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Cited by 287Amyotrophic Lateral Sclerosis ResearchHereditary Neurological DisordersGenetic Neurodegenerative Diseases

Gene discovery in amyotrophic lateral sclerosis: implications for clinical management

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Al-Chalabi, Ammar, van den Berg, Leonard H., Veldink, Jan·2017·Nature Reviews Neurology
DOI 10.1038/nrneurol.2016.182
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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease predominantly affecting upper and lower motor neurons. The disease leads to relentlessly progressive weakness of voluntary muscles, with death typically resulting from diaphragmatic failure within 2-5 years. Since the discovery of mutations in SOD1, which account for ∼2% of ALS cases, increasing efforts have been made to understand the genetic component of ALS risk, with the expectation that this insight will not only aid diagnosis and classification, but also guide personalized treatment and reveal the mechanisms that cause motor neuron death. In this Review, we outline previous and current efforts to characterize genes that are associated with ALS, describe current knowledge about the genetic architecture of ALS - including the relevance of family history - and the probable nature of future gene discoveries, and explore how our understanding of ALS genetics affects present and future clinical decisions. We observe that many gene variants associated with ALS have effect sizes between those of mutations that greatly increase risk and those of common variants that have a small effect on risk, and combine this observation with insights from next-generation sequencing to explore the implications for genetic counselling.

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  • Approximately 10% of ALS cases are familial with autosomal dominant inheritance of mutations reported in at least 15 genes, including SOD1, TARDBP, FUS, ANG, and OPTN, and an expanded hexanucleotide repeat of GGGGCC in a noncoding region of the C9ORF72 gene.

    “Approximately 10% of ALS cases are familial with autosomal dominant inheritance of mutations reported in at least 15 genes, including to name a few SOD1 , TARDBP , FUS , ANG , and OPTN (11, 18, 174, 465), and an expanded hexanucleotide repeat of GGGGCC in a noncoding region of the C9ORF72 gene (140, 497).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [11]

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  • Ninety percent of amyotrophic lateral sclerosis cases are sporadic with no clear genetic linkage.

    “Ninety percent of ALS cases are sporadic with no clear genetic linkage (11, 313).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [11]

    In “Does sporadic ALS have a genetic component?” (page not available), the paper says 5–20% of people with ALS report a positive family history, consistent with roughly 90% being classified as sporadic. But it also reports substantial heritability in apparently sporadic ALS, so “no clear genetic linkage” is supported only if it means no evident family history, not no genetic contribution. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Mutations in SOD1, which encodes the antioxidant enzyme superoxide dismutase 1, account for 2% of all ALS cases.

    “Mutations in SOD1 , which encodes the antioxidant enzyme superoxide dismutase 1, account for 2% of all ALS cases (11).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [11]

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References 93 · Cited by 287

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  1. Phukan, J., Pender, N. P. & Hardiman, O. Cognitive impairment in amyotrophic lateral sclerosis. The Lancet. Neurology 6, 994-1003, doi:10.1016/S1474- 4422(07)70265-X (2007). · DOI
  2. Goldstein, L. H. & Abrahams, S. Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. The Lancet. Neurology 12, 368-380, doi:10.1016/S1474-4422(13)70026-7 (2013). · DOI
  3. Johnston, C. A. et al. Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. Journal of neurology 253, 1642-1643, doi:10.1007/s00415-006-0195-y (2006). · DOI
  4. Marin, B. et al. Variation in worldwide incidence of amyotrophic lateral sclerosis: a meta-analysis. Int J Epidemiol, doi:10.1093/ije/dyw061 (2016). · DOI
  5. Al-Chalabi, A. & Hardiman, O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nature reviews. Neurology 9, 617-628, doi:10.1038/nrneurol.2013.203 (2013). · DOI
  6. Manjaly, Z. R. et al. The sex ratio in amyotrophic lateral sclerosis: A population based study. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 11, 439-442, doi:10.3109/17482961003610853 (2010). · DOI
  7. Byrne, S. et al. Aggregation of neurologic and neuropsychiatric disease in amyotrophic lateral sclerosis kindreds: a population-based case-control cohort study of familial and sporadic amyotrophic lateral sclerosis. Annals of neurology 74, 699- 708, doi:10.1002/ana.23969 (2013). · DOI
  8. Al-Chalabi, A. et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. Journal of neurology, neurosurgery, and psychiatry 81, 1324-1326, doi:10.1136/jnnp.2010.207464 (2010). · DOI
  9. Wingo, T. S., Cutler, D. J., Yarab, N., Kelly, C. M. & Glass, J. D. The heritability of amyotrophic lateral sclerosis in a clinically ascertained United States research registry. PloS one 6, e27985, doi:10.1371/journal.pone.0027985 (2011). · DOI
  10. McLaughlin, R. L., Vajda, A. & Hardiman, O. Heritability of Amyotrophic Lateral Sclerosis: Insights From Disparate Numbers. JAMA neurology 72, 857-858, doi:10.1001/jamaneurol.2014.4049 (2015). · DOI
  11. Byrne, S., Elamin, M., Bede, P. & Hardiman, O. Absence of consensus in diagnostic criteria for familial neurodegenerative diseases. Journal of neurology, neurosurgery, and psychiatry 83, 365-367, doi:10.1136/jnnp-2011-301530 (2012). · DOI
  12. Al-Chalabi, A. & Lewis, C. M. Modelling the effects of penetrance and family size on rates of sporadic and familial disease. Human heredity 71, 281-288, doi:10.1159/000330167 (2011). · DOI
  13. Andersen, P. M. & Al-Chalabi, A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nature reviews. Neurology 7, 603-615, doi:10.1038/nrneurol.2011.150 (2011). · DOI · Paper page
  14. Williams, K. L. et al. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Commun 7, 11253, doi:10.1038/ncomms11253 (2016). · DOI
  15. van Es, M. A. et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nature genetics 41, 1083-1087, doi:10.1038/ng.442 (2009). · DOI
  16. Shatunov, A. et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. The Lancet. Neurology 9, 986-994, doi:10.1016/s1474-4422(10)70197-6 (2010). · DOI
  17. Fogh, I. et al. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Human molecular genetics 23, 2220-2231, doi:10.1093/hmg/ddt587 (2014). · DOI
  18. van Rheenen, W. et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nature genetics 48, 1043-1048, doi:10.1038/ng.3622 (2016). · DOI
  19. Kenna, K. P. et al. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nature genetics 48, 1037-1042, doi:10.1038/ng.3626 (2016). · DOI
  20. Abel, O., Powell, J. F., Andersen, P. M. & Al-Chalabi, A. ALSoD: A user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics. Human mutation 33, 1345-1351, doi:10.1002/humu.22157 (2012). · DOI
  21. Wroe, R., Wai-Ling Butler, A., Andersen, P. M., Powell, J. F. & Al-Chalabi, A. ALSOD: the Amyotrophic Lateral Sclerosis Online Database. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 9, 249-250, doi:10.1080/17482960802146106 (2008). · DOI
  22. Amberger, J. S., Bocchini, C. A., Schiettecatte, F., Scott, A. F. & Hamosh, A. OMIM.org: Online Mendelian Inheritance in Man (OMIM(R)), an online catalog of human genes and genetic disorders. Nucleic acids research 43, D789-798, doi:10.1093/nar/gku1205 (2015). · DOI · Paper page
  23. Morita, M. et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66, 839-844, doi:10.1212/01.wnl.0000200048.53766.b4 (2006). · DOI
  24. Vance, C. et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain : a journal of neurology 129, 868-876, doi:10.1093/brain/awl030 (2006). · DOI
  25. Hsiung, G. Y. et al. Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain : a journal of neurology 135, 709-722, doi:10.1093/brain/awr354 (2012). · DOI
  26. Pearson, J. P. et al. Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p. Journal of neurology 258, 647- 655, doi:10.1007/s00415-010-5815-x (2011). · DOI · Paper page
  27. Boxer, A. L. et al. Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. Journal of neurology, neurosurgery, and psychiatry 82, 196-203, doi:10.1136/jnnp.2009.204081 (2011). · DOI
  28. Gijselinck, I. et al. Identification of 2 Loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol 67, 606-616, doi:10.1001/archneurol.2010.82 (2010). · DOI
  29. Valdmanis, P. N. et al. Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. Arch Neurol 64, 240-245, doi:10.1001/archneur.64.2.240 (2007). · DOI
  30. Greenway, M. J. et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nature genetics 38, 411-413, doi:10.1038/ng1742 (2006). · DOI
  31. Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069-1075, doi:10.1038/nature09320 (2010). · DOI
  32. Simpson, C. L. et al. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Human molecular genetics 18, 472-481, doi:10.1093/hmg/ddn375 (2009). · DOI
  33. Blauw, H. M. et al. A large genome scan for rare CNVs in amyotrophic lateral sclerosis. Human molecular genetics 19, 4091-4099, doi:10.1093/hmg/ddq323 (2010). · DOI
  34. Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285-291, doi:10.1038/nature19057 (2016). · DOI · Paper page
  35. Appel, S. H. & Rowland, L. P. Amyotrophic lateral sclerosis, frontotemporal lobar dementia, and p62: a functional convergence? Neurology 79, 1526-1527, doi:10.1212/WNL.0b013e31826e26ec (2012). · DOI
  36. Shaw, C. E. et al. Mutations in all five exons of SOD-1 may cause ALS. Annals of neurology 43, 390-394, doi:10.1002/ana.410430319 (1998). · DOI
  37. Ionita-Laza, I., McCallum, K., Xu, B. & Buxbaum, J. D. A spectral approach integrating functional genomic annotations for coding and noncoding variants. Nature genetics 48, 214-220, doi:10.1038/ng.3477 (2016). · DOI
  38. Rao, S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665-1680, doi:10.1016/j.cell.2014.11.021 (2014). · DOI · Paper page
  39. Carvunis, A. R. et al. Evidence for a common evolutionary rate in metazoan transcriptional networks. Elife 4, doi:10.7554/eLife.11615 (2015). · DOI
  40. Campbell, I. M., Shaw, C. A., Stankiewicz, P. & Lupski, J. R. Somatic mosaicism: implications for disease and transmission genetics. Trends Genet 31, 382-392, doi:10.1016/j.tig.2015.03.013 (2015). · DOI · Paper page
  41. Cirulli, E. T. et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science (New York, N.Y.) 347, 1436-1441, doi:10.1126/science.aaa3650 (2015). · DOI · Paper page
  42. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918-934, doi:10.1016/j.cell.2010.02.016 (2010). · DOI · Paper page
  43. Fang, X. et al. The NEK1 interactor, C21ORF2, is required for efficient DNA damage repair. Acta Biochim Biophys Sin (Shanghai) 47, 834-841, doi:10.1093/abbs/gmv076 (2015). · DOI
  44. Lai, C. K. et al. Functional characterization of putative cilia genes by high-content analysis. Mol Biol Cell 22, 1104-1119, doi:10.1091/mbc.E10-07-0596 (2011). · DOI
  45. Ma, X., Peterson, R. & Turnbull, J. Adenylyl cyclase type 3, a marker of primary cilia, is reduced in primary cell culture and in lumbar spinal cord in situ in G93A SOD1 mice. BMC Neurosci 12, 71, doi:10.1186/1471-2202-12-71 (2011). · DOI
  46. Smith, B. N. et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron 84, 324-331, doi:10.1016/j.neuron.2014.09.027 (2014). · DOI
  47. Puls, I. et al. Mutant dynactin in motor neuron disease. Nature genetics 33, 455-456, doi:10.1038/ng1123 (2003). · DOI
  48. Hand, C. K. et al. Compound heterozygous D90A and D96N SOD1 mutations in a recessive amyotrophic lateral sclerosis family. Annals of neurology 49, 267-271 (2001).
  49. van Blitterswijk, M. et al. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Human molecular genetics 21, 3776-3784, doi:10.1093/hmg/dds199 (2012). · DOI
  50. van Blitterswijk, M. et al. VAPB and C9orf72 mutations in 1 familial amyotrophic lateral sclerosis patient. Neurobiology of aging 33, 2950 e2951-2954, doi:10.1016/j.neurobiolaging.2012.07.004 (2012). · DOI
  51. Bury, J. J. et al. Oligogenic inheritance of optineurin (OPTN) and C9ORF72 mutations in ALS highlights localisation of OPTN in the TDP-43-negative inclusions of C9ORF72-ALS. Neuropathology : official journal of the Japanese Society of Neuropathology 36, 125-134, doi:10.1111/neup.12240 (2016). · DOI
  52. Kramer, N. J. et al. Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. Science (New York, N.Y.) 353, 708-712, doi:10.1126/science.aaf7791 (2016). · DOI
  53. Diekstra, F. P. et al. C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis. Annals of neurology 76, 120-133, doi:10.1002/ana.24198 (2014). · DOI
  54. Chio, A. et al. Genetic counselling in ALS: facts, uncertainties and clinical suggestions. Journal of neurology, neurosurgery, and psychiatry 85, 478-485, doi:10.1136/jnnp-2013-305546 (2014). · DOI
  55. Smith, B. N. et al. The C9ORF72 expansion mutation is a common cause of ALS+/- FTD in Europe and has a single founder. European journal of human genetics : EJHG 21, 102-108, doi:10.1038/ejhg.2012.98 (2013). · DOI
  56. Al-Chalabi, A. et al. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. The Lancet. Neurology 13, 1108-1113, doi:10.1016/s1474-4422(14)70219-4 (2014). · DOI
  57. Agosta, F. et al. The El Escorial criteria: strengths and weaknesses. Amyotrophic lateral sclerosis & frontotemporal degeneration 16, 1-7, doi:10.3109/21678421.2014.964258 (2015). · DOI
  58. Miller, T. M. et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. The Lancet. Neurology 12, 435-442, doi:10.1016/S1474- 4422(13)70061-9 (2013). · DOI · Paper page
  59. Atanasio, A. et al. C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci Rep 6, 23204, doi:10.1038/srep23204 (2016). · DOI · Paper page
  60. Doudna, J. A. & Charpentier, E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science (New York, N.Y.) 346, 1258096, doi:10.1126/science.1258096 (2014). · DOI · Paper page
  61. Heidenreich, M. & Zhang, F. Applications of CRISPR-Cas systems in neuroscience. Nat Rev Neurosci 17, 36-44, doi:10.1038/nrn.2015.2 (2016). · DOI
  62. Do, R., Kathiresan, S. & Abecasis, G. R. Exome sequencing and complex disease: practical aspects of rare variant association studies. Human molecular genetics 21, R1-9, doi:10.1093/hmg/dds387 (2012). · DOI
  63. Gitcho, M. A. et al. TDP-43 A315T mutation in familial motor neuron disease. Annals of neurology 63, 535-538, doi:10.1002/ana.21344 (2008). · DOI
  64. Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nature genetics 40, 572-574, doi:10.1038/ng.132 (2008). · DOI · Paper page
  65. Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science (New York, N.Y.) 319, 1668-1672, doi:10.1126/science.1154584 (2008). · DOI · Paper page
  66. Al-Chalabi, A. et al. Variants in the ALS2 gene are not associated with sporadic amyotrophic lateral sclerosis. Neurogenetics 4, 221-222, doi:10.1007/s10048-003- 0152-1 (2003). · DOI
  67. Hadano, S. et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nature genetics 29, 166-173, doi:10.1038/ng1001-166 (2001). · DOI
  68. Takahashi, Y. et al. ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19. American journal of human genetics 93, 900-905, doi:10.1016/j.ajhg.2013.09.008 (2013). · DOI
  69. Parkinson, N. et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 67, 1074-1077, doi:10.1212/01.wnl.0000231510.89311.8b (2006). · DOI · Paper page
  70. Brenner, D. et al. NEK1 mutations in familial amyotrophic lateral sclerosis. Brain : a journal of neurology 139, e28, doi:10.1093/brain/aww033 (2016). · DOI
  71. Johnson, J. O. et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci 17, 664-666, doi:10.1038/nn.3688 (2014). · DOI
  72. Muller, T. J. et al. Phenotype of matrin-3-related distal myopathy in 16 German patients. Annals of neurology 76, 669-680, doi:10.1002/ana.24255 (2014). · DOI
  73. Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 68, 1440-1446, doi:10.1001/archneurol.2011.250 (2011). · DOI · Paper page
  74. Hirano, M. et al. Mutations in the gene encoding p62 in Japanese patients with amyotrophic lateral sclerosis. Neurology 80, 458-463, doi:10.1212/WNL.0b013e31827f0fe5 (2013). · DOI
  75. Le Ber, I. et al. SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis. JAMA neurology 70, 1403-1410, doi:10.1001/jamaneurol.2013.3849 (2013). · DOI
  76. Rubino, E. et al. SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 79, 1556-1562, doi:10.1212/WNL.0b013e31826e25df (2012). · DOI · Paper page
  77. Chow, C. Y. et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. American journal of human genetics 84, 85-88, doi:10.1016/j.ajhg.2008.12.010 (2009). · DOI · Paper page
  78. Al-Saif, A., Al-Mohanna, F. & Bohlega, S. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Annals of neurology 70, 913-919, doi:10.1002/ana.22534 (2011). · DOI
  79. Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857-864, doi:10.1016/j.neuron.2010.11.036 (2010). · DOI · Paper page
  80. Kaneb, H. M. et al. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Human molecular genetics 24, 1363-1373, doi:10.1093/hmg/ddu545 (2015). · DOI
  81. Chance, P. F. et al. Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. American journal of human genetics 62, 633-640, doi:10.1086/301769 (1998). · DOI
  82. Chen, Y. Z. et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). American journal of human genetics 74, 1128- 1135, doi:10.1086/421054 (2004). · DOI
  83. De Jonghe, P. et al. Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder? Brain : a journal of neurology 125, 1320-1325 (2002).
  84. Maruyama, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465, 223-226, doi:10.1038/nature08971 (2010). · DOI · Paper page
  85. Pottier, C. et al. Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta neuropathologica 130, 77-92, doi:10.1007/s00401-015-1436-x (2015). · DOI · Paper page
  86. Gros-Louis, F. et al. A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis. J Biol Chem 279, 45951-45956, doi:10.1074/jbc.M408139200 (2004). 100 · DOI
  87. Kim, H. J. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467-473, doi:10.1038/nature11922 (2013). 101 · DOI
  88. Daoud, H. et al. Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis. Arch Neurol 68, 739-742, doi:10.1001/archneurol.2011.111 (2011). 102 · DOI
  89. Van Damme, P. et al. Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2. Neurology 76, 2066-2072, doi:10.1212/WNL.0b013e31821f445b (2011). 103 · DOI
  90. Millecamps, S. et al. SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations. Journal of medical genetics 47, 554-560, doi:10.1136/jmg.2010.077180 (2010). 104 · DOI
  91. van Es, M. A. et al. A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation. Neurology 72, 287-288, doi:10.1212/01.wnl.0000339487.84908.00 (2009). 105 · DOI
  92. Wu, D. et al. Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Annals of neurology 62, 609-617, doi:10.1002/ana.21221 (2007). 106 · DOI
  93. Orlacchio, A. et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain : a journal of neurology 133, 591-598, doi:10.1093/brain/awp325 (2010). 108 · DOI
  94. Hubers, A. et al. De novo FUS mutations are the most frequent genetic cause in early- onset German ALS patients. Neurobiology of aging 36, 3117 e3111-3116, doi:10.1016/j.neurobiolaging.2015.08.005 (2015). 109 · DOI
  95. Kwiatkowski, T. J., Jr. et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science (New York, N.Y.) 323, 1205- 1208, doi:10.1126/science.1166066 (2009). 110 · DOI
  96. Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science (New York, N.Y.) 323, 1208-1211, doi:10.1126/science.1165942 (2009). 111 · DOI
  97. Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499-503, doi:10.1038/nature11280 (2012). 112 · DOI
  98. Hand, C. K. et al. A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. American journal of human genetics 70, 251-256 (2002). 113
  99. Sapp, P. C. et al. Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. American journal of human genetics 73, 397-403, doi:10.1086/377158 (2003). 114 · DOI
  100. Nishimura, A. L. et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. American journal of human genetics 75, 822-831, doi:10.1086/425287 (2004). 115 · DOI
  101. Alexander, M. D. et al. "True" sporadic ALS associated with a novel SOD-1 mutation. Annals of neurology 52, 680-683, doi:10.1002/ana.10369 (2002). 116 · DOI
  102. Andersen, P. M. et al. Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase. Nature genetics 10, 61-66, doi:10.1038/ng0595-61 (1995). 117 · DOI
  103. Bannwarth, S. et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain : a journal of neurology 137, 2329-2345, doi:10.1093/brain/awu138 (2014). 118 · DOI
  104. Vechio, J. D., Bruijn, L. I., Xu, Z., Brown, R. H., Jr. & Cleveland, D. W. Sequence variants in human neurofilament proteins: absence of linkage to familial amyotrophic lateral sclerosis. Annals of neurology 40, 603-610, doi:10.1002/ana.410400410 (1996). 122 · DOI
  105. Deng, H. X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211-215, doi:10.1038/nature10353 (2011). 123 · DOI · Paper page
  106. Fahed, A. C. et al. UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration. Annals of neurology 75, 793-798, doi:10.1002/ana.24164 (2014). 124 · DOI
  107. Hoglinger, G. U. et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nature genetics 43, 699-705, doi:10.1038/ng.859 (2011). 125 · DOI
  108. Lambrechts, D. et al. Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype. Journal of medical genetics 46, 840-846, doi:10.1136/jmg.2008.058222 (2009). 126 · DOI
  109. Wills, A. M. et al. A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS. Neurology 73, 16-24, doi:10.1212/WNL.0b013e3181a18674 (2009). 127 · DOI
  110. Blauw, H. M. et al. SMN1 gene duplications are associated with sporadic ALS. Neurology 78, 776-780, doi:10.1212/WNL.0b013e318249f697 (2012). 128 · DOI
  111. Corcia, P. et al. SMN1 gene, but not SMN2, is a risk factor for sporadic ALS. Neurology 67, 1147-1150, doi:10.1212/01.wnl.0000233830.85206.1e (2006). · DOI

Authors
Al-Chalabi, A., van den Berg, L. H., & Veldink, J.
Affiliations
University Medical Center Utrecht (NL)
ORCID
Veldink, Jan
Venue
Nature Reviews Neurology
Publisher
Springer Science and Business Media LLC
Published
2016-12-16
Volume
13
Issue
2
Pages
96-104
ISSN
  • 1759-4758 (ISSN-L)
  • 1759-4766
DOI
10.1038/nrneurol.2016.182
OpenAlex
W2562565311
Cited by
287
References
93
Citations by year
2026: 16 · 2025: 17 · 2024: 24 · 2023: 32 · 2022: 29 · 2021: 39 · 2020: 36 · 2019: 30 · 2018: 35 · 2017: 29
FWCI
4.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders
  • Biogen
  • South London and Maudsley NHS Foundation Trust (633413)
  • Prize4Life
  • Baxalta
  • EU Joint Programme – Neurodegenerative Disease Research
  • Cytokinetics
  • E-Rare
  • National Institute for Health and Care Research (FP7/2007–2013)
  • Motor Neurone Disease Association (AL-CHALABI/APR15/844-791, ALCHALABI-DOBSON/APR14/829-791)
  • King's College London
  • ZonMw
  • Prinses Beatrix Spierfonds
  • Horizon 2020 Framework Programme (FP7/2007-2013, 633413, H2020-PHC-2014)
  • Medical Research Council (FP7/20072013, 259867, MC_G1000733, MR/L501529/1)
  • Economic and Social Research Council (ES/L008238/1, 633413, FP7/2007-2013)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
amyotrophic lateral sclerosis, genetic architecture, SOD1 mutations, motor neuron degeneration, genetic risk variants, family history (medicine), genetic counseling, personalized treatment, next-generation sequencing
MeSH terms
Amyotrophic Lateral Sclerosis, Humans, Mutation, Genetic Predisposition to Disease

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