Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disease that presents substantial diagnostic and therapeutic challenges. In this focus issue, experts highlight recent progress in understanding the genetic and molecular underpinnings of ALS, including the discovery of biomarkers for rapid diagnosis of the condition and monitoring of disease progression. Current and future treatment and management approaches are also addressed, along with prospects for improving the design of clinical trials in ALS.
RESEARCH HIGHLIGHT
Neurodegenerative disease: A hexanucleotide repeat expansion in C9ORF72 links amyotrophic lateral sclerosis and frontotemporal dementia
Heather Wood
doi:10.1038/nrneurol.2011.162
Nature Reviews Neurology 7, 595 (2011)
NEWS AND VIEWS
Motor neuron disease: A role for ubiquilin 2 mutations in neurodegeneration
Hussein Daoud & Guy A. Rouleau
doi:10.1038/nrneurol.2011.163
Nature Reviews Neurology 7, 599-600 (2011)
REVIEWS
Clinical genetics of amyotrophic lateral sclerosis: what do we really know?
Peter M. Andersen & Ammar Al-Chalabi
doi:10.1038/nrneurol.2011.150
Nature Reviews Neurology 7, 603-615 (2011)
Until the early 1990s, the prevailing view was that amyotrophic lateral sclerosis (ALS) was rarely familial, but subsequent genetic discoveries have overturned this idea. Andersen and Al-Chalabi document the rapidly changing genetic landscape in ALS, highlighting the lack of a clear distinction between heritable and apparently sporadic ALS, and providing recommendations for genetic counseling.
Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations
Robert Bowser, Martin R. Turner & Jeremy Shefner
doi:10.1038/nrneurol.2011.151
Nature Reviews Neurology 7, 631-638 (2011)
Research into amyotrophic lateral sclerosis (ALS) has improved our understanding of the molecular mechanisms underlying disease pathogenesis, but diagnosis of patients with ALS has remained difficult. Bowser et al. highlight recent discoveries of biomarkers for ALS—from proteins in biofluids to neurophysiological and neuroimaging findings—and discuss the benefits and limitations of these biomarkers as diagnostic and prognostic indicators of disease.
Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis
Laura Ferraiuolo, Janine Kirby, Andrew J. Grierson, Michael Sendtner & Pamela J. Shaw
doi:10.1038/nrneurol.2011.152
Nature Reviews Neurology 7, 616-630 (2011)
An improved understanding of the cellular events that lead to motor neuron injury in amyotrophic lateral sclerosis (ALS) could highlight promising new therapeutic strategies. Pamela Shaw and colleagues provide a comprehensive overview of the numerous molecular mechanisms that are involved in ALS, including oxidative stress, mitochondrial dysfunction and excitotoxicity. They discuss features specific to motor neurons that might render this cell type vulnerable to damage, and highlight important links between cellular events and clinical features of the disease.
Clinical diagnosis and management of amyotrophic lateral sclerosis
Orla Hardiman, Leonard H. van den Berg & Matthew C. Kiernan
doi:10.1038/nrneurol.2011.153
Nature Reviews Neurology 7, 639-649 (2011)
Amyotrophic lateral sclerosis is a devastating neurodegenerative motor neuron disease that results in progressive loss of bulbar and limb function. In this Review, Hardiman et al. provide an overview of the clinical aspects of the disease, discussing epidemiology, clinical presentation, diagnosis and management, with an emphasis on recent key advances.
PERSPECTIVES
How can we improve clinical trials in amyotrophic lateral sclerosis?
Paul H. Gordon & Vincent Meininger
doi:10.1038/nrneurol.2011.147
Nature Reviews Neurology 7, 650-654 (2011)
Clinical trials for amyotrophic lateral sclerosis have failed to yield a single new drug over the past 17 years. In their Opinion article, Gordon and Meininger provide insights into possible reasons for the lack of success, such as the heterogeneity of the disease, limitations of preclinical models, and the choice of clinical end points. They also present possible strategies to address the ongoing challenges, including appropriate dose selection and development of suitable biomarkers.
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