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Progress in Clinical Neurosciences: The Evidence for ALS as a Multisystems Disorder of Limited Phenotypic Expression

Published online by Cambridge University Press:  02 December 2014

Michael J. Strong
Michael J. Strong*
Affiliation:
Department of Clinical Neurological Sciences, The University of Western Ontario, London, Ontario, Canada
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Abstract

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Traditionally, amyotrophic lateral sclerosis (ALS) is considered to be a unique neurodegeneration disorder in which motor neurons are selectively vulnerable to a single disease process. Our current understanding of ALS, however, suggests that this is far too limited an approach. While motor neuron degeneration remains the central component to this process, there is considerable phenotypic variability including broad ranges in survivorship and the presence or absence of cognitive impairment. The number of familial variants of ALS for which unique genetic linkage has been identified is increasing, attesting further to the biological heterogeneity of the disorder. At the cellular level, derangements in cytoskeletal protein and glutamate metabolism, mitochondrial function, and in glial interactions are clearly evident. When considered in this fashion, ALS can be justifiably considered a disorder of multiple biological processes sharing in common the degeneration of motor neurons.

Résumé:

RÉSUMÉ:

Observations indiquant que la SLA est une maladie multisystémique à expression phénotypique limitée. Traditionnellement, la SLA était considérée comme une maladie neurodégénérative dans laquelle les motoneurones sont vulnérables de façon sélective à un processus pathologique unique. Notre compréhension actuelle de la SLA suggère cependant que cette approche est beaucoup trop étroite. Bien que la dégénérescence des motoneurones demeure l'élément central de ce processus, il existe une variabilité phénotypique considérable particulièrement quant à la survie et à la présence ou à l'absence de déficit cognitif. Le nombre de variantes familiales de la SLA pour lesquelles une liaison génétique a été identifiée augmente, attestant de l'hétérogénéité biologique de la maladie. Au niveau cellulaire, il existe des perturbations de la protéine cytosquelettique et du métabolisme du glutamate, de la fonction mitochondriale et des interactions gliales. Quand on regarde la SLA sous cet aspect, on peut à juste titre la considérer comme une maladie due à des processus biologiques multiples ayant en commun la dégénérescence de motoneurones.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 28 , Issue 4 , November 2001 , pp. 283 - 298
Copyright
Copyright © The Canadian Journal of Neurological 2001

References

1. Charcot, JM, Joffroy, A. Deux cas d’atrophie musculaire progressive avec lésions de la substance grise et des faisceaux antérolatéraux de la moelle épinière. Arch Physiol Norm Pathol 1869; 2:354–744.Google Scholar
2. Ben Hamida, M, Hentati, F, Ben Hamida, C. Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Brain 1990; 113:347–363.CrossRefGoogle ScholarPubMed
3. McDaniel, JL, Via, BG. Aging issues in the workplace. Assisting workers who provide eldercare. AAOHN J 1997; 45(5):261–269.Google Scholar
4. Lilienfeld, DE, Ehland, J, Landrigan, PJ, et al. Rising mortality from motoneuron disease in the USA, 1962–84. Lancet 1989; 1:710–713.CrossRefGoogle ScholarPubMed
5. Durrleman, S, Alperovitch, A. Increasing trend of ALS in France and elsewhere: are the changes real? Neurology 1989; 39:768–773.Google Scholar
6. 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; 55:207–220.CrossRefGoogle ScholarPubMed
7. Neilson, S, Gunnarsson, L-G, Robinson, I. Rising mortality from motor neurone disease in Sweden 1961 – 1990: the relative role of increased population life expectancy and environmental factors. Acta Neurol Scand 1994; 902:150–159.Google Scholar
8. Gunnarsson, L-G, Lindberg, G, Söderfelt, B, Axelson, O. The mortality of motor neuron disease in Sweden. Arch Neurol 1990; 47:42–46.CrossRefGoogle ScholarPubMed
9. Kahana, E, Zilber, N. Changes in the incidence of amyotrophic lateral sclerosis in Israel. Arch Neurol 1984; 41:157–160.Google Scholar
10. Buckley, J, Warlow, C, Smith, P, et al. Motor neuron disease in England and Wales, 1959 – 1979. J Neurol Neurosurg Psychiat 1983; 46:197–205.CrossRefGoogle ScholarPubMed
11. Hudson, AJ, Davenport, A, Hader, WJ. The incidence of amyotrophic lateral sclerosis in southwestern Ontario, Canada. Neurology 1986; 36:1524–1528.CrossRefGoogle ScholarPubMed
12. Strong, MJ. Exogenous neurotoxins. In: Brown, RH Jr, Meininger, V, Swash, M, eds. Amyotrophic Lateral Sclerosis. London: Martin Dunitz Ltd., 2000: 279–287.Google Scholar
13. Garruto, RM. Amyotrophic lateral sclerosis and Parkinsonism-dementia of Guam: clinical, epidemiological and genetic patterns. Am J Human Biol 1989; 1:367–382.CrossRefGoogle ScholarPubMed
14. Garruto, RM. Pacific paradigms of environmentally-induced neurological disorders: Clinical, epidemiological and molecular perspectives. Neurotoxicology 1991; 12:347–378.Google Scholar
15. Garruto, RM, Shankar, SK, Yanagihara, R, et al. Low-calcium, high aluminum diet-induced motor neuron pathology in cynomolgus monkeys. Acta Neuropathol 1989; 78:210–219.CrossRefGoogle ScholarPubMed
16. Giagheddu, M, Puggioni, G, Biancu, F, et al. Epidemiological study of amyotrophic lateral sclerosis in Sardinia, Italy. Acta Neurol Scand 1983; 68:394–404.Google Scholar
17. Strong, MJ, Hudson, AJ, Alvord, WG. Familial amyotrophic lateral sclerosis, 1850-1989: a statistical analysis of the world literature. Can J Neurol Sci 1991; 18:45–58.CrossRefGoogle Scholar
18. Eisen, A, Schulzer, M, MacNeil, M, Pant, B, Mak, E. Duration of amyotrophic lateral sclerosis is age dependent. Muscle Nerve 1993; 16:27–32.Google Scholar
19. Jablecki, CK, Berry, C, Leach, J. Survival prediction in amyotrophic lateral sclerosis. Muscle Nerve 1989; 12:833–841.Google Scholar
20. Hudson, A. Amyotrophic lateral sclerosis and its association with dementia, parkinsonism and other neurological disorders: a review. Brain 1981; 194:217–247.Google Scholar
21. Massman, PJ, Sims, J, Cooke, N, et al. Prevalence and correlates of neuropsychological deficits in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiat 1996; 61:450–455.Google Scholar
22. Kew, JJM, Goldstein, LH, Leigh, PN, et al. The relationship between abnormalities of cognitive function and cerebral activation in amyotrophic lateral sclerosis. Brain 1993; 116:1399–1423.Google Scholar
23. David, AS, Gillham, RA. Neuropsychological study of motor neuron disease. Psychosomatics 1986; 27:441–445.Google Scholar
24. Iwasaki, Y, Kinoshita, M, Ikeda, K, Takamiya, K, Shiojima, T. Neuropsychological dysfunctions in amyotrophic lateral sclerosis: relation to motor disabilities. Intern J Neurosci 1990; 54:191–195.Google Scholar
25. Neary, D, Snowden, JS, Gustafson, L, et al. Frontotemporal lobar degeneration. A consensus on clinical diagnostic criteria. Neurology 1998; 51:1546–1554.Google Scholar
26. Bak, TH, O’Donovan, DG, Xuereb, JH, Boniface, S, Hodges, JR. Selective impairment of verb processing associated with pathological changes in Brodmann areas 44 and 45 in the motor neuron disease-dementia-aphasia syndrome. Brain 2001; 124:103–120.Google Scholar
27. Caselli, RJ, Windebank, AJ, Petersen, RC, et al. Rapidly progressing aphasic dementia and motor neuron disease. Ann Neurol 1993; 33:200–207.CrossRefGoogle ScholarPubMed
28. Devinsky, O, Morrell, MJ, Vogt, BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995; 118:279–306.CrossRefGoogle ScholarPubMed
29. Strong, MJ, Grace, GM, Orange, JB, Leeper, HA. Cognition, language and speech in amyotrophic lateral sclerosis: a review. J Clin Exp Neuropsych 1996; 18(2):291–303.CrossRefGoogle ScholarPubMed
30. Strong, MJ, Grace, GM, Orange, JB, et al. A prospective study of cognitive impairment in ALS. Neurology 1999; 53:1665–1670.CrossRefGoogle ScholarPubMed
31. Poloni, M, Capitani, E, Mazzini, L, Ceroni, M. Neuropsychological measures in amyotrophic lateral sclerosis and their relationship with CT scan-assessed cerebral atrophy. Acta Neurol Scand 1986; 74:257–260.Google Scholar
32. Gallassi, R, Montagna, P, Morreale, A, et al. Neuropsychological, electroencephalogram and brain computed tomography findings in motor neuron disease. Eur Neurol 1989; 29:115–120.CrossRefGoogle ScholarPubMed
33. Ludolph, AC, Elger, CE, Böttger, IW, et al. N-isopropyl-p-123I-amphetamine single photon emission computer tomography in motor neuron disease. Eur Neurol 1989; 29:255–260.CrossRefGoogle ScholarPubMed
34. Ohnishi, T, Hoshi, H, Nagamachi, S, et al. Regional cerebral blood flow study with 123I-IMP in patients with degenerative dementia. Am J Neuroradiol 1991; 12:513–520.Google Scholar
35. Waldemar, G, Varstrup, S, Jensen, TS, Johnsen, A, Boysen, G. Focal reductions in cerebral blood flow in amyotrophic lateral sclerosis: a [99mTc]-d,l-HMPAO SPECT study. J Neurol Sci 1992; 107:19–28.Google Scholar
36. Talbot, PR, Goulding, PJ, Lloyd, JJ, et al. Inter-relation between “classic” motor neuron disease and frontotemporal dementia: neuropsychological and single photon emission computed tomography study. J Neurol Neurosurg Psychiat 1995; 58:541–547.CrossRefGoogle ScholarPubMed
37. Tanaka, M, Kondo, S, Hirai, S, et al. Cerebral blood flow and oxygen metabolism in progressive dementia associated with amyotrophic lateral sclerosis. J Neurol Sci 1993; 120:22–28.Google Scholar
38. Ludolph, AC, Langen, KJ, Regard, M, et al. Frontal lobe function in amyotrophic lateral sclerosis: a neuropsychological and positron emission tomography study. Acta Neurol Scand 1992; 85:81–89.Google Scholar
39. Abrahams, S, Leigh, PN, Kew, JJM, et al. A positron emission tomography study of frontal lobe function (verbal fluency) in amyotrophic lateral sclerosis. J Neurol Sci 1995; 129(Suppl.):44–46.Google Scholar
40. Abrahams, S, Goldstein, LH, Lloyd, CM, Brooks, DJ, Leigh, PN. Cognitive deficits in nondemented amyotrophic lateral sclerosis patients: a neuropsychological investigation. J Neurol Sci 1995; 129(Suppl.):54–55.Google Scholar
41. Mitsuyama, Y. Presenile dementia with motor neuron disease in Japan: clinico-pathological review of 26 cases. J Neurol Neurosurg Psychiat 1984; 47:953–959.Google Scholar
42. Okamoto, K, Hirai, S, Yamazaki, T, Sun, X, Nakazato, Y. New ubiquitin-positive intraneuronal inclusions in the extra-motor cortices in patients with amyotrophic lateral sclerosis. Neurosci Lett 1991; 129:233–236.CrossRefGoogle ScholarPubMed
43. Wightman, G, Anderson, VER, Martin, J, et al. Hippocampal and neocortical ubiquitin-immunoreactive inclusions in amyotrophic lateral sclerosis with dementia. Neurosci Lett 1992; 139:269–274.Google Scholar
44. Anderson, VER, Cairns, NJ, Leigh, PN. Involvement of the amygdala, dentate and hippocampus in motor neuron disease. J Neurol Sci 1995; 129(Suppl.):75–78.CrossRefGoogle ScholarPubMed
45. Wilson, CM, Grace, GM, Munoz, DG, He, BP, Strong, MJ. Cognitive impairment in sporadic ALS. A pathological continuum underlying a multisystem disorder. Neurology 2001; 57:651–657.Google Scholar
46. Munoz, DG. The pathology of Pick complex. In: Kertesz, A, Munoz, DG, eds. Pick’s disease and Pick complex. New York: John Wiley and Sons, 1998: 211–239.Google Scholar
47. Jackson, M, Lowe, J. The new neuropathology of degenerative frontotemporal dementias. Acta Neuropathol 1996; 91:127–134.CrossRefGoogle ScholarPubMed
48. Giannakopoulos, P, Hof, PR, Bouras, C. Dementia lacking distinctive histopathology: clinicopathological evaluation of 32 cases. Acta Neuropathol (Berl) 1995; 89:346–355.CrossRefGoogle ScholarPubMed
49. Hayashi, H, Kato, S. Total manifestations of amyotrophic lateral sclerosis. J Neurol Sci 1989; 93:19–35.Google Scholar
50. Mizutani, T, Aki, A, Shiozawa, R, et al. Development of ophthalmoplegia in amyotrophic lateral sclerosis during long-term use of respirators. J Neurol Sci 1990; 99:311–319.Google Scholar
51. Hayashi, H, Kato, S, Kawada, A. Amyotrophic lateral sclerosis patients living beyond respiratory failure. J Neurol Sci 1991; 105:73–78.Google Scholar
52. Kishikawa, M, Nakamura, T, Iseki, M, et al. A long surviving case of amyotrophic lateral sclerosis with atrophy of the frontal lobe: a comparison with the Mitsuyama type. Acta Neuropathol 1995; 89:189–193.Google Scholar
53. Hosler, BA, Siddique, T, Sapp, PC, et al. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21–q22. JAMA 2000; 284(13):1664–1669.Google Scholar
54. Lynch, T, Sano, M, Marder, KS, et al. Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex. Neurology 1994; 44:1878–1884.Google Scholar
55. 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.CrossRefGoogle ScholarPubMed
56. Beckman, JS, Carson, M, Smith, CD, Koppenol, WH. ALS, SOD and peroxynitrite. Science 1993; 364:584–584.Google Scholar
57. Bruijn, LI, Beal, FM, Becher, MW, et al. Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. Proc Natl Acad Sci USA 1997; 94(14):7606–7611.Google Scholar
58. Bogdanov, MB, Ramos, LE, Xu, Z, Beal, FM. Elevated “hydroxyl radical” generation in vivo in an animal model of amyotrophic lateral sclerosis. J Neurochem 1998; 71:1321–1324.Google Scholar
59. Ferrante, RJ, Browne, SE, Shinobu, LA, et al. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem 1997; 69:2064–2074.Google Scholar
60. Wiedau-Pazos, M, Goto, JJ, et al. Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science 1996; 271:515–518.Google Scholar
61. Tu, P-H, Gurney, ME, Julien, J-P, Lee, VMY, Trojanowski, JQ. Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease. Lab Invest 1997; 76(4):441–456.Google Scholar
62. Ince, PG, Shaw, PJ, Slade, JY, Jones, C, Hudgson, P. Familial amyotrophic lateral sclerosis with a mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and immunocytochemical changes. Acta Neuropathol 1996; 92:395–403.Google Scholar
63. Orrell, RW, King, AW, Hilton, DA, et al. Familial amyotrophic lateral sclerosis with a point mutation of SOD-1: intrafamilial heterogeneity of disease duration associated with neurofibrillary tangles. J Neurol Neurosurg Psychiat 1995; 59:266–270.Google Scholar
64. Rouleau, GA, Clark, AW, Rooke, K, et al. SOD1 mutation is associated with accumulation of neurofilaments in amyotrophic lateral sclerosis. Ann Neurol 1996; 39:128–131.Google Scholar
65. Shibata, N, Hirano, A, Kobayashi, M, et al. Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement. J Neuropathol Exp Neurol 1996; 55(4):481–490.CrossRefGoogle ScholarPubMed
66. Takahashi, H, Makifuchi, T, Nakano, R, et al. Familial amyotrophic lateral sclerosis with a mutation in the Cu/Zn superoxide dismutase gene. Acta Neuropathol 1994; 88:185–188.CrossRefGoogle ScholarPubMed
67. Anderson, PM, Nilsson, P, Ala-Hurula, V, et al. Amyotrophic lateral sclerosis associated with homozygosity for a Asp90Ala mutation in CuZn-superoxide dismutase. Nat Genet 1995; 10:61–66.CrossRefGoogle Scholar
68. 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; 119:1153–1172.Google Scholar
69. Gurney, ME, Pu, H, Chiu, AY, et al. Motor neuron degeneration in mice that express a human CuZn superoxide dismutase mutation. Science 1994; 264:1772–1775.Google Scholar
70. Tu, P-H, Raju, P, Robinson, KA, et al. Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions. Proc Natl Acad Sci USA 1996; 93:3155–3160.Google Scholar
71. Bruijn, LI, Becher, MW, Lee, MK, et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 1997; 18:327–338.Google Scholar
72. Bergeron, C, Muntasser, S, Somerville, MJ, Weyer, L, Percy, ME. Copper/Zinc superoxide dismutase mRNA levels are increased in sporadic amyotrophic lateral sclerosis. Brain Res 1994; 659:272–276.Google Scholar
73. Deng, H-X, Hentati, A, Tainer, JA, et al. Amyotrophic lateral sclerosis and structural defects in CuZn superoxide dismutase. Science 1993; 261:1047–1051.Google Scholar
74. Troy, CM, Shelanski, ML. Down-regulation of copper/zinc superoxide dismutase causes apoptotic death in PC12 neuronal cells. Proc Natl Acad Sci USA 1994; 91:6384–6387.Google Scholar
75. Rabizadeh, S, Gralla, EB, Borchelt, DR, et al. Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an antiapoptotic gene to a proapoptotitc gene: studies in yeast and neural cells. Proc Natl Acad Sci USA 1995; 92:3024#x2013;3028.CrossRefGoogle Scholar
76. Reaume, AG, Elliott, JL, Hoffman, EK, et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 1996; 13:43–47.Google Scholar
77. Bruijn, LI, Houseweart, MK, Kato, S, et al. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 1998; 281:1851–1854.CrossRefGoogle ScholarPubMed
78. Bredesen, DE, Ellerby, LM, Hart, PJ, Wiedau-Pazos, M, Valentine, JS. Do posttranslational modifications of CuZnSOD lead to sporadic amyotrophic lateral sclerosis? Ann Neurol 1997; 42(2):135–137.CrossRefGoogle ScholarPubMed
79. Pasinelli, P, Houseweart, MK, Brown, RH Jr, Cleveland, DW. Caspase-1 and -3 are sequentially activated in motor neuron death in CuZn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2000; 97(25):13901–13906.CrossRefGoogle Scholar
80. Li, M, Ona, VO, Guégan, C, et al. Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 2000; 288:335–339.CrossRefGoogle Scholar
81. Migheli, A, Piva, R, Atzori, C, Troost, D, Schiffer, D. c-Jun, JNK/SAPK kinases and transcription fact NF-kB are selectively activated in astrocytes, but not motor neurons, in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 1997; 56(12):1314–1322.Google Scholar
82. He, BP, Strong, MJ. Motor neuronal death in amyotrophic lateral sclerosis (ALS) is not apoptotic. A comparative analysis of ALS and chronic aluminum neurotoxicity in New Zealand white rabbits. J Neuropathol Appl Neurobiol 2000;26:1–13.Google Scholar
83. Ono, S, Imai, T, Aso, A, et al. Alterations in skin glycosaminoglycans in patients with ALS. Neurology 1998; 51:399–404.Google Scholar
84. Hirano, A. Cytopathology of amyotrophic lateral sclerosis. In: Rowland, LP, ed. Amyotrophic lateral sclerosis and other motor neuron disorders. New York: Raven Press, 1991: 91–101.Google Scholar
85. Hirano, A, Kurland, LT, Sayre, GP. Familial amyotrophic lateral sclerosis. Arch Neurol 1967; 16:232–242.CrossRefGoogle ScholarPubMed
86. Chou, SM. Motor neuron inclusions in ALS are heavily ubiquitinated. J Neuropathol Exp Neurol 1988; 47:334.Google Scholar
87. Murayama, S, Mori, H, Ihara, Y, et al. Immunocytochemical and ultrastructural studies of lower motor neurons in amyotrophic lateral sclerosis. Ann Neurol 1990; 27:137–148.Google Scholar
88. Leigh, P, Swash, M. Cytoskeletal pathology in motor neuron disease. In: Rowland, LP, ed. Advances in Neurology. Amyotrophic lateral sclerosis and other motor neuron diseases. New York: Raven Press, 1991: 115–124.Google Scholar
89. Chou, SM. Neuropathology of amyotrophic lateral sclerosis: new perspectives on an old disease. J Formos Med Assoc 1997; 96(7):488–498.Google Scholar
90. Wong, N, He, BP, Strong, MJ. Characterization of neuronal intermediate filament protein expression in cervical spinal motor neurons in sporadic amyotrophic lateral sclerosis (ALS). J Neuropathol Exp Neurol 2000; 59(11):972–982.Google Scholar
91. Migheli, A, Pezzulo, T, Attanasio, A, Schiffer, D. Peripherin immunoreactive structures in amyotrophic lateral sclerosis. Lab Invest 1993; 68(2):185–191.Google ScholarPubMed
92. Shaw, PJ, Eggett, CJ. Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. J Neurol 2000; 247(Suppl 1):117–127.Google Scholar
93. Geisler, N, Kaufmann, E, Fischer, S, Plessman, U, Weber, K. Neurofilament architecture combines structural principles of intermediate filaments with carboxy-terminal extensions increasing in size between triplet proteins. EMBO 1983; 2:1295–1302.Google Scholar
94. Ching, GY, Liem, RKH. Assembly of type IV neuronal intermediate filaments in nonneuronal cells in the absence of preexisting cytoplasmic intermediate filaments. J Cell Biol 1993; 122:1323–1335.Google Scholar
95. Lee, MK, Xu, Z, Wong, PC, Cleveland, DW. Neurofilaments are obligate heteropolymers in vivo. J Cell Biol 1993; 122:1337–1350.Google Scholar
96. Sihag, RK, Nixon, RA. Identification of Ser-55 as a major protein kinase A phosphorylation site on the 70-kDa subunit of neurofilaments. J Biol Chem 1991; 266:18861–18867.Google Scholar
97. Nixon, RA, Shea, TB. Dynamics of neuronal intermediate filaments: a developmental perspective. Cell Motil Cytoskel 1992; 22:81–91.Google Scholar
98. Côte, F, Collard, J-F, Julien, J-P. Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis. Cell 1993; 73:35–46.Google Scholar
99. Julien, J-P, Côte, F, Collard, J-F. Mice overexpressing the human neurofilament heavy gene as a model of ALS. Neurobiol Aging 1995; 16(3):487–492.Google Scholar
100. Xu, Z, Cork, LC, Griffin, JW, Cleveland, DW. Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell 1993; 73:23–33.Google Scholar
101. Beaulieu, J-M, Nguyen, MD, Julien, J-P. Late-onset death of motor neurons in mice overexpressing wild-type peripherin. J Cell Biol 1999; 147(3):531–544.Google Scholar
102. Bergeron, C, Beric-Maskarel, K, Muntasser, S, et al. Neurofilament light and polyadenylated mRNA levels are decreased in amyotrophic lateral sclerosis motor neurons. J Neuropathol Exp Neurol 1994; 53:221–230.Google Scholar
103. Crow, JP, Ye, YZ, Strong, MJ, et al. Superoxide dismutase catalyzes nitration of tyrosines by peroxynitrite in the rod and head domains of neurofilament-L. J Neurochem 1997; 69:1945–1953.Google Scholar
104. Wong, N, Strong, MJ. Nitric oxide synthase expression in cervical motor neurons of sporadic amyotrophic lateral sclerosis. Eur J Cell Biol 1998; 77:338–343.Google Scholar
105. Chou, SM, Wang, HS, Taniguchi, A. Role of SOD-1 and nitric oxide/cyclic GMP cascade on neurofilament aggregation in ALS/MND. J Neurol Sci 1996; 139(Suppl.):16–26.Google Scholar
106. Bergeron, C, Petrunka, C, Weyer, L. Copper/zinc superoxide dismutase expression in the human nervous system. Correlation with selective neuronal vulnerability. Am J Pathol 1996; 148(1):273–279.Google Scholar
107. Pardo, CA, Xu, Z, Borchelt, DR, et al. Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons. Proc Natl Acad Sci USA 1999; 32:954–958.Google Scholar
108. Shaw, PJ, Chinnery, RM, Thagesen, H, Borthwick, GM, Ince, PG. Immunocytochemical study of the distribution of the free radical scavenging enzymes Cu/Zn superoxide dismutase (SOD1); MN superoxide dismutase (MN SOD) and catalase in the normal human spinal cord and in motor neurons. J Neurol Sci 1997; 147(2):115–125.Google Scholar
109. Chou, SM, Wang, HS, Komai, K. Colocalization of NOS and SOD1 in neurofilament accumulation within motor neurons of amyotrophic lateral sclerosis: an immunohistochemical study. J Chem Neuroanat 1996; 10:249–258.Google Scholar
110. Beal, FM, Ferrante, RJ, Browne, SE, et al. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann Neurol 1997; 42:646–654.Google Scholar
111. Ferrante, RJ, Shinobu, LA, Schulz, JB, et al. Increased 3-nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation. Ann Neurol 1997; 42:326–334.Google Scholar
112. Crow, JP, Sampson, JB, Zhuang, Y, Thompson, JA, Beckman, JS. Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhance catalysis of tyrosine nitration by peroxynitrite. J Neurochem 1997; 69:1936–1944.Google Scholar
113. Strong, MJ, Sopper, MM, Crow, JP, Strong, WL, Beckman, JS. Nitration of the low molecular weight neurofilament (NFL) is equivalent in sporadic amyotrophic lateral sclerosis and control cervical spinal cord. Biochem Biophys Res Comm 1998; 248(1):157–164.Google Scholar
114. Strong, MJ, Sopper, MM, He, BP. In vitro reactive nitrating species toxicity in dissociated spinal motor neurons from NFL (-/-) and HNFL transgenic mice. Neurology 2001; 56(Suppl 3):A83–A84. Google Scholar
115. Figlewicz, DA, Krizus, A, Martinoli, MG, et al. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet 1994; 3:1757–1761.Google Scholar
116. Rooke, K, Figlewicz, DA, Han, FY, Rouleau, GA. Analysis of the KSP repeat of the neurofilament heavy subunit in familial amyotrophic lateral sclerosis. Neurology 1996; 46(3):789–790.Google Scholar
117. Tomkins, J, Usher, P, Slade, JY, et al. Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). Neuroreport 1998; 9(17):3670–3697.Google Scholar
118. Al-Chalabi, A, Andersen, PM, Nilsson, D, et al. Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet 1999; 8(2):157–164.Google Scholar
119. Vechio, JD, Bruijn, LI, Xu, Z, Brown, RH Jr., Cleveland, DW. Sequence variants in human neurofilament proteins: absence of linkage to familial amyotrophic lateral sclerosis. Ann Neurol 1996; 40:603–610.Google ScholarPubMed
120. Strong, MJ, Strong, WL, Jaffe, H, et al. Phosphorylation state of the native high molecular weight neurofilament subunit protein (NFH) from cervical spinal cord in sporadic amyotrophic lateral sclerosis. J Neurochem 2001; 76:1315–1325.Google Scholar
121. Siklos, L, Englehardt, J, Harati, Y, et al. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis. Ann Neurol 1996; 39(2):203–216.Google Scholar
122. Masui, Y, Mozai, T, Kakehi, K. Functional and morphometric study of the liver in motor neuron disease. J Neurol 1985; 232:15–19.Google Scholar
123. Nakano, Y, Hirayama, K, Terao, K. Hepatic ultrastrucutral changes and liver dysfunction in amyotrophic lateral sclerosis. Arch Neurol 1987; 44:103–106.Google Scholar
124. Wiedemann, FR, Winkler, K, Kuznetsov, A, et al. Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis. J Neurol Sci 1998; 156:65–72.Google Scholar
125. Fujita, K, Yamauchi, M, Shibayama, K, et al. Decreased cytochrome C oxidase activity but unchanged superoxide dismutase and glutathione peroxidase activities in the spinal cords of patients with amyotrophic lateral sclerosis. J Neurosci Res 1996; 45:276–281.Google Scholar
126. Bowling, AC, Schulz, JB, Brown, RH Jr., Beal, MF. Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem 1993; 61:2322–2325.Google Scholar
127. Browne, SE, Bowling, AC, Baik, MJ, et al. Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis. J Neurochem 1998; 71:281–287.Google Scholar
128. Swerdlow, RH, Parks, JK, Cassarino, DS, et al. Mitochondria in sporadic amyotrophic lateral sclerosis. Exp Neurol 1998; 153:135–142.Google Scholar
129. Curti, D, Malaspina, A, Facchetti, G, et al. Amyotrophic lateral sclerosis: oxidative enery metabolism and calcium homeostasis in peripheral blood lymphocytes. Neurology 1996; 47:1060–1064.Google Scholar
130. Ince, P, Stout, N, Shaw, P, et al. Parvalbumin and calbindin D-28K in the human motor system and in motor neuron disease. Neuropathol Appl Neurobiol 1993; 19(4):291–299.Google Scholar
131. Alexianu, ME, Ho, BK, Mohamed, AH, et al. The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis. Ann Neurol 1994; 36(6):846–858.CrossRefGoogle ScholarPubMed
132. Elliott, JL, Snider, WD. Parvalbumin is a marker of ALS-resistant motor neurons. Neuroreport 1995; 15(6):449–452.Google Scholar
133. Siklos, L, Engelhardt, JI, Alexianu, ME, et al. Intracellular calcium parallels motoneuron degeneration in SOD-1 mutant mice. J Neuropathol Exp Neurol 1998; 57(6):571–587.Google Scholar
134. Knirsch, U, Sturm, S, Reuter, A, et al. Calcineurin A and calbindin immunoreactivity in the spinal cord of G93A superoxide dismutase transgenic mice. Brain Res 2001; 889:234–238.Google Scholar
135. Vanselow, BK, Keller, BU. Calcium dynamics and buffering in oculomotor neurones from mouse that are particularly resistant during amyotrophic lateral sclerosis (ALS)-related motor neuron disease. J Physiol 2000; 552.2:433–445.Google Scholar
136. Przedborksi, S, Donaldson, DM, Murphy, PL, et al. Blood superoxide dismutase, catalase and glutathione peroxidase activities in familial and sporadic amyotrophic lateral sclerosis. Neurodegeneration 1996; 5:57–64.Google Scholar
137. Przedborksi, S, Donaldson, D, Jakowec, M, et al. Brain superoxide dismutase, catalase, and glutathione peroxidase activities in amyotrophic lateral sclerosis. Ann Neurol 1996; 39:158–165.Google Scholar
138. Shaw, PJ, Ince, PG, Falkous, G, Mantle, D. Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol 1995; 38:691–695.Google Scholar
139. Beckman, JS, Beckman, TW, Chen, J, Marshall, PA, Freeman, BA. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 1990; 87:1620–1624.Google Scholar
140. Rothstein, JD, Jin, L, Dykes-Hoberg, M, Kuncl, RW. Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc Natl Acad Sci USA 1993; 90:6591–6595.Google Scholar
141. Carriedo, SG, Yin, HZ, Weiss, JH. Motor neurons are selectively vulnerable to AMP/Kianate receptor-mediated injury in vitro. J Neurosci 1996; 16(13):4069–4079.Google Scholar
142. Rothstein, JD, Van Kammen, M, Levey, AI, Martin, LJ, Kuncl, RW. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995; 38:73–84.Google Scholar
143. Lin, C-LG, Bristol, LA, Jin, L, et al. Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 1998; 20:589–602.Google Scholar
144. Jackson, M, Steers, G, Leigh, PN, Morrison, KE. Polymorphisms in the glutamate transporter gene EAAT2 in European ALS patients. J Neurol 1999; 246:1140–1144.Google Scholar
145. Meyer, T, Lenk, U, Kuther, G, et al. Studies of the coding region of the neuronal glutamate transporter gene in amyotrophic lateral sclerosis. Ann Neurol 1995; 37:817–819.Google Scholar
146. Meyer, T, Münch, C, Völkel, H, Booms, P, Ludolph, AC. The EAAT2 (GLT-1) gene in motor neuron disease: absence of mutations in amyotrophic lateral sclerosis and a point mutation in patients with hereditary spastic paraplegia. J Neurol Neurosurg Psychiat 1998; 65:594–596.CrossRefGoogle Scholar
147. Vartiainen, N, Tikka, T, Keinänen, R, Chan, PH, Koistinaho, J. Glutamatergic receptors regulate expression, phosphorylation and accumulation of neurofilaments in spinal cord neurons. Neuroscience 1999; 93(5):1123–1133.Google Scholar
148. Lampson, LA, Kushner, PD, Sobel, RA. Strong expression of class II major histocompatibility complex (MHC) antigens in the absence of detectable T cell infiltration in amyotrophic lateral sclerosis (ALS) spinal cord. J Neuropathol Exp Neurol 1988; 47:353–353.Google Scholar
149. Lampson, LA, Kushner, PD, Sobel, RA. Major histocompatibility complex antigen expression in the affected tissues in amyotrophic lateral sclerosis. Ann Neurol 1990; 28:365–372.Google Scholar
150. Troost, D, van den Oord, JJ, de Jong, JMBV, Swaab, DF. Lymphocyte infiltration in the spinal cord of patients with amyotrophic lateral sclerosis. Clin Neuropath 1989; 8:289–294.Google Scholar
151. Kawamata, T, Akiyama, H, Yamada, T, McGeer, PL. Immunological reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol 1992; 140:691–707.Google Scholar
152. Barron, KD, Marciano, FF, Amundson, R, Mankes, R. Perineuronal glial response after axotomy of central and peripheral axons. A comparison. Brain Res 1990; 523:219–229.Google Scholar
153. Streit, WJ. Microglial-neuronal interactions. J Chem Neuroanat 1993; 6:261–266.Google Scholar
154. Thanos, S, Mey, J, Wild, M. Treatment of the adult retina with microglia-suppressing factors retards axotomy-induced neuronal degradation and enhances axonal regeneration in vivo and in vitro. J Neurosci 1993; 13:455–466.Google Scholar
155. Thanos, S. The relationship of microglial cells to dying neurons during natural neuronal cell death and axotomy-induced degeneration of the rat retina. Eur J Neurosci 1991; 3:1189–1207.Google Scholar
156. Giulian, D, Roberston, C. Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord. Ann Neurol 1990; 27:33–42.Google Scholar
157. Coffey, PJ, Perry, VH, Rawlins, JNP. An investigation into the early stages of the inflammatory response following ibotenic acid-induced neuronal degeneration. Neuroscience 1990; 35:121–132.Google Scholar
158. Piani, D, Frei, K, Do, KQ, Cuenod, M, Fontana, A. Murine brain macrophages induce NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neurosci Lett 1991; 133:159–162.Google Scholar
159. Popovich, PG, Reinhard, JF Jr., Flanagan, EM, Stokes, BT. Elevation of the neurotoxin quinolinic acid occurs following spinal cord trauma. Brain Res 1994; 633:348–352.Google Scholar
160. Thery, C, Chamak, B, Mallat, M. Cytotoxic effect of brain macrophages on developing neurons. Eur J Neurosci 1991; 3:1155–1164.Google Scholar
161. Gehrmann, J, Banati, RB, Wiessnert, C, Hossman, K-A, Kreutzberg, GW. Reactive microglia in cerebral ischemia: an early mediator of tissue damage? Neuropathol Appl Neurobiol 1995; 21:277–289.Google Scholar
162. Toku, K, Tanaka, J, Yano, H, et al. Microglial cells prevent nitric oxide-induced neuronal apoptosis in vitro. J Neurosci Res 1998; 53:415–425.3.0.CO;2-9>CrossRefGoogle ScholarPubMed
163. Strong, MJ, Gaytan-Garcia, S, Jakowec, D. Reversibility of neurofilamentous inclusion formation following repeated sublethal intracisternal inoculums of AlCl3 in New Zealand white rabbits. Acta Neuropathol 1995; 90(1):57–67.Google Scholar
164. He, BP, Strong, MJ. A morphological analysis of the motor neuron degeneration and microglial reaction in acute and chronic in vivo aluminum chloride neurotoxicity. J Chem Neuroanat 2000; 17(4):207–215.Google Scholar
165. Krieger, C, Perry, TL, Ziltener, HJ. Amyotrophic lateral sclerosis: interleukin-6 levels in cerebrospinal fluid. Can J Neurol Sci 1992; 19(3):357–359.Google Scholar
166. Sekizawa, T, Openshaw, H, Ohbo, K, et al. Cerebrospinal fluid interleukin-6 in amyotrophic lateral sclerosis: immunological parameter and comparison with inflammatory and noninflammatory central nervous system diseases. J Neurol Sci 1998; 154(2):194–199.Google Scholar
167. Demaerschalk, BM, Strong, MJ. Amyotrophic lateral sclerosis. Curr Treat Options Neurol 2000; 2:13–22.Google Scholar
168. Lacomblez, L, Bensimon, G, Leigh, PN, Guillet, P, Meininger, V, for the Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet 1996; 347(May 25):1425–1431.Google Scholar
169. Riviere, M, Meininger, V, Zeisser, P, Munsat, T. An analysis of extended survival in patients with amyotrophic lateral sclerosis treated with riluzole. Arch Neurol 1998; 55(4):526–528.Google Scholar
170. Kalra, S, Cashman, NR, Genge, A, Arnold, DL. Recovery of N-acetylaspartate in corticomotor neurons in patients with ALS after riluzole therapy. Neuroreport 1998; 9(8):1757–1761.Google Scholar
171. Blin, O, Pouget, J, Aubrespy, G, et al. A double-blind, placebo-controlled trial of L-threonine in amyotrophic lateral sclerosis. J Neurol 1992; 239:79–81.Google Scholar
172. Tandan, R, Bromberg, MB, Forshew, DA, et al. A controlled trial of amino acid therapy in amyotrophic lateral sclerosis: I. Clinical, functional, and maximum isometric torque data. Neurology 1996; 47:1220–1226.Google Scholar
173. The Italian ALS Study Group. Branched-chain amino acids and amyotrophic lateral sclerosis: a treatment failure? Neurology 1993; 43:2466–2470.Google Scholar
174. Gredal, O, Werdelin, L, Bak, S, et al. A clinical trial of dextromethorphan in amyotrophic lateral sclerosis. Acta Neurol Scand 1997; 96:8–13.Google Scholar
175. Miller, RG, Moore, D, Young, LA, et al. Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 1996; 47:1383–1388.Google Scholar
176. Eisen, A, Stewart, H, Schulzer, M, Cameron, D. Antiglutamate therapy in amyotrophic lateral sclerosis: a trial using lamotrigine. Can J Neurol Sci 1993; 20:297–301.Google Scholar
177. Miller, RG, Smith, SA, Murphy, JR, et al. A clinical trial of verapamil in amyotrophic lateral sclerosis. Muscle Nerve 1996; 19:511–515.Google Scholar
178. Lai, EC, Felice, KJ, Festoff, BW, et al. Effect of recombinant human insulin-like growth factor on progression of ALS. A placebo controlled study. Neurology 1997; 49:1621–1630.Google Scholar
179. Ackerman, SJ, Sullivan, EM, Beusterien, KM, et al. Cost effectiveness of recombinant human insulin-like growth factor I therapy in patients with ALS. Pharmacoeconomics 1999; 15:179#x2013;195.Google Scholar
180. Borasio, GD, Robberecht, W, Leigh, PN, et al. A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. Neurology 1998; 51:583–586.Google Scholar
181. ALS CNTF Treatment Study Group. A double-blind, placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 1996; 46:1244–1249.Google Scholar
182. Miller, RG, Petajan, J, Bryan, WW, et al. A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. Ann Neurol 1996; 39:256–260.Google Scholar
183. Smith, RA, Melmed, S, Sherman, B, et al. Recombinant growth hormone treatment of amyotrophic lateral sclerosis. Muscle Nerve 1993; 16:624–633.Google Scholar
184. Brooke, MH, Florence, JM, Heller, SL, et al. Controlled trial of thyrotropin releasing hormone in amyotrophic lateral sclerosis. Neurology 1986; 36:146–151.Google Scholar
185. Mitsumoto, H, Salgado, ED, Negroski, D, et al. Amyotrophic lateral sclerosis: effects of acute intravenous and chronic subcutaneous administration of thyrotropin-releasing hormone in controlled trials. Neurology 1986; 36:152z–159.Google Scholar
186. Imoto, K, Saida, K, Iwamura, K, Saida, T, Nishitani, H. Amyotrophic lateral sclerosis: a double-blind crossover trial of thyrotropin-releasing hormone. J Neurol Neurosurg Psychiat 1984; 47:1332–1334.Google Scholar
187. Caroscio, JT, Cohen, JA, Zawodniak, J, et al. A double-blind, placebo-controlled trial of TRH in amyotrophic lateral sclerosis. Neurology 1986; 36:141–145.Google Scholar
188. Brown, RH Jr., Hauser, SL, Harrington, H, Weiner, HL. Failure of immunosuppression with a ten- to 14-day course of high-dose intravenous cyclophosphamide to alter the progression of amyotrophic lateral sclerosis. Arch Neurol 1986; 43:383–384.Google Scholar
189. Gourie-Devi, M, Nalini, A, Subbakrishna, DK. Temporary amelioration of symptoms with intravenous cyclophosphamide in amyotrophic lateral sclerosis. J Neurol Sci 1997; 150:167–172.Google Scholar
190. Tan, E, Lynn, J, Amato, AA, et al. Immunosuppressive treatment of motor neuron syndromes. Arch Neurol 1994; 51:194–200.Google Scholar
191. Meucci, N, Nobile-Orazio, E, Scarlato, G. Intravenous immunoglobulin therapy in amyotrophic lateral sclerosis. J Neurol 1996; 243:117–120.Google Scholar
192. Olarte, MR, Schoenfeldt, RS, McKiernan, G, Rowland, LP. Plasmapheresis in amyotrophic lateral sclerosis. Ann Neurol 1980; 8:644–645.Google Scholar
193. Kelemen, J, Hedlund, W, Orlin, JB, Berkman, EM, Munsat, TL. Plasmapheresis with immunosuppression in amyotrophic lateral sclerosis. Arch Neurol 1983; 40:752–753.Google Scholar
194. Drachman, DB, Chaudhry, V, Cornblath, DR, et al. Trial of immunosuppression in amyotrophic lateral sclerosis using total lymphoid irradiation. Ann Neurol 1994; 35:142–150.Google Scholar
195. Appel, SH, Stewart, SS, Appel, V, et al. A double-blind study of the effectiveness of cyclosporine in amyotrophic lateral sclerosis. Arch Neurol 1988; 45:381–386.Google Scholar
196. Lange, DJ, Murphy, PL, Diamond, B, Appel, V, et al. Selegiline is ineffective in a collaborative double-blind, placebo-controlled trial for treatment of amyotrophic lateral sclerosis. Arch Neurol 1998; 55:93–96.Google Scholar
197. Jossan, SS, Ekblom, J, Gudjonsson, O, Hagbarth, K-E, Aquilonius, S-M. Double blind cross over trial with deprenyl in amyotrophic lateral sclerosis. J Neural Trans 1994; 41(Suppl.):237–241.Google Scholar
198. Mazzini, L, Testa, D, Balzarini, C, Mora, G. An open-randomized clinical trial of selegeline in amyotrophic lateral sclerosis. J Neurol 1994; 241:223–227.Google Scholar
199. Mendell, JR, Chase, TN, Engel, WK. Amyotrophic lateral sclerosis. A trial of central monoamine metabolism and therapeutic trial of levodopa. Arch Neurol 1971; 25:320–325.Google Scholar
200. Norris, FH, Tan, Y, Fallat, RJ, Elias, L. Trial of oral physostigmine in amyotrophic lateral sclerosis. Clin Pharmacol Ther 1993; 54:680–682.Google Scholar
201. Aquilonius, S-M, Askmark, H, Eckernâs, S-A, et al. Cholinesterase inhibitors lack therapeutic effect in amyotrophic lateral sclerosis. A controlled study of physostigmine versus neostigmine. Acta Neurol Scand 1986; 73:628–632.Google Scholar
202. Aisen, ML, Sevilla, D, Edelstein, L, Blass, J. A double-blind placebo-controlled study of 3,4-diaminopyridine in amyotrophic lateral sclerosis patients on a rehabilitation unit. J Neurol Sci 1996; 138:93–96.Google Scholar
203. Askmark, H, Aquilonius, S-M, Gillberg, P-G, et al. Functional and pharmacokinetic studies of tetrahydroaminoacridine in patients with amyotrophic lateral sclerosis. Acta Neurol Scand 1990; 82:253–258.Google Scholar
204. Olson, WH, Simons, JA, Halaas, GW. Therapeutic trial of tilorone in ALS: lack of benefit in a double-blind, placebo-controlled study. Neurology 1978; 28:1293–1295.Google Scholar
205. Rivera, VM, Grabois, M, Deaton, W, Breitbach, W, Hines, M. Modified snake venom in amyotrophic lateral sclerosis. Arch Neurol 1980; 37:201–203.Google Scholar
206. Cole, N, Siddique, T. Genetic disorders of motor neurons. Sem Neurol 1999; 19(4):407–418.Google Scholar
207. Siddique, T, Figlewicz, DA, Pericak-Vance, MA, et al. Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. N Engl J Med 1991; 324:1381–1384.Google Scholar
208. 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; 62:633–640.Google Scholar
209. Rabin, BA, Griffin, JW, Crain, BJ, et al. Autosomal dominant juvenile amyotrophic lateral sclerosis. Brain 1999; 122:1539–1550.Google Scholar
210. Siliceo, EO, Arriada-Mendicoa, N, Balderrama, J. Juvenile familial amyotrophic lateral sclerosis: four cases with long survival. Dev Med Child Neurol 1998; 40:425–428.Google Scholar
211. Hentati, A, Bejaoui, K, Pericak-Vance, MA, et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nat Genet 1994; 7:425–428.Google Scholar
212. Hentati, A, Ouahchi, K, Pericak-Vance, MA, et al. Linkage of a common locus for recessive amyotrophic lateral sclerosis. Am J Hum Genet 1997; 61:A279.Google Scholar
213. Van Laere, MJ. Paralysie bulbo-pontine chronique progressive familiale avec surdité. Un cas de syndrome de Klippel-Trenaunay dans la même fratrie. Problèmes diagnostiques et génétiques. Rev Neurol (Paris) 1966; 115:289–295.Google Scholar
214. Kennedy, WR, Alter, M, Sung, JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. Neurology 1968; 18:671–680.Google Scholar
215. Harding, AE, Thomas, PK, Baraitser, M, et al. X-linked recessive bulbospinal neuronopathy: a report of ten cases. J Neurol Neurosurg Psychiat 1982; 45:1012–1019.Google Scholar
216. La Spada, AR, Wilson, EM, Lubahn, DB, Harding, AE, Fischbeck, KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352:77–79.Google Scholar
217. Parboosingh, JS, Figlewicz, D, Krizus, A, et al. Spinobulbar muscular atrophy can mimic ALS: the importance of genetic testing in male patients with atypical ALS. Neurology 1998; 49:568–572.Google Scholar
218. Mitsumoto, H, Sliman, RJ, Schafer, IA, et al. Motor neuron disease and adult hexosaminidase A deficiency in two families: evidence for multisystem degeneration. Ann Neurol 1985; 17:378–385.Google Scholar
219. Cashman, NR, Antel, JP, Hancock, LW, et al. N-acetyl-b-hexosaminidase b locus defect and juvenile motor neuron disease: a case study. Ann Neurol 1986; 19:568–572.CrossRefGoogle ScholarPubMed
220. Rubin, M, Karparti, G, Wolfe, LS, et al. Adult onset motor neuronopathy in the juvenile type of hexosaminidase A and B deficiency. J Neurol Sci 1988; 87:103–119.Google Scholar
221. Banerjee, P, Siciliano, L, Oliveri, D, et al. Molecular basis of an adult form of b-hexosaminidase B deficiency with motor neuron disease. Biochem Biophys Res Comm 1991; 181(1):108–115.Google Scholar
222. Andersen, PM, Morita, M, Brown, RH Jr. Genetics of amyotrophic lateral sclerosis: an overview. In: Brown, RH Jr., Meininger, V, Swash, M, eds. Amyotrophic lateral sclerosis. London: Martin Dunitz Ltd., 2000: 223–250.Google Scholar