UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

家族性肌萎缩侧索硬化症

Authors
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
Translators
谢琰臣, 副主任医师，副教授

引言

肌萎缩侧索硬化症(amyotrophic lateral sclerosis, ALS)是范围更广的运动神经元病的一种特殊类型。这些疾病可以不同地累及脊髓前角(腹侧)运动神经元、脑桥和延髓脑神经运动核以及额叶皮质等区域。家族性ALS占所有ALS病例的5%-10%。

ALS是一种持续进展性神经变性疾病，可导致肌无力、失能并最终死亡；其特征为上运动神经元(upper motor neuron, UMN)和下运动神经元(lower motor neuron, LMN)同时受累。肌无力、萎缩和肌束颤动等LMN表现是肌肉去神经支配的直接后果，故使用术语“肌萎缩”；反射亢进和痉挛等UMN表现是由脊髓侧面的皮质脊髓束变性所致，尸检时发现为胶质增生且触诊变硬，故使用术语“侧索硬化”。

本专题将讨论家族性ALS。ALS的流行病学和临床特点将单独讨论。 (参见“肌萎缩侧索硬化症的流行病学和发病机制”和“肌萎缩侧索硬化症和其他运动神经元病的临床特征”)

概述

家族性ALS约占所有ALS病例的5%-10%[1,2]，其余为散发型(特发型)。我们对宾夕法尼亚大学中399例ALS病例(具有4代系谱)进行的一项病例系列研究发现，10%的个体有一级或二级受累亲属[2]。

家族性ALS的表型和基因型具有异质性。尽管大部分家族性ALS病例遵循常染色体显性遗传方式，但隐性遗传或者X-连锁遗传方式也已有报道。现认为至少有15个不同的基因位点可出现导致ALS的突变。ALS1-ALS15的命名源于其发现顺序，而不是来自于任何特定的临床分类。列出的类型中有许多仅在1个或2个家族中报道，并且遗传性ALS中某些分型的基因型-表型相关性显著高于其他分型。在大部分个体病例中，仅根据临床背景很难确定ALS为家族性还是散发性，特别是在发病初期。若患者存在非典型特征如年轻时起病、感觉缺失、确定有ALS阳性家族史，有其他神经变性病及痴呆，则提示临床医生警惕家族性ALS的可能性。

                                       

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: 2017-06 . | This topic last updated: 2016-12-02.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  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 Falcone D, McCluskey L. Unpublished data. 2011.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. 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.
  43. 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.
  44. 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.
  45. 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.
  46. Greenway MJ, Alexander MD, Ennis S, et al. A novel candidate region for ALS on chromosome 14q11.2. Neurology 2004; 63:1936.
  47. Greenway MJ, Andersen PM, Russ C, et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet 2006; 38:411.
  48. Wu D, Yu W, Kishikawa H, et al. Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann Neurol 2007; 62:609.
  49. 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.
  50. Sreedharan J, Blair IP, Tripathi VB, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 2008; 319:1668.
  51. Yokoseki A, Shiga A, Tan CF, et al. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 2008; 63:538.
  52. 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.
  53. Kabashi E, Valdmanis PN, Dion P, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 2008; 40:572.
  54. 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.
  55. Corcia P, Valdmanis P, Millecamps S, et al. Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. Neurology 2012; 78:1519.
  56. 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.
  57. 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.
  58. Maruyama H, Morino H, Ito H, et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 2010; 465:223.
  59. 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.
  60. 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.
  61. Johnson JO, Mandrioli J, Benatar M, et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 2010; 68:857.
  62. González-Pérez P, Cirulli ET, Drory VE, et al. Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis. Neurology 2012; 79:2201.
  63. 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.
  64. 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.
  65. 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.
  66. Wu CH, Fallini C, Ticozzi N, et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 2012; 488:499.
  67. Gydesen S, Brown JM, Brun A, et al. Chromosome 3 linked frontotemporal dementia (FTD-3). Neurology 2002; 59:1585.
  68. Parkinson N, Ince PG, Smith MO, et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 2006; 67:1074.
  69. 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.
  70. 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.
  71. 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.
  72. 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.
  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. Gascon GG, Chavis P, Yaghmour A, et al. Familial childhood primary lateral sclerosis with associated gaze paresis. Neuropediatrics 1995; 26:313.
  77. 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.
  78. Orlacchio A, Babalini C, Borreca A, et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 2010; 133:591.
  79. 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.
  80. 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.
  81. 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.
  82. Fecto F, Yan J, Vemula SP, et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 2011; 68:1440.
  83. Rubino E, Rainero I, Chiò A, et al. SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 2012; 79:1556.
  84. 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.
  85. 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).