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Amyotrophic lateral sclerosis

Reviewed August 2007

What is amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis is a progressive disease that affects motor neurons, which are specialized nerve cells in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). Motor neurons are important for controlling muscle movement and strength. Most people with amyotrophic lateral sclerosis have a form of the condition that is described as sporadic or noninherited. The cause of sporadic amyotrophic lateral sclerosis is largely unknown but probably involves a combination of genetic and environmental factors. About 10 percent of people with amyotrophic lateral sclerosis have a familial form of the condition, which is caused by an inherited genetic mutation.

The first signs and symptoms of amyotrophic lateral sclerosis may be so subtle that they are overlooked. The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Speech may become slurred, and later there is difficulty chewing or swallowing. Muscles become weaker as the disease progresses, and arms and legs begin to look thinner as muscle tissue is lost (atrophies). Individuals with this disorder lose their strength, the ability to walk, and use of their hands and arms. Breathing becomes difficult because the muscles of the respiratory system weaken. Most people with amyotrophic lateral sclerosis die from respiratory failure.

Different types of familial amyotrophic lateral sclerosis are distinguished by genetic cause, age when symptoms begin, and disease progression. Researchers have identified genetic mutations that cause amyotrophic lateral sclerosis types 1, 2, 4, and 8. Onset of symptoms in adulthood is characteristic of types 1 and 8. Symptoms of type 1 usually begin between ages 40 and 60. Depending on the genetic mutation involved, the condition may progress slowly or rapidly. Symptoms of type 8 amyotrophic lateral sclerosis begin earlier than type 1 (usually between ages 25 and 44) but progress slowly over several years to several decades. Early onset of symptoms is characteristic of amyotrophic lateral sclerosis types 2 and 4. Type 2 symptoms usually begin in early childhood or adolescence and slowly worsen for 10 to 15 years. Symptoms of type 4 amyotrophic lateral sclerosis typically begin before age 25 and slowly progress over several decades.

Additional types of amyotrophic lateral sclerosis have been reported, but the responsible mutations have not been adequately described.

How common is amyotrophic lateral sclerosis?

About 5,000 people in the United States are diagnosed with amyotrophic lateral sclerosis each year. Worldwide, this disorder occurs in 4 to 8 per 100,000 individuals. Only a small percentage of cases have a known genetic cause.

What genes are related to amyotrophic lateral sclerosis?

Mutations in the ALS2, SETX, SOD1, and VAPB genes cause amyotrophic lateral sclerosis.

Variations of the ANG, DCTN1, NEFH, PRPH, SMN1, and SMN2 genes increase the risk of developing amyotrophic lateral sclerosis.

Each type of familial amyotrophic lateral sclerosis is caused by mutations in a specific gene. Type 1 is caused by mutations in the SOD1 gene, type 2 by ALS2 mutations, type 4 by mutations in the SETX gene, and type 8 by VAPB mutations. It is unclear how mutations in these genes contribute to the death of motor neurons, which leads to muscle weakness and atrophy. Research findings suggest that these mutations lead to the production of toxic substances or clumps (aggregates) of misshapen proteins that accumulate and damage motor neurons. Another possible effect is the altered development of axons, the specialized extensions of nerve cells (such as motor neurons) that transmit nerve impulses. The altered axons may impair transmission of impulses from nerves to muscles, which leads to muscle weakness and atrophy. Other genes are thought to cause familial amyotrophic lateral sclerosis, but they have not been identified or fully characterized.

Mutations in the ANG, DCTN1, NEFH, or PRPH gene appear to increase the risk of developing amyotrophic lateral sclerosis. Research findings also suggest that a decrease in the number of SMN1 or SMN2 genes may lead to an increased chance of developing this disorder. It is unclear how variations in these genes lead to increased susceptibility.

How do people inherit amyotrophic lateral sclerosis?

About 90 percent of amyotrophic lateral sclerosis cases are sporadic and are not inherited.

Among the estimated 10 percent of familial cases of this disorder, the pattern of inheritance varies with the type of amyotrophic lateral sclerosis. Type 2 amyotrophic lateral sclerosis is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

Amyotrophic lateral sclerosis types 1, 4, and 8 are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Studies in Sweden and Finland revealed a small number of type 1 cases that are inherited in an autosomal recessive pattern.

Where can I find information about treatment for amyotrophic lateral sclerosis?

You may find information on treatment or management of amyotrophic lateral sclerosis or some of its symptoms in the links below, particularly the links for Gene Reviews, MedlinePlus Encyclopedia, Educational resources, and Patient support.

Where can I find additional information about amyotrophic lateral sclerosis?

You may find the following resources about amyotrophic lateral sclerosis helpful. These materials are written for the general public.

  • MedlinePlus - Health information
    • Encyclopedia: Amyotrophic lateral sclerosis (http://www.nlm.nih.gov/medlineplus/ency/article/000688.htm)
    • Health Topic: Amyotrophic Lateral Sclerosis (http://www.nlm.nih.gov/medlineplus/amyotrophiclateralsclerosis.html)
    • Tutorials: Amyotrophic Lateral Sclerosis (http://www.nlm.nih.gov/medlineplus/tutorials/amyotrophiclateralsclerosis/htm/index.htm)
  • Additional NIH Resources - National Institutes of Health
    • National Center for Biotechnology Information: Genes and Disease (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.194)
    • National Institute of Neurological Disorders and Stroke: ALS fact sheet (http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_amyotrophiclateralsclerosis.htm)
    • National Institute of Neurological Disorders and Stroke: Senataxin gene linked to juvenile-onset ALS (http://www.ninds.nih.gov/news_and_events/news_articles/news_article_als4.htm)
  • Educational resources - Information pages
    • American Speech-Language-Hearing Association (http://www.asha.org/public/speech/disorders/ALS.htm)
    • Ask the Geneticist: inheritance of amyotrophic lateral sclerosis and egg donors (http://www.askthegen.org/question.php?question_id=175)
    • Columbia St. Mary's Hospital (http://www.columbia-stmarys.org/Content.asp?PageID=P00771)
    • Duke Center for Human Genetics (http://www.chg.duke.edu/diseases/als.html)
    • KidsHealth (Nemours Foundation) (http://kidshealth.org/kid/grownup/conditions/als.html)
    • Mayo Clinic (http://www.mayoclinic.org/lou-gehrigs-disease/index.html)
    • Merck Manual of Medical Information, Second Home Edition (http://www.merck.com/mmhe/sec06/ch095/ch095b.html#sec06-ch095-ch095b-1377)
    • Neuroscience (second edition, 2001): Amyotrophic Lateral Sclerosis (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.box.1124)
    • New York Online Access to Health (NOAH) (http://www.noah-health.org/en/bns/disorders/lougehrig/index.html)
    • Orphanet (http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=803)
    • Penn State College of Medicine (http://www.hmc.psu.edu/healthinfo/a/als.htm)
    • The Cleveland Clinic Health Information Center (http://my.clevelandclinic.org/disorders/amyotrophic_lateral_sclerosis/ns_overview.aspx)
    • University of Michigan Health System (http://www.med.umich.edu/1libr/aha/aha_als_sha.htm)
    • World Federation of Neurology-ALS (http://www.wfnals.org)
  • Patient support - For patients and families
    • Family Village (http://www.familyvillage.wisc.edu/lib_als.htm)
    • Les Turner Amyotrophic Lateral Sclerosis Foundation (http://www.lesturnerals.org/als.htm)
    • Muscular Dystrophy Association (http://als.mdausa.org/)
    • National Organization for Rare Disorders (NORD) (http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Amyotrophic+Lateral+Sclerosis)
    • Project ALS (http://www.projectals.org)
    • The ALS Association (http://www.alsa.org/als)
    • The ALS Society of Canada (http://www.als.ca/)
    • U.S. Department of Veterans Affairs: National Registry of Veterans with ALS (http://www.durham.hsrd.research.va.gov/alsregistry.asp)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

  • Gene Reviews - Clinical summary
    • Gene Reviews: ALS2-related disorders (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=iahsp)
    • Gene Reviews: Amyotrophic lateral sclerosis overview (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=als-overview)
  • Gene Tests - DNA tests ordered by healthcare professionals
    • Gene Tests: ALS2-Related Disorders (http://www.genetests.org/query?testid=240656)
    • Gene Tests: SOD1-Related Amyotrophic Lateral Sclerosis (http://www.genetests.org/query?testid=2035)
    • Gene Tests: VAPB-Related Amyotrophic Lateral Sclerosis (http://www.genetests.org/query?testid=264423)
  • ClinicalTrials.gov - Linking patients to medical research (http://clinicaltrials.gov/search/condition=%22amyotrophic+lateral+sclerosis%22)
  • PubMed - Recent literature (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=PubMed&term=(Amyotrophic+Lateral+Sclerosis[MAJR])+AND+(amyotrophic+lateral+sclerosis[TI])+AND+review[pt]+AND+english[la]+AND+human[mh]&orig_db=PubMed&filters=ON&pmfilter_EDatLimit=720+Days)
  • OMIM - Genetic disorder catalog
    • OMIM: amyotrophic lateral sclerosis 1 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=105400)
    • OMIM: amyotrophic lateral sclerosis 2, juvenile (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=205100)
    • OMIM: amyotrophic lateral sclerosis 4, juvenile (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602433)
    • OMIM: amyotrophic lateral sclerosis 8 (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608627)

What other names do people use for amyotrophic lateral sclerosis?

  • ALS
  • Charcot disease
  • Lou Gehrig Disease
  • Motor Neuron Disease, Amyotrophic Lateral Sclerosis

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about amyotrophic lateral sclerosis?

  • See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.
  • Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).
  • Submit your question to Ask the Geneticist (http://www.askthegen.org/).

What glossary definitions help with understanding amyotrophic lateral sclerosis?

aggregate ; atrophy ; autosomal ; autosomal dominant ; autosomal recessive ; axons ; cell ; familial ; gene ; inheritance ; motor ; motor neuron ; mutation ; nerve cell ; neuron ; pattern of inheritance ; progression ; protein ; recessive ; respiratory ; sclerosis ; sign ; sporadic ; susceptibility ; symptom ; tissue ; toxic

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References
  • Andersen PM. Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene. Curr Neurol Neurosci Rep. 2006 Jan;6(1):37-46. Review. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=16469270)
  • Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004 Jun;74(6):1128-35. Epub 2004 Apr 21. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=15106121)
  • Gene Reviews: Amyotrophic lateral sclerosis overview (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=als-overview)
  • Gros-Louis F, Gaspar C, Rouleau GA. Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):956-72. Epub 2006 Feb 10. Review. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=16503123)
  • Hand CK, Rouleau GA. Familial amyotrophic lateral sclerosis. Muscle Nerve. 2002 Feb;25(2):135-59. Review. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=11870681)
  • Jackson M, Llado J, Rothstein JD. Therapeutic developments in the treatment of amyotrophic lateral sclerosis. Expert Opin Investig Drugs. 2002 Oct;11(10):1343-64. Review. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=12387699)
  • Kunst CB. Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Dec;75(6):933-47. Epub 2004 Oct 11. No abstract available. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=15478096)
  • Manfredi G, Xu Z. Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion. 2005 Apr;5(2):77-87. Review. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=16050975)
  • National Institute of Neurological Disorders and Stroke: ALS fact sheet (http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_amyotrophiclateralsclerosis.htm)
  • Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci. 2006 Sep;7(9):710-23. Review. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=16924260)
  • Rao SD, Weiss JH. Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis. Trends Neurosci. 2004 Jan;27(1):17-23. Review. No abstract available. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=14698606)
  • Simpson CL, Al-Chalabi A. Amyotrophic lateral sclerosis as a complex genetic disease. Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):973-85. Epub 2006 Aug 5. Review. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=16973338)
  • Strong MJ, Kesavapany S, Pant HC. The pathobiology of amyotrophic lateral sclerosis: a proteinopathy? J Neuropathol Exp Neurol. 2005 Aug;64(8):649-64. Review. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=16106213)
  • Veldink JH, Kalmijn S, Van der Hout AH, Lemmink HH, Groeneveld GJ, Lummen C, Scheffer H, Wokke JH, Van den Berg LH. SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS. Neurology. 2005 Sep 27;65(6):820-5. Epub 2005 Aug 10. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&dopt=Abstract&list_uids=16093455)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: August 2007
Published: May 4, 2009