaluation régulière de l’intensité des troubles observés et de leurs répercussions physiques, sociales et psychologiques. Un bilan annuel de suivi est recommandé. La prise en charge de la DMFSH doit être multidisciplinaire, associant le conseil génétique, le bilan fonctionnel, la prescription de traitements symptomatiques et la prévention des complications connues de cette maladie. La prescription des séances de kinésithérapie et d’appareillage sont à adapter en fonction des déficiences et des rétractions. Un bilan ergothérapique peut être proposé.
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