FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 344:1688-1700 May 31, 2001 Number 22 Next

	Since this article has no abstract, we have provided an extract of the first 100 words of the full text and any section headings.

	Full Text PDF Purchase this article Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

Charcot described amyotrophic lateral sclerosis (ALS) in 1874. Despite progress, this creeping paralysis, known colloquially as Lou Gehrig's disease, is still not visibly affected by available therapies. However, advances in genetics have accelerated the pace of ALS research in the past decade, promising more effective treatment.

Definition of the Disease

ALS has two meanings. In one sense, it refers to several adult-onset conditions characterized by progressive degeneration of motor neurons (Figure 1). In the United Kingdom, the term motor neuron disease is used for these disorders. In the second sense, ALS refers to one specific form of motor neuron disease in which . . . [Full Text of this Article]

Diagnosis

Proposed Underlying Causes

Genetic Causes

            Familial Motor Neuron Diseases

            Genetic Susceptibility

Environmental Causes

            Epidemiologic Features

            Exposure to Heavy Metals

Viral Infection and Prion Disease as Causes

Alternative Theories

Histopathological Features

Pathogenesis

SOD1-Induced Toxicity

            Peroxynitrite and Zinc

            Copper and SOD1 Aggregates

Disorganization of Intermediate Filaments

            Neurofilaments

            Peripherin

Calcium Homeostasis and Excitotoxicity

            Calcium-Binding Proteins

            Glutamate Receptors and Transporters

Apoptosis

Therapy

Pharmacotherapy

Mechanical Ventilatory Support

Treatment for Depression

Proposed Treatments

End-of-Life Issues

Conclusions

Source Information

From the Eleanor and Lou Gehrig MDA/ALS Center, Neurological Institute, Columbia–Presbyterian Medical Center, New York–Presbyterian Hospital, and Columbia University College of Physicians and Surgeons — all in New York.

Address reprint requests to Dr. Rowland at the Neurological Institute, Columbia–Presbyterian Medical Center, 701 W. 168th St., New York, NY 10032, or at lprl@columbia.edu.

References

This article has been cited by other articles:

• Beers, D. R., Henkel, J. S., Zhao, W., Wang, J., Appel, S. H. (2008). CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc. Natl. Acad. Sci. USA 105: 15558-15563 [Abstract] [Full Text]  
• Fang, F., Valdimarsdottir, U., Furst, C. J., Hultman, C., Fall, K., Sparen, P., Ye, W. (2008). Suicide among patients with amyotrophic lateral sclerosis. Brain 0: awn161v1-awn161 [Abstract] [Full Text]  
• Vucic, S., Nicholson, G. A., Kiernan, M. C. (2008). Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 131: 1540-1550 [Abstract] [Full Text]  
• Fang, F., Kamel, F., Sandler, D. P., Sparen, P., Ye, W. (2008). Maternal Age, Exposure to Siblings, and Risk of Amyotrophic Lateral Sclerosis. Am J Epidemiol 167: 1281-1286 [Abstract] [Full Text]  
• Fang, F., Ye, W., Fall, K., Lekander, M., Wigzell, H., Sparen, P., Adami, H.-O., Valdimarsdottir, U. (2008). Loss of a Child and the Risk of Amyotrophic Lateral Sclerosis. Am J Epidemiol 167: 203-210 [Abstract] [Full Text]  
• Logroscino, G, Traynor, B J, Hardiman, O, Chio', A, Couratier, P, Mitchell, J D, Swingler, R J, Beghi, E, for EURALS, (2008). Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. J. Neurol. Neurosurg. Psychiatry 79: 6-11 [Abstract] [Full Text]  
• Vucic, S., Krishnan, A. V, Kiernan, M. C (2007). Fatigue and activity dependent changes in axonal excitability in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 78: 1202-1208 [Abstract] [Full Text]  
• Sutedja, N. A., Veldink, J. H., Fischer, K., Kromhout, H., Wokke, J.H.J., Huisman, M. H.B., Heederik, D. J.J., Van den Berg, L. H. (2007). Lifetime occupation, education, smoking, and risk of ALS. Neurology 69: 1508-1514 [Abstract] [Full Text]  
• Mori, H., Yagishita, A., Takeda, T., Mizutani, T. (2007). Symmetric Temporal Abnormalities on MR Imaging in Amyotrophic Lateral Sclerosis with Dementia. Am. J. Neuroradiol. 28: 1511-1516 [Abstract] [Full Text]  
• Irwin, D., Lippa, C. F., Swearer, J.M. (2007). Cognition and Amyotrophic Lateral Sclerosis (ALS). AM J ALZHEIMERS DIS OTHER DEMEN 22: 300-312 [Abstract]  
• Mitsumoto, H., Rabkin, J. G. (2007). Palliative Care for Patients With Amyotrophic Lateral Sclerosis: "Prepare for the Worst and Hope for the Best". JAMA 298: 207-216 [Abstract] [Full Text]  
• Carreras, M. C., Poderoso, J. J. (2007). Mitochondrial nitric oxide in the signaling of cell integrated responses. Am. J. Physiol. Cell Physiol. 292: C1569-C1580 [Abstract] [Full Text]  
• Mezzapesa, D.M., Ceccarelli, A., Dicuonzo, F., Carella, A., De Caro, M.F., Lopez, M., Samarelli, V., Livrea, P., Simone, I.L. (2007). Whole-Brain and Regional Brain Atrophy in Amyotrophic Lateral Sclerosis. Am. J. Neuroradiol. 28: 255-259 [Abstract] [Full Text]  
• Wang, Y., Ou Mao, X., Xie, L., Banwait, S., Marti, H. H., Greenberg, D. A., Jin, K. (2007). Vascular Endothelial Growth Factor Overexpression Delays Neurodegeneration and Prolongs Survival in Amyotrophic Lateral Sclerosis Mice. J. Neurosci. 27: 304-307 [Abstract] [Full Text]  
• Sutedja, N. A., Sinke, R. J., Van Vught, P. W. J., Van der Linden, M. W., Wokke, J. H. J., Van Duijn, C. M., Njajou, O. T., Van der Schouw, Y. T., Veldink, J. H., Van den Berg, L. H. (2007). The Association Between H63D Mutations in HFE and Amyotrophic Lateral Sclerosis in a Dutch Population. Arch Neurol 64: 63-67 [Abstract] [Full Text]  
• Pacher, P., Beckman, J. S., Liaudet, L. (2007). Nitric Oxide and Peroxynitrite in Health and Disease. Physiol. Rev. 87: 315-424 [Abstract] [Full Text]  
• Pacher, P., Batkai, S., Kunos, G. (2006). The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacol. Rev. 58: 389-462 [Abstract] [Full Text]  
• Wu, D.-C., Re, D. B., Nagai, M., Ischiropoulos, H., Przedborski, S. (2006). The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proc. Natl. Acad. Sci. USA 103: 12132-12137 [Abstract] [Full Text]  
• Traynor, B. J., Bruijn, L., Conwit, R., Beal, F., O'Neill, G., Fagan, S. C., Cudkowicz, M. E. (2006). Neuroprotective agents for clinical trials in ALS: A systematic assessment.. Neurology 67: 20-27 [Abstract] [Full Text]  
• Ciccarelli, O., Behrens, T. E., Altmann, D. R., Orrell, R. W., Howard, R. S., Johansen-Berg, H., Miller, D. H., Matthews, P. M., Thompson, A. J. (2006). Probabilistic diffusion tractography: a potential tool to assess the rate of disease progression in amyotrophic lateral sclerosis. Brain 129: 1859-1871 [Abstract] [Full Text]  
• Lechtzin, N., Shade, D., Clawson, L., Wiener, C. M. (2006). Supramaximal Inflation Improves Lung Compliance in Subjects With Amyotrophic Lateral Sclerosis. Chest 129: 1322-1329 [Abstract] [Full Text]  
• Sharifullina, E., Nistri, A. (2006). Glutamate uptake block triggers deadly rhythmic bursting of neonatal rat hypoglossal motoneurons. J. Physiol. 572: 407-423 [Abstract] [Full Text]  
• Kanai, K., Kuwabara, S., Misawa, S., Tamura, N., Ogawara, K., Nakata, M., Sawai, S., Hattori, T., Bostock, H. (2006). Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain 129: 953-962 [Abstract] [Full Text]  
• Rosenfeld, J., Swash, M. (2006). What's in a name?: Lumping or splitting ALS, PLS, PMA, and the other motor neuron diseases. Neurology 66: 624-625 [Full Text]  
• Rippon, G. A., Scarmeas, N., Gordon, P. H., Murphy, P. L., Albert, S. M., Mitsumoto, H., Marder, K., Rowland, L. P., Stern, Y. (2006). An Observational Study of Cognitive Impairment in Amyotrophic Lateral Sclerosis.. Arch Neurol 63: 345-352 [Abstract] [Full Text]  
• Schonhoff, C. M., Matsuoka, M., Tummala, H., Johnson, M. A., Estevéz, A. G., Wu, R., Kamaid, A.és, Ricart, K. C., Hashimoto, Y., Gaston, B., Macdonald, T. L., Xu, Z., Mannick, J. B. (2006). S-nitrosothiol depletion in amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 103: 2404-2409 [Abstract] [Full Text]  
• Banci, L., Bertini, I., Cantini, F., D'Amelio, N., Gaggelli, E. (2006). Human SOD1 before Harboring the Catalytic Metal: SOLUTION STRUCTURE OF COPPER-DEPLETED, DISULFIDE-REDUCED FORM. J. Biol. Chem. 281: 2333-2337 [Abstract] [Full Text]  
• Murray, C., Viehman, A., Lippa, C. F. (2006). The corpus callosum in Pick's disease, Alzheimer's disease, and amyotrophic lateral sclerosis: Gliosis implies possible clinical consequence. AM J ALZHEIMERS DIS OTHER DEMEN 21: 37-43 [Abstract]  
• Di Noto, L., Whitson, L. J., Cao, X., Hart, P. J., Levine, R. L. (2005). Proteasomal Degradation of Mutant Superoxide Dismutases Linked to Amyotrophic Lateral Sclerosis. J. Biol. Chem. 280: 39907-39913 [Abstract] [Full Text]  
• Carter, C. D., Kitchen, L. E., Au, W.-C., Babic, C. M., Basrai, M. A. (2005). Loss of SOD1 and LYS7 Sensitizes Saccharomyces cerevisiae to Hydroxyurea and DNA Damage Agents and Downregulates MEC1 Pathway Effectors. Mol. Cell. Biol. 25: 10273-10285 [Abstract] [Full Text]  
• Choudry, R. B., Cudkowicz, M. E. (2005). Clinical Trials in Amyotrophic Lateral Sclerosis: The Tenuous Past and the Promising Future. J Clin Pharmacol 45: 1334-1344 [Abstract] [Full Text]  
• Banci, L., Bertini, I., D'Amelio, N., Gaggelli, E., Libralesso, E., Matecko, I., Turano, P., Valentine, J. S. (2005). Fully Metallated S134N Cu,Zn-Superoxide Dismutase Displays Abnormal Mobility and Intermolecular Contacts in Solution. J. Biol. Chem. 280: 35815-35821 [Abstract] [Full Text]  
• Turner, M R, Osei-Lah, A D, Hammers, A, Al-Chalabi, A, Shaw, C E, Andersen, P M, Brooks, D J, Leigh, P N, Mills, K R (2005). Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS. J. Neurol. Neurosurg. Psychiatry 76: 1279-1285 [Abstract] [Full Text]  
• Tiwari, A., Xu, Z., Hayward, L. J. (2005). Aberrantly Increased Hydrophobicity Shared by Mutants of Cu,Zn-Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis. J. Biol. Chem. 280: 29771-29779 [Abstract] [Full Text]  
• Chang, J. L., Lomen-Hoerth, C., Murphy, J., Henry, R. G., Kramer, J. H., Miller, B. L., Gorno-Tempini, M. L. (2005). A voxel-based morphometry study of patterns of brain atrophy in ALS and ALS/FTLD. Neurology 65: 75-80 [Abstract] [Full Text]  
• Kieran, D., Hafezparast, M., Bohnert, S., Dick, J. R.T., Martin, J., Schiavo, G., Fisher, E. M.C., Greensmith, L. (2005). A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice. J. Cell Biol. 169: 561-567 [Abstract] [Full Text]  
• Tummala, H., Jung, C., Tiwari, A., Higgins, C. M. J., Hayward, L. J., Xu, Z. (2005). Inhibition of Chaperone Activity Is a Shared Property of Several Cu,Zn-Superoxide Dismutase Mutants That Cause Amyotrophic Lateral Sclerosis. J. Biol. Chem. 280: 17725-17731 [Abstract] [Full Text]  
• Kuner, R., Groom, A. J., Bresink, I., Kornau, H.-C., Stefovska, V., Muller, G., Hartmann, B., Tschauner, K., Waibel, S., Ludolph, A. C., Ikonomidou, C., Seeburg, P. H., Turski, L. (2005). Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit. Proc. Natl. Acad. Sci. USA 102: 5826-5831 [Abstract] [Full Text]  
• Turner, M. R., Rabiner, E. A., Hammers, A., Al-Chalabi, A., Grasby, P. M., Shaw, C. E., Brooks, D. J., Leigh, P. N. (2005). [11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS. Brain 128: 896-905 [Abstract] [Full Text]  
• Chio, A., Benzi, G., Dossena, M., Mutani, R., Mora, G. (2005). Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 128: 472-476 [Abstract] [Full Text]  
• Turner, B. J., Atkin, J. D., Farg, M. A., Zang, D. W., Rembach, A., Lopes, E. C., Patch, J. D., Hill, A. F., Cheema, S. S. (2005). Impaired Extracellular Secretion of Mutant Superoxide Dismutase 1 Associates with Neurotoxicity in Familial Amyotrophic Lateral Sclerosis. J. Neurosci. 25: 108-117 [Abstract] [Full Text]  
• Govek, E.-E., Newey, S. E., Van Aelst, L. (2005). The role of the Rho GTPases in neuronal development. Genes Dev. 19: 1-49 [Abstract] [Full Text]  
• Ishigaki, S., Hishikawa, N., Niwa, J.-i., Iemura, S.-i., Natsume, T., Hori, S., Kakizuka, A., Tanaka, K., Sobue, G. (2004). Physical and Functional Interaction between Dorfin and Valosin-containing Protein That Are Colocalized in Ubiquitylated Inclusions in Neurodegenerative Disorders. J. Biol. Chem. 279: 51376-51385 [Abstract] [Full Text]  
• Shaw, A. S., Ampong, M. A., Rio, A., McClure, J., Leigh, P. N., Sidhu, P. S. (2004). Entristar Skin-Level Gastrostomy Tube: Primary Placement with Radiologic Guidance in Patients with Amyotrophic Lateral Sclerosis. Radiology 233: 392-399 [Abstract] [Full Text]  
• Khare, S. D., Caplow, M., Dokholyan, N. V. (2004). The rate and equilibrium constants for a multistep reaction sequence for the aggregation of superoxide dismutase in amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 101: 15094-15099 [Abstract] [Full Text]  
• da Rocha, A. J., Oliveira, A. S.B., Fonseca, R. B., Maia, A. C. M. Jr, Buainain, R. P., Lederman, H. M. (2004). Detection of Corticospinal Tract Compromise in Amyotrophic Lateral Sclerosis with Brain MR Imaging: Relevance of the T1-Weighted Spin-Echo Magnetization Transfer Contrast Sequence. Am. J. Neuroradiol. 25: 1509-1515 [Abstract] [Full Text]  
• Niemann, S, Joos, H, Meyer, T, Vielhaber, S, Reuner, U, Gleichmann, M, Dengler, R, Muller, U (2004). Familial ALS in Germany: origin of the R115G SOD1 mutation by a founder effect. J. Neurol. Neurosurg. Psychiatry 75: 1186-1188 [Abstract] [Full Text]  
• Yasuda, H, Ebihara, S, Yamaya, M, Asada, M, Sasaki, H, Aoki, M (2004). Increased arterial carboxyhaemoglobin concentrations in patients with sporadic amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 75: 1076-1077 [Full Text]  
• Zhu, S., Li, M., Figueroa, B. E., Liu, A., Stavrovskaya, I. G., Pasinelli, P., Beal, M. F., Brown, R. H. Jr, Kristal, B. S., Ferrante, R. J., Friedlander, R. M. (2004). Prophylactic Creatine Administration Mediates Neuroprotection in Cerebral Ischemia in Mice. J. Neurosci. 24: 5909-5912 [Abstract] [Full Text]  
• Topp, J. D., Gray, N. W., Gerard, R. D., Horazdovsky, B. F. (2004). Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor. J. Biol. Chem. 279: 24612-24623 [Abstract] [Full Text]  
• Gordon, P. H., Moore, D. H., Gelinas, D. F., Qualls, C., Meister, M. E., Werner, J., Mendoza, M., Mass, J., Kushner, G., Miller, R. G. (2004). Placebo-controlled phase I/II studies of minocycline in amyotrophic lateral sclerosis. Neurology 62: 1845-1847 [Abstract] [Full Text]  
• Bergmann, F., Keller, B. U. (2004). Impact of mitochondrial inhibition on excitability and cytosolic Ca2+ levels in brainstem motoneurones from mouse. J. Physiol. 555: 45-59 [Abstract] [Full Text]  
• Lowenfels, A. B., Makins, R., Castillo, C. F.-d. (2003). Case 27-2003: A 36-Year-Old Man with Recurrent Epigastric Pain and Elevated Amylase Levels. NEJM 349: 2171-2172 [Full Text]  
• Lidman, O., Swanberg, M., Horvath, L., Broman, K. W., Olsson, T., Piehl, F. (2003). Discrete Gene Loci Regulate Neurodegeneration, Lymphocyte Infiltration, and Major Histocompatibility Complex Class II Expression in the CNS. J. Neurosci. 23: 9817-9823 [Abstract] [Full Text]  
• Laghi, F., Tobin, M. J. (2003). Disorders of the Respiratory Muscles. Am. J. Respir. Crit. Care Med. 168: 10-48 [Abstract] [Full Text]  
• Stathopulos, P. B., Rumfeldt, J. A. O., Scholz, G. A., Irani, R. A., Frey, H. E., Hallewell, R. A., Lepock, J. R., Meiering, E. M. (2003). Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro. Proc. Natl. Acad. Sci. USA 100: 7021-7026 [Abstract] [Full Text]  
• Lomen-Hoerth, C., Murphy, J., Langmore, S., Kramer, J. H., Olney, R. K., Miller, B. (2003). Are amyotrophic lateral sclerosis patients cognitively normal?. Neurology 60: 1094-1097 [Abstract] [Full Text]  
• Friedlander, R. M. (2003). Apoptosis and Caspases in Neurodegenerative Diseases. NEJM 348: 1365-1375 [Full Text]  
• Valentine, J. S., Hart, P. J. (2003). Bioinorganic Chemistry Special Feature: Misfolded CuZnSOD and amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 100: 3617-3622 [Abstract] [Full Text]  
• Tiwari, A., Hayward, L. J. (2003). Familial Amyotrophic Lateral Sclerosis Mutants of Copper/Zinc Superoxide Dismutase Are Susceptible to Disulfide Reduction. J. Biol. Chem. 278: 5984-5992 [Abstract] [Full Text]  
• Mockett, R. J., Radyuk, S. N., Benes, J. J., Orr, W. C., Sohal, R. S. (2003). Phenotypic effects of familial amyotrophic lateral sclerosis mutant Sod alleles in transgenic Drosophila. Proc. Natl. Acad. Sci. USA 100: 301-306 [Abstract] [Full Text]  
• Gamez, J., Barcelo, M. J., Munoz, X., Carmona, F., Cusco, I., Baiget, M., Cervera, C., Tizzano, E.F. (2002). Survival and respiratory decline are not related to homozygous SMN2 deletions in ALS patients. Neurology 59: 1456-1460 [Abstract] [Full Text]  
• Priori, A., Cinnante, C., Pesenti, A., Carpo, M., Cappellari, A., Nobile-Orazio, E., Scarlato, G., Barbieri, S. (2002). Distinctive abnormalities of motor axonal strength-duration properties in multifocal motor neuropathy and in motor neurone disease. Brain 125: 2481-2490 [Abstract] [Full Text]  
• Taylor, J. P., Hardy, J., Fischbeck, K. H. (2002). Toxic Proteins in Neurodegenerative Disease. Science 296: 1991-1995 [Abstract] [Full Text]  
• Johnson, M. A., Macdonald, T. L., Mannick, J. B., Conaway, M. R., Gaston, B. (2001). Accelerated S-Nitrosothiol Breakdown by Amyotrophic Lateral Sclerosis Mutant Copper,Zinc-Superoxide Dismutase. J. Biol. Chem. 276: 39872-39878 [Abstract] [Full Text]  
• Vandenberghe, W., Brorson, J. R., Rowland, L. P., Shneider, N. A. (2001). Amyotrophic Lateral Sclerosis. NEJM 345: 1131-1132 [Full Text]  
• Jubelt, B., Berger, J. R. (2001). Does viral disease underlie ALS?: Lessons from the AIDS pandemic. Neurology 57: 945-946 [Full Text]