CONTINUUM Lifelong Learning in Neurology最新文献

Scientific advances have provided the ability to modify the course of genetic diseases through the use of genetic therapies. These therapies include RNA-based approaches that either reduce the translation of a toxic protein or skip exons to produce a more functional protein. Adeno-associated virus-based delivery of missing gene products has also been demonstrated to modify the overall course of diseases. The science has advanced beyond the ability of our health system infrastructure to keep pace. Challenges with drug pricing, manufacturing, regulatory pathways, and patient access remain. The ability to overcome these challenges will directly influence the ability to deliver these highly promising therapies to patients waiting for them.

Objective: This article provides an overview of the dystrophinopathies, which are primary muscle disorders inherited in an X-linked recessive fashion due to pathogenic variants in DMD on chromosome Xp21 encoding the protein dystrophin. These include Duchenne and Becker muscular dystrophies, as well as an intermediate phenotype, dilated cardiomyopathy, and manifesting female carriers. Clinical examples illustrate the workup and management of patients with suspected dystrophinopathy.

Latest developments: Historically, the management of the dystrophinopathies was largely supportive, with corticosteroids as the only pharmacologic option to delay loss of ambulation and respiratory and cardiac complications. Newer formulations of corticosteroids aim to improve their side effect profile while preserving efficacy. The US Food and Drug Administration (FDA) recently approved treatments directed at the underlying genetic defect in Duchenne muscular dystrophy, including exon-skipping and microdystrophin-based gene therapies and a new class of histone deacetylase inhibitors. The impact of these newer therapies on the natural history of the disease is unknown. Two patient deaths in the spring of 2025 were deemed related to delandistrogene moxeparvovec use in nonambulatory patients, and dosing in these patients has been paused.

Essential points: Dystrophinopathies may present with motor delay, progressive proximal and axial weakness, calf hypertrophy, and elevated creatine kinase greater than 1000 U/L. Elevated transaminases in the setting of elevated creatine kinase with normal γ-glutamyl transferase and speech delay or autism in boys are less common initial presentations. Genetic testing is typically the next step in diagnosis and, depending on the nature of the variation and predicted severity of the phenotype, can guide the choice of treatment.

Objective: This article describes the various idiopathic inflammatory myopathies, including their clinical presentation, pathogenesis, diagnosis, and treatments. While many disorders fall under this umbrella, this article focuses on dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy, polymyositis, and overlap syndrome.

Latest developments: The diagnosis of inflammatory myopathy has traditionally relied heavily on muscle biopsy, which continues to be an essential diagnostic tool. However, the identification of myositis-specific antibodies has allowed for the deferment of biopsy in some cases, while also providing guidance on severity, prognosis, risk for underlying cancer, other organ involvement, and therapy. The treatment of inflammatory myopathy hinges on the use of evolving immunotherapies.

Essential points: Given that highly effective treatments exist for inflammatory myopathy, neurologists must use all available diagnostic tools to quickly identify inflammatory myopathy and initiate appropriate therapy. While the primary goal is to treat muscle weakness, it is important to consider other organs that may be affected by these conditions, including the lungs, heart, joints, and skin, and to exclude underlying malignancy or infection when appropriate.

Objective: This article summarizes the current understanding of paroxysmal movement disorders, including clinical features, pathophysiology, assessment, genetics, and treatment. It additionally discusses the intriguing overlap of these disorders with epilepsy.

Latest developments: There is an expansion of the traditional genotype-phenotype correlation among paroxysmal movement disorders. A single genotype may present with many clinical presentations, and different genetic variations may present with a similar phenotype. In addition to recognizing the clinical presentation through careful history and examination, the approach to patients with paroxysmal movement disorders increasingly includes genetic testing for treatment and prognostication.

Essential points: The spectrum of paroxysmal movement disorders continues to expand. Prompt and accurate recognition of the presenting syndrome can lead to effective treatment and symptomatic relief. It is imperative to recognize secondary causes of paroxysmal movement disorders. A greater understanding of shared molecular mechanisms and genetics may help to better tailor therapeutic strategies in the future.

Objective: Ataxia refers to incoordination that may occur in isolation or as part of many conditions. This article provides a framework for the clinical recognition and treatment of ataxia.

Latest developments: The development of genetic techniques, including next-generation sequencing, over the past 30 years has facilitated the characterization of many forms of ataxia, including spinocerebellar ataxia. Spinocerebellar ataxia type 27b was described as a late-onset hereditary ataxia, and it appears to be a common form of spinocerebellar ataxia. The genetic basis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) was identified in 2019 as a biallelic intronic repeat expansion in the RFC1 gene. The first drug to treat Friedreich ataxia, omaveloxolone, was approved by the US Food and Drug Administration (FDA) in 2023.

Essential points: Cerebellar ataxias encompass a wide range of diseases. Recognizing ataxia as a symptom is crucial for initiating the diagnostic process. Genetic testing and counseling can be used to identify the type of ataxia and to assess the risk for unaffected family members. Significant progress has been made in understanding cerebellar syndromes, and there is optimism for the development of new therapies.