SpringerLink
Log in

Genotypic and Phenotypic Heterogeneity in Amyotrophic Lateral Sclerosis

  • Chapter
  • First Online:
Neurodegenerative Diseases

Abstract

Genetic risk factors play a major role in the susceptibility to amyotrophic lateral sclerosis (ALS), the most common motor neuron disease of the adult. Although genetic studies have partially elucidated the genetic background of the disease, a large part of ALS heritability is still missing. In this chapter, we discuss the major genes implicated in the pathogenesis of motor neuron diseases; the clinical, pathological, and genetic links between ALS and frontotemporal dementia; and the vast genotypic and phenotypic heterogeneity of ALS. Lastly, we review the most recent strategies for identification of novel genetic risk factors in ALS, detailing their advantages and potential pitfalls.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
EUR 29.95
Price includes VAT (Germany)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
EUR 96.29
Price includes VAT (Germany)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
EUR 128.39
Price includes VAT (Germany)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info
Hardcover Book
EUR 181.89
Price includes VAT (Germany)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Chiò A, Logroscino G, Traynor BJ, et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013;41:118–30. https://doi.org/10.1159/000351153.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Alonso A, Logroscino G, Jick SS, Hernán MA. Incidence and lifetime risk of motor neuron disease in the United Kingdom: a population-based study. Eur J Neurol. 2009;16:745–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Logroscino G, Traynor BJ, Hardiman O, et al. Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. J Neurol Neurosurg Psychiatry. 2008;79:6–11. https://doi.org/10.1136/jnnp.2006.104828.

    Article  CAS  PubMed  Google Scholar 

  4. Statland JM, Barohn RJ, McVey AL, et al. Patterns of weakness, classification of motor neuron disease, and clinical diagnosis of sporadic amyotrophic lateral sclerosis. Neurol Clin. 2015;33:735–48. https://doi.org/10.1016/j.ncl.2015.07.006.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chiò A, Calvo A, Moglia C, et al. Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry. 2011;82:740–6. https://doi.org/10.1136/jnnp.2010.235952.

    Article  PubMed  Google Scholar 

  6. Ferrari R, Kapogiannis D, Huey ED, Momeni P. FTD and ALS: a tale of two diseases. Curr Alzheimer Res. 2011;8:273–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Swinnen B, Robberecht W. The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol. 2014;10:661–70. https://doi.org/10.1038/nrneurol.2014.184.

    Article  PubMed  Google Scholar 

  8. Kurland LT, Mulder DW. Epidemiologic investigations of amyotrophic lateral sclerosis. 2. Familial aggregations indicative of dominant inheritance. I. Neurology. 1955;5:182–96.

    Article  CAS  PubMed  Google Scholar 

  9. Kurland LT, Mulder DW. Epidemiologic investigations of amyotrophic lateral sclerosis. 2. Familial aggregations indicative of dominant inheritance. II. Neurology. 1955;5:249–68.

    Article  CAS  PubMed  Google Scholar 

  10. Al-Chalabi A, Fang F, Hanby MF, et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry. 2010;81:1324–6. https://doi.org/10.1136/jnnp.2010.207464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Riggs JE. Longitudinal Gompertzian analysis of amyotrophic lateral sclerosis mortality in the U.S., 1977-1986: evidence for an inherently susceptible population subset. Mech Ageing Dev. 1990;55:207–20.

    Article  CAS  PubMed  Google Scholar 

  12. Hanby MF, Scott KM, Scotton W, et al. The risk to relatives of patients with sporadic amyotrophic lateral sclerosis. Brain J Neurol. 2011;134:3454–7. https://doi.org/10.1093/brain/awr248.

    Article  Google Scholar 

  13. Fang F, Kamel F, Lichtenstein P, et al. Familial aggregation of amyotrophic lateral sclerosis. Ann Neurol. 2009;66:94–9. https://doi.org/10.1002/ana.21580.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol. 2011;7:603–15. https://doi.org/10.1038/nrneurol.2011.150.

    Article  CAS  PubMed  Google Scholar 

  15. Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17:17–23. https://doi.org/10.1038/nn.3584.

    Article  CAS  PubMed  Google Scholar 

  16. Al-Chalabi A, Lewis CM. Modelling the effects of penetrance and family size on rates of sporadic and familial disease. Hum Hered. 2011;71:281–8. https://doi.org/10.1159/000330167.

    Article  PubMed  Google Scholar 

  17. Byrne S, Bede P, Elamin M, et al. Proposed criteria for familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2011;12:157–9. https://doi.org/10.3109/17482968.2010.545420.

    Article  PubMed  Google Scholar 

  18. Abel O, Powell JF, Andersen PM, Al-Chalabi A. ALSoD: a user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics. Hum Mutat. 2012;33:1345–51. https://doi.org/10.1002/humu.22157.

    Article  CAS  PubMed  Google Scholar 

  19. Kenna KP, McLaughlin RL, Hardiman O, Bradley DG. Using reference databases of genetic variation to evaluate the potential pathogenicity of candidate disease variants. Hum Mutat. 2013;34:836–41. https://doi.org/10.1002/humu.22303.

    Article  CAS  PubMed  Google Scholar 

  20. Al-Chalabi A, Jones A, Troakes C, et al. The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol. 2012;124:339–52. https://doi.org/10.1007/s00401-012-1022-4.

    Article  CAS  PubMed  Google Scholar 

  21. Johnson JO, Mandrioli J, Benatar M, et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron. 2010;68:857–64. https://doi.org/10.1016/j.neuron.2010.11.036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Conte A, Lattante S, Zollino M, et al. P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis. Neuromuscul Disord. 2012;22:73–5. https://doi.org/10.1016/j.nmd.2011.08.003.

    Article  PubMed  Google Scholar 

  23. Ticozzi N, Silani V, LeClerc AL, et al. Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort. Neurology. 2009;73:1180–5. https://doi.org/10.1212/WNL.0b013e3181bbff05.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kenna KP, McLaughlin RL, Byrne S, et al. Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing. J Med Genet. 2013;50:776–83. https://doi.org/10.1136/jmedgenet-2013-101795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chiò A, Calvo A, Mazzini L, et al. Extensive genetics of ALS: a population-based study in Italy. Neurology. 2012;79:1983–9. https://doi.org/10.1212/WNL.0b013e3182735d36.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lattante S, Conte A, Zollino M, et al. Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease. Neurology. 2012;79:66–72. https://doi.org/10.1212/WNL.0b013e31825dceca.

    Article  CAS  PubMed  Google Scholar 

  27. Hadano S, Hand CK, Osuga H, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001;29:166–73. https://doi.org/10.1038/ng1001-166.

    Article  CAS  PubMed  Google Scholar 

  28. Yang Y, Hentati A, Deng HX, et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001;29:160–5. https://doi.org/10.1038/ng1001-160.

    Article  CAS  PubMed  Google Scholar 

  29. Yeh T-H, Lai S-C, Weng Y-H, et al. Screening for C9orf72 repeat expansions in parkinsonian syndromes. Neurobiol Aging. 2013;34:1311.e3–4. https://doi.org/10.1016/j.neurobiolaging.2012.09.002.

    Article  CAS  Google Scholar 

  30. Orlacchio A, Babalini C, Borreca A, et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain J Neurol. 2010;133:591–8. https://doi.org/10.1093/brain/awp325.

    Article  Google Scholar 

  31. Nishimura AL, Mitne-Neto M, Silva HCA, et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004;75:822–31. https://doi.org/10.1086/425287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Greenway MJ, Andersen PM, Russ C, et al. ANG mutations segregate with familial and “sporadic” amyotrophic lateral sclerosis. Nat Genet. 2006;38:411–3. https://doi.org/10.1038/ng1742.

    Article  CAS  PubMed  Google Scholar 

  33. Chow CY, Landers JE, Bergren SK, et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet. 2009;84:85–8. https://doi.org/10.1016/j.ajhg.2008.12.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Maruyama H, Morino H, Ito H, et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010;465:223–6. https://doi.org/10.1038/nature08971.

    Article  CAS  PubMed  Google Scholar 

  35. Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362:59–62. https://doi.org/10.1038/362059a0.

    Article  CAS  PubMed  Google Scholar 

  36. McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969;244:6049–55.

    CAS  PubMed  Google Scholar 

  37. Andersen PM, Sims KB, **n WW, et al. Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. Amyotroph Lateral Scler Mot Neuron Disord. 2003;4:62–73.

    Article  CAS  Google Scholar 

  38. Cudkowicz ME, McKenna-Yasek D, Sapp PE, et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol. 1997;41:210–21. https://doi.org/10.1002/ana.410410212.

    Article  CAS  PubMed  Google Scholar 

  39. Juneja T, Pericak-Vance MA, Laing NG, et al. Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase. Neurology. 1997;48:55–7.

    Article  CAS  PubMed  Google Scholar 

  40. Aoki M, Ogasawara M, Matsubara Y, et al. Mild ALS in Japan associated with novel SOD mutation. Nat Genet. 1993;5:323–4. https://doi.org/10.1038/ng1293-323.

    Article  CAS  PubMed  Google Scholar 

  41. Luigetti M, Madia F, Conte A, et al. SOD1 G93D mutation presenting as paucisymptomatic amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2009;10:479–82. https://doi.org/10.3109/17482960802302261.

    Article  CAS  PubMed  Google Scholar 

  42. Orrell RW, Habgood JJ, Malaspina A, et al. Clinical characteristics of SOD1 gene mutations in UK families with ALS. J Neurol Sci. 1999;169:56–60.

    Article  CAS  PubMed  Google Scholar 

  43. Andersen PM, Forsgren L, Binzer M, et al. Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients. Brain J Neurol. 1996;119(Pt 4):1153–72.

    Article  Google Scholar 

  44. Al-Chalabi A, Andersen PM, Chioza B, et al. Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor. Hum Mol Genet. 1998;7:2045–50.

    Article  CAS  PubMed  Google Scholar 

  45. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130–3. https://doi.org/10.1126/science.1134108.

    Article  CAS  PubMed  Google Scholar 

  46. Sreedharan J, Blair IP, Tripathi VB, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319:1668–72. https://doi.org/10.1126/science.1154584.

    Article  CAS  PubMed  Google Scholar 

  47. Van Deerlin VM, Leverenz JB, Bekris LM, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7:409–16. https://doi.org/10.1016/S1474-4422(08)70071-1.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kwiatkowski TJ, Bosco DA, Leclerc AL, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323:1205–8. https://doi.org/10.1126/science.1166066.

    Article  CAS  PubMed  Google Scholar 

  49. Vance C, Rogelj B, Hortobágyi T, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323:1208–11. https://doi.org/10.1126/science.1165942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ravits J, Paul P, Jorg C. Focality of upper and lower motor neuron degeneration at the clinical onset of ALS. Neurology. 2007;68:1571–5. https://doi.org/10.1212/01.wnl.0000260965.20021.47.

    Article  PubMed  Google Scholar 

  51. Gourie-Devi M, Nalini A, Sandhya S. Early or late appearance of “dropped head syndrome” in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2003;74:683–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Munoz DG, Neumann M, Kusaka H, et al. FUS pathology in basophilic inclusion body disease. Acta Neuropathol. 2009;118:617–27. https://doi.org/10.1007/s00401-009-0598-9.

    Article  CAS  PubMed  Google Scholar 

  53. Neumann M, Rademakers R, Roeber S, et al. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain J Neurol. 2009;132:2922–31. https://doi.org/10.1093/brain/awp214.

    Article  Google Scholar 

  54. Seelaar H, Klijnsma KY, de Koning I, et al. Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration. J Neurol. 2010;257:747–53. https://doi.org/10.1007/s00415-009-5404-z.

    Article  CAS  PubMed  Google Scholar 

  55. Ratti A, Buratti E. Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J Neurochem. 2016;138(Suppl 1):95–111. https://doi.org/10.1111/jnc.13625.

    Article  CAS  PubMed  Google Scholar 

  56. Fujii R, Okabe S, Urushido T, et al. The RNA binding protein TLS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology. Curr Biol. 2005;15:587–93. https://doi.org/10.1016/j.cub.2005.01.058.

    Article  CAS  PubMed  Google Scholar 

  57. Wang I-F, Wu L-S, Chang H-Y, Shen C-KJ. TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J Neurochem. 2008;105:797–806. https://doi.org/10.1111/j.1471-4159.2007.05190.x.

    Article  CAS  PubMed  Google Scholar 

  58. Liu-Yesucevitz L, Bassell GJ, Gitler AD, et al. Local RNA translation at the synapse and in disease. J Neurosci. 2011;31:16086–93. https://doi.org/10.1523/JNEUROSCI.4105-11.2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fallini C, Bassell GJ, Rossoll W. The ALS disease protein TDP-43 is actively transported in motor neuron axons and regulates axon outgrowth. Hum Mol Genet. 2012;21:3703–18. https://doi.org/10.1093/hmg/dds205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245–56. https://doi.org/10.1016/j.neuron.2011.09.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257–68. https://doi.org/10.1016/j.neuron.2011.09.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Majounie E, Renton AE, Mok K, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11:323–30. https://doi.org/10.1016/S1474-4422(12)70043-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Farg MA, Sundaramoorthy V, Sultana JM, et al. C9ORF72, implicated in amyotrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet. 2014;23:3579–95. https://doi.org/10.1093/hmg/ddu068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ji YJ, Ugolino J, Brady NR, et al. Systemic deregulation of autophagy upon loss of ALS- and FTD-linked C9orf72. Autophagy. 2017;13:1254–5. https://doi.org/10.1080/15548627.2017.1299312.

    Article  CAS  PubMed  Google Scholar 

  65. Haeusler AR, Donnelly CJ, Periz G, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014;507:195–200. https://doi.org/10.1038/nature13124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ash PEA, Bieniek KF, Gendron TF, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. 2013;77:639–46. https://doi.org/10.1016/j.neuron.2013.02.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mori K, Weng S-M, Arzberger T, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013;339:1335–8. https://doi.org/10.1126/science.1232927.

    Article  CAS  PubMed  Google Scholar 

  68. Byrne S, Elamin M, Bede P, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol. 2012;11:232–40. https://doi.org/10.1016/S1474-4422(12)70014-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gijselinck I, Van Langenhove T, van der Zee J, et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 2012;11:54–65. https://doi.org/10.1016/S1474-4422(11)70261-7.

    Article  CAS  PubMed  Google Scholar 

  70. Snowden JS, Adams J, Harris J, et al. Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16:497–505. https://doi.org/10.3109/21678421.2015.1074700.

    Article  CAS  PubMed  Google Scholar 

  71. Simón-Sánchez J, Dopper EGP, Cohn-Hokke PE, et al. The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain J Neurol. 2012;135:723–35. https://doi.org/10.1093/brain/awr353.

    Article  Google Scholar 

  72. Beck J, Poulter M, Hensman D, et al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet. 2013;92:345–53. https://doi.org/10.1016/j.ajhg.2013.01.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Majounie E, Abramzon Y, Renton AE, et al. Repeat expansion in C9ORF72 in Alzheimer’s disease. N Engl J Med. 2012;366:283–4. https://doi.org/10.1056/NEJMc1113592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lindquist SG, Duno M, Batbayli M, et al. Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease. Clin Genet. 2013;83:279–83. https://doi.org/10.1111/j.1399-0004.2012.01903.x.

    Article  CAS  PubMed  Google Scholar 

  75. Lesage S, Le Ber I, Condroyer C, et al. C9orf72 repeat expansions are a rare genetic cause of parkinsonism. Brain J Neurol. 2013;136:385–91. https://doi.org/10.1093/brain/aws357.

    Article  Google Scholar 

  76. Hensman Moss DJ, Poulter M, Beck J, et al. C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology. 2014;82:292–9. https://doi.org/10.1212/WNL.0000000000000061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Novarino G, Fenstermaker AG, Zaki MS, et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014;343:506–11. https://doi.org/10.1126/science.1247363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chen Y-Z, Bennett CL, Huynh HM, et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004;74:1128–35. https://doi.org/10.1086/421054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Deng H-X, Chen W, Hong S-T, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011;477:211–5. https://doi.org/10.1038/nature10353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. C-H W, Fallini C, Ticozzi N, et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012;488:499–503. https://doi.org/10.1038/nature11280.

    Article  Google Scholar 

  81. Tennessen JA, Bigham AW, O’Connor TD, et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012;337:64–9. https://doi.org/10.1126/science.1219240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lee S, Abecasis GR, Boehnke M, Lin X. Rare-variant association analysis: study designs and statistical tests. Am J Hum Genet. 2014;95:5–23. https://doi.org/10.1016/j.ajhg.2014.06.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cirulli ET, Lasseigne BN, Petrovski S, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015;347:1436–41. https://doi.org/10.1126/science.aaa3650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Smith BN, Ticozzi N, Fallini C, et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron. 2014;84:324–31. https://doi.org/10.1016/j.neuron.2014.09.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kenna KP, van Doormaal PTC, Dekker AM, et al. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nat Genet. 2016;48:1037–42. https://doi.org/10.1038/ng.3626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. James PA, Talbot K. The molecular genetics of non-ALS motor neuron diseases. Biochim Biophys Acta. 2006;1762:986–1000. https://doi.org/10.1016/j.bbadis.2006.04.003.

    Article  CAS  PubMed  Google Scholar 

  87. Beetz C, Pieber TR, Hertel N, et al. Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V. Am J Hum Genet. 2012;91:139–45. https://doi.org/10.1016/j.ajhg.2012.05.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Züchner S, Wang G, Tran-Viet K-N, et al. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet. 2006;79:365–9. https://doi.org/10.1086/505361.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Auer PL, Lettre G. Rare variant association studies: considerations, challenges and opportunities. Genome Med. 2015;7:16. https://doi.org/10.1186/s13073-015-0138-2.

    Article  PubMed  PubMed Central  Google Scholar 

  90. van Rheenen W, Shatunov A, Dekker AM, et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat Genet. 2016;48:1043–8. https://doi.org/10.1038/ng.3622.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy

    Nicola Ticozzi & Vincenzo Silani

  2. Department of Pathophysiology and Transplantation, ‘Dino Ferrari’ Center, University of Milan, Milan, Italy

    Nicola Ticozzi & Vincenzo Silani

Authors
  1. Nicola Ticozzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vincenzo Silani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicola Ticozzi .

Editor information

Editors and Affiliations

  1. University of Milan, Fondazione Ca’ Granda, IRCCS Ospedale Policlinico, Milan, Italy

    Daniela Galimberti

  2. University of Milan, Fondazione Ca’ Granda, IRCCS Ospedale Policlinico, Milan, Italy

    Elio Scarpini

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ticozzi, N., Silani, V. (2018). Genotypic and Phenotypic Heterogeneity in Amyotrophic Lateral Sclerosis. In: Galimberti, D., Scarpini, E. (eds) Neurodegenerative Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-72938-1_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-72938-1_13

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-72937-4

  • Online ISBN: 978-3-319-72938-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation