CONTINUUM Lifelong Learning in Neurology最新文献

Objective: This article reviews the current classification system, common subtypes, differential diagnosis, diagnostic algorithms, current management strategies, and evolving therapeutic areas for limb-girdle muscular dystrophies (LGMDs).

Latest developments: There are currently five dominantly inherited LGMDs (LGMD-D1 to D5) and 29 recessively inherited LGMDs (LGMD-R1 to R29). Progress in molecular genetics makes next-generation sequencing gene panels the initial step in diagnosing LGMD and, in some cases, obviates the need for muscle biopsy. The panel should include LGMD genes and genes responsible for other hereditary myopathies and congenital myasthenic syndromes. Whole-exome sequencing or whole-genome sequencing can be performed before or after a muscle biopsy, depending on the specifics of each case. Once a diagnosis of LGMD is established, genetic counseling, symptomatic and supportive care, and cardiopulmonary surveillance remain the cornerstones of management. However, results from preclinical studies and early-stage clinical trials of genetic therapies for common LGMD-R subtypes are promising.

Essential points: Progressive proximal weakness and hyperCKemia are hallmark features of LGMDs; however, they are not specific and can also be observed in many acquired and hereditary myopathies. Muscle biopsy is typically reserved for patients with negative or inconclusive genetic testing and can be particularly useful for verifying the pathogenicity of variants of uncertain significance. Advances in molecular genetics and genetic therapies have revolutionized the diagnostic landscape of LGMDs and paved the way for future disease-specific treatments.

Objective: This article reviews the diagnosis and management of autoimmune myasthenia gravis (MG), encompassing epidemiology, clinical features including disease heterogeneity, pathophysiology, and therapeutic approaches.

Latest developments: Recent advances in MG pathophysiology and clinical outcome measures have catalyzed the development of novel therapies, including complement and neonatal Fc receptor inhibitors, which target specific components of the autoimmune attack on the muscle endplate.

Essential points: Patients with MG exhibit fluctuating muscle weakness. Diagnosis is confirmed by acetylcholine receptor or muscle-specific kinase (MuSK) antibodies, electrodiagnostic testing, or both. Management involves tailored combinations of therapies based on patient and MG-specific factors. The treatment of patients with MG with exclusively ocular weakness, thymoma, child-bearing potential, myasthenic crisis, or MG related to cancer immunotherapy has unique considerations. Prompt diagnosis and treatment are crucial to restore neuromuscular function and minimize treatment-related complications.

Objective: This article reviews the genetic basis, pathogenic mechanisms, epidemiology, clinical presentation, multiorgan involvement, and multidisciplinary management of myotonic dystrophy type 1 (DM1) and type 2 (DM2), as well as the differential diagnosis of myotonic disorders (DM versus nondystrophic myotonic disorders) and electrical myotonia.

Latest developments: Due to underdiagnosis, the prevalence of DM is likely higher than currently recognized. Patients with late-onset or mild phenotypes with little or no skeletal muscle involvement may never be evaluated by a neurologist and thus never diagnosed. Still, DM1 is the most common muscular dystrophy in adults. Scientific progress in understanding the pathogenic mechanism of DM and its broad and variable phenotype has facilitated the design of gene therapy clinical trials in DM1. Nucleic acid-based therapies that target expanded DNA or RNA are in early-stage clinical development. Although caused by a different genetic variation, DM2 shares a common pathogenic mechanism with DM1, which is hopeful for a cure for both subtypes.

Essential points: Neurologists and other clinicians need to recognize DM to ensure prompt diagnosis, effective symptom management, and prevention of life-threatening events. Life-threatening events (eg, sudden death) may occur at any time in the disease course and not necessarily in patients with more severe phenotypes. Investigational drugs may have the potential to have a greater disease-modifying effect when initiated in the early or mild stages of disease, rather than in advanced stages where the therapeutic window may have been missed.

Objective: This article addresses the clinical presentation, diagnostic workup, and management of patients with inclusion body myositis (IBM). It also provides an overview of the clinical trial landscape and explores future directions in the pursuit of an effective treatment for the disease.

Latest developments: Muscle biopsy remains the cornerstone of the diagnosis, and cytosolic nucleotidase 1A antibodies and muscle imaging have been increasingly used to support the diagnosis. The 2024 European Neuromuscular Centre diagnostic criteria offer a new diagnostic framework that integrates these developments. The clinical trial landscape for IBM remains limited, and the complex nature of the underlying pathophysiology of IBM and other diseases of aging presents a significant challenge for the development of effective treatments.

Essential points: IBM is a disease of aging that is more prevalent in males. It is characterized by slowly progressive weakness, predominantly affecting deep finger flexors and quadriceps muscles, with a predilection for swallowing and respiratory muscles. However, this clinical phenotype is not specific to IBM, as other inherited and acquired myopathies may present similarly. Furthermore, atypical presentations of IBM occur and may manifest with a wide range of weakness patterns, most commonly with isolated dysphagia. The diagnosis of IBM requires the integration of historical, clinical, and laboratory data. Management consists of a multidisciplinary approach to address comorbidities and potential complications. Untangling the complexity of aging-related disorders will help advance the field in IBM and facilitate the discovery of effective treatments.

Objective: This article covers the clinical presentations, investigations, differential diagnosis, and principles of management of botulism, Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes.

Latest developments: Well-recognized guidelines exist for the management of botulism and LEMS, but resource limitations may affect implementation globally. Several genes recently reported to cause congenital myasthenic syndromes are involved in ubiquitously expressed proteins and present with a complex non-neuromuscular junction phenotype, wherein abnormal neuromuscular junction transmission is only one component of the gene defect. There have been a few promising preclinical studies on novel treatments in congenital myasthenic syndromes, including gene replacement therapy, raising the prospect of clinical trials in the near future.

Essential points: Early recognition, diagnosis, and initiation of treatment are crucial in managing all three disorders to reduce morbidity and mortality. Congenital myasthenic syndromes should be considered in patients with seronegative myasthenia gravis. Tumor screening is essential in patients with LEMS. Botulism can mimic other cranial neuropathies.

Objective: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy, affecting individuals across the lifespan with variable severity. This article provides an overview of the distinctive genetic mechanisms underlying FSHD, its clinical manifestations, including pediatric-specific features, treatment, and the evolving landscape of clinical trials targeting disease-modifying therapies.

Latest developments: FSHD arises from derepression of the transcription factor DUX4, which is toxic to skeletal muscle. This misexpression leads to a characteristic and progressive pattern of muscle weakness involving the facial, shoulder girdle, upper extremity, trunk, and leg muscles. Extramuscular manifestations, such as pain and fatigue, are frequently reported. Children with a severe, early-onset phenotype experience higher rates of extramuscular features, including hearing loss, cognitive impairment, and spinal deformities. Advances in the understanding of DUX4 as the causative gene, combined with innovations in gene therapy, gene editing, small-molecule development, and drug delivery, have catalyzed the initiation of several clinical trials focusing on disease-targeted treatments in the near future.

Essential points: FSHD is caused by toxic expression of DUX4 and presents with progressive, often asymmetric muscle weakness and extramuscular manifestations in a subset of patients. Advances in genetic understanding and therapeutic development have led to clinical trials targeting DUX4. Although care remains supportive, the field is entering an era of promising disease-modifying strategies.