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Familial amyotrophic lateral sclerosis

Leo McCluskey, MD, MBE
Dana Falcone, MS, CGC
Section Editors
Jeremy M Shefner, MD, PhD
Ira N Targoff, MD
Benjamin A Raby, MD, MPH
Deputy Editor
John F Dashe, MD, PhD


Amyotrophic lateral sclerosis (ALS) is one specific type of the more general group of motor neuron diseases. These disorders variably affect motor neurons located in the anterior (ventral) horn regions of the spinal cord, the cranial nerve motor nuclei in the pons and medulla, and the frontal cortex. Familial amyotrophic lateral sclerosis accounts for 5 to 10 percent of all ALS cases.

ALS is a relentlessly progressive neurodegenerative disorder that causes muscle weakness, disability, and eventually death. The hallmark of ALS is the combination of upper motor neuron (UMN) and lower motor neuron (LMN) involvement. The LMN findings of weakness, atrophy, and fasciculations are a direct consequence of muscle denervation, hence the term "amyotrophic." The UMN findings of hyperreflexia and spasticity result from degeneration of the lateral corticospinal tracts in the spinal cord, which are gliotic and hardened to palpation at autopsy, hence the term "lateral sclerosis."

This topic review will discuss familial ALS. The epidemiology and clinical features of ALS are discussed separately. (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis" and "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease".)


Familial ALS accounts for approximately 5 to 10 percent of all ALS cases [1,2], with the rest being sporadic (idiopathic) in origin. In our series of 399 cases of ALS at the University of Pennsylvania with a four-generation pedigree, 10 percent of individuals had an affected first or second-degree relative [2].

Familial ALS is phenotypically and genetically heterogeneous. Although most familial ALS cases follow an autosomal dominant inheritance pattern, recessive and X-linked forms have been described. At least 15 different loci are thought to harbor ALS-causing mutations. The nomenclature of ALS1 through ALS15 arises from the order of their discovery and not from any particular clinical classification. Many of the types listed have been described only in one or two families, and genotype-phenotype correlation is stronger for some forms of genetic ALS than for others. In most individual cases, it may be difficult to determine on clinical grounds alone if ALS is familial or sporadic, especially at the onset of disease. The presence of atypical features such as young age of onset, sensory loss, and of course a positive family history of ALS, other neurodegenerative disorders, and dementia should alert the clinician to the possibility of familial ALS.


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Literature review current through: Jul 2017. | This topic last updated: Dec 02, 2016.
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  1. Byrne S, Walsh C, Lynch C, et al. Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2011; 82:623.
  2. Falcone D, McCluskey L. Unpublished data. 2011.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Rutherford NJ, DeJesus-Hernandez M, Baker MC, et al. C9ORF72 hexanucleotide repeat expansions in patients with ALS from the Coriell Cell Repository. Neurology 2012; 79:482.
  9. van Rheenen W, van Blitterswijk M, Huisman MH, et al. Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases. Neurology 2012; 79:878.
  10. Morita M, Al-Chalabi A, Andersen PM, et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 2006; 66:839.
  11. Vance C, Al-Chalabi A, Ruddy D, et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain 2006; 129:868.
  12. Valdmanis PN, Dupre N, Bouchard JP, et al. Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. Arch Neurol 2007; 64:240.
  13. Le Ber I, Camuzat A, Berger E, et al. Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease. Neurology 2009; 72:1669.
  14. Hosler BA, Siddique T, Sapp PC, et al. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 2000; 284:1664.
  15. Mackenzie IR, Rademakers R. The molecular genetics and neuropathology of frontotemporal lobar degeneration: recent developments. Neurogenetics 2007; 8:237.
  16. 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.
  17. Siddique N, Siddique T. Genetics of amyotrophic lateral sclerosis. Phys Med Rehabil Clin N Am 2008; 19:429.
  18. Millecamps S, Salachas F, Cazeneuve C, et al. SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations. J Med Genet 2010; 47:554.
  19. ALS online genetics database. http://alsod.iop.kcl.ac.uk/Als/index.aspx (Accessed on September 20, 2010).
  20. Andersen PM, Sims KB, Xin 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 Other Motor Neuron Disord 2003; 4:62.
  21. Ratovitski T, Corson LB, Strain J, et al. Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds. Hum Mol Genet 1999; 8:1451.
  22. Cudkowicz ME, McKenna-Yasek D, Chen C, et al. Limited corticospinal tract involvement in amyotrophic lateral sclerosis subjects with the A4V mutation in the copper/zinc superoxide dismutase gene. Ann Neurol 1998; 43:703.
  23. Andersen PM. Genetics of sporadic ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 2001; 2 Suppl 1:S37.
  24. Gellera C. Genetics of ALS in Italian families. Amyotroph Lateral Scler Other Motor Neuron Disord 2001; 2 Suppl 1:S43.
  25. Gellera C, Castellotti B, Riggio MC, et al. Superoxide dismutase gene mutations in Italian patients with familial and sporadic amyotrophic lateral sclerosis: identification of three novel missense mutations. Neuromuscul Disord 2001; 11:404.
  26. Hays AP, Naini A, He CZ, et al. Sporadic amyotrophic lateral sclerosis and breast cancer: Hyaline conglomerate inclusions lead to identification of SOD1 mutation. J Neurol Sci 2006; 242:67.
  27. Aksoy H, Dean G, Elian M, et al. A4T mutation in the SOD1 gene causing familial amyotrophic lateral sclerosis. Neuroepidemiology 2003; 22:235.
  28. Arisato T, Okubo R, Arata H, et al. Clinical and pathological studies of familial amyotrophic lateral sclerosis (FALS) with SOD1 H46R mutation in large Japanese families. Acta Neuropathol 2003; 106:561.
  29. Rezania K, Yan J, Dellefave L, et al. A rare Cu/Zn superoxide dismutase mutation causing familial amyotrophic lateral sclerosis with variable age of onset, incomplete penetrance and a sensory neuropathy. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:162.
  30. Régal L, Vanopdenbosch L, Tilkin P, et al. The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis. Arch Neurol 2006; 63:262.
  31. Andersen PM, Nilsson P, Ala-Hurula V, et al. Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase. Nat Genet 1995; 10:61.
  32. 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 1996; 119 ( Pt 4):1153.
  33. Robberecht W, Aguirre T, Van den Bosch L, et al. D90A heterozygosity in the SOD1 gene is associated with familial and apparently sporadic amyotrophic lateral sclerosis. Neurology 1996; 47:1336.
  34. Hand CK, Khoris J, Salachas F, et al. A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. Am J Hum Genet 2002; 70:251.
  35. Chance PF, Rabin BA, Ryan SG, et al. Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet 1998; 62:633.
  36. Chen YZ, 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.
  37. Asaka T, Yokoji H, Ito J, et al. Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX. Neurology 2006; 66:1580.
  38. Chen YZ, Hashemi SH, Anderson SK, et al. Senataxin, the yeast Sen1p orthologue: characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease. Neurobiol Dis 2006; 23:97.
  39. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009; 323:1205.
  40. 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.
  41. Yan J, Deng HX, Siddique N, et al. Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology 2010; 75:807.
  42. Akiyama T, Warita H, Kato M, et al. Genotype-phenotype relationships in familial amyotrophic lateral sclerosis with FUS/TLS mutations in Japan. Muscle Nerve 2016; 54:398.
  43. Hewitt C, Kirby J, Highley JR, et al. Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 2010; 67:455.
  44. Sapp PC, Hosler BA, McKenna-Yasek D, et al. Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am J Hum Genet 2003; 73:397.
  45. Nishimura AL, Mitne-Neto M, Silva HC, et al. A novel locus for late onset amyotrophic lateral sclerosis/motor neurone disease variant at 20q13. J Med Genet 2004; 41:315.
  46. Nishimura AL, Mitne-Neto M, Silva HC, 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.
  47. Greenway MJ, Alexander MD, Ennis S, et al. A novel candidate region for ALS on chromosome 14q11.2. Neurology 2004; 63:1936.
  48. Greenway MJ, Andersen PM, Russ C, et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet 2006; 38:411.
  49. Wu D, Yu W, Kishikawa H, et al. Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann Neurol 2007; 62:609.
  50. van Es MA, Diekstra FP, Veldink JH, et al. A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation. Neurology 2009; 72:287.
  51. Sreedharan J, Blair IP, Tripathi VB, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 2008; 319:1668.
  52. Yokoseki A, Shiga A, Tan CF, et al. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 2008; 63:538.
  53. 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.
  54. Kabashi E, Valdmanis PN, Dion P, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 2008; 40:572.
  55. Kühnlein P, Sperfeld AD, Vanmassenhove B, et al. Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations. Arch Neurol 2008; 65:1185.
  56. Corcia P, Valdmanis P, Millecamps S, et al. Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. Neurology 2012; 78:1519.
  57. Borroni B, Archetti S, Del Bo R, et al. TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course. Rejuvenation Res 2010; 13:509.
  58. 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.
  59. Maruyama H, Morino H, Ito H, et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 2010; 465:223.
  60. Del Bo R, Tiloca C, Pensato V, et al. Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2011; 82:1239.
  61. Belzil VV, Daoud H, Desjarlais A, et al. Analysis of OPTN as a causative gene for amyotrophic lateral sclerosis. Neurobiol Aging 2011; 32:555.e13.
  62. Johnson JO, Mandrioli J, Benatar M, et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 2010; 68:857.
  63. González-Pérez P, Cirulli ET, Drory VE, et al. Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis. Neurology 2012; 79:2201.
  64. Watts GD, Wymer J, Kovach MJ, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 2004; 36:377.
  65. Nalbandian A, Donkervoort S, Dec E, et al. The multiple faces of valosin-containing protein-associated diseases: inclusion body myopathy with Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis. J Mol Neurosci 2011; 45:522.
  66. Ju JS, Fuentealba RA, Miller SE, et al. Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 2009; 187:875.
  67. Wu CH, Fallini C, Ticozzi N, et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 2012; 488:499.
  68. Gydesen S, Brown JM, Brun A, et al. Chromosome 3 linked frontotemporal dementia (FTD-3). Neurology 2002; 59:1585.
  69. Parkinson N, Ince PG, Smith MO, et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 2006; 67:1074.
  70. Mitchell J, Paul P, Chen HJ, et al. Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase. Proc Natl Acad Sci U S A 2010; 107:7556.
  71. Al-Chalabi A, Andersen PM, Nilsson P, et al. Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet 1999; 8:157.
  72. Kim HJ, Kim NC, Wang YD, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 2013; 495:467.
  73. Gros-Louis F, Meijer IA, Hand CK, et al. An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. Ann Neurol 2003; 53:144.
  74. 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.
  75. Kress JA, Kühnlein P, Winter P, et al. Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis. Ann Neurol 2005; 58:800.
  76. Sheerin UM, Schneider SA, Carr L, et al. ALS2 mutations: juvenile amyotrophic lateral sclerosis and generalized dystonia. Neurology 2014; 82:1065.
  77. Gascon GG, Chavis P, Yaghmour A, et al. Familial childhood primary lateral sclerosis with associated gaze paresis. Neuropediatrics 1995; 26:313.
  78. Eymard-Pierre E, Lesca G, Dollet S, et al. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet 2002; 71:518.
  79. Hentati A, Ouahchi K, Pericak-Vance MA, et al. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics 1998; 2:55.
  80. Orlacchio A, Babalini C, Borreca A, et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 2010; 133:591.
  81. Stevanin G, Santorelli FM, Azzedine H, et al. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 2007; 39:366.
  82. Deng HX, Chen W, Hong ST, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 2011; 477:211.
  83. Gellera C, Tiloca C, Del Bo R, et al. Ubiquilin 2 mutations in Italian patients with amyotrophic lateral sclerosis and frontotemporal dementia. J Neurol Neurosurg Psychiatry 2013; 84:183.
  84. Fecto F, Yan J, Vemula SP, et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 2011; 68:1440.
  85. Rubino E, Rainero I, Chiò A, et al. SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 2012; 79:1556.
  86. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 1995; 57:1233.
  87. Donkervoort S, Siddique T. Amyotrophic lateral sclerosis overview. In: GeneReviews [Internet]. www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=als-overview (Accessed on October 10, 2011).
  88. Benatar M, Stanislaw C, Reyes E, et al. Presymptomatic ALS genetic counseling and testing: Experience and recommendations. Neurology 2016; 86:2295.