Amyotrophic lateral sclerosis and other disorders of the lower motor neuron

TY - CHAP

T1 - Amyotrophic lateral sclerosis and other disorders of the lower motor neuron

AU - Shaw, Christopher E.

AU - Sreedharan, Jemeen

AU - Vance, Caroline A.

AU - Al-Chalabi, Ammar

PY - 2012/1/1

Y1 - 2012/1/1

N2 - Introduction In this chapter, we will critically review the epidemiology, clinical phenotype, and genetic basis of the heritable forms of amyotrophic lateral sclerosis (ALS) and other disorders of the lower motor neuron (LMN) including Kennedy's disease (spinobulbar muscular atrophy), the spinal muscular atrophies (SMA), and hereditary motor neuropathies (HMN). The identification of mutations in ALS genes in both sporadic (SALS) and familial ALS (FALS) has blurred any distinction between inherited and acquired ALS. The discovery that the TAR DNA binding protein (TDP-43) forms cytoplasmic inclusions within motor neurons and glia in ~90% of ALS cases and that mutations in the gene (TARDBP) segregate with disease confirms its pathogenicity. The discovery of mutations in other RNA processing genes, survival motor neuron 1 (SMN1) in SMA, and fused in sarcoma (FUS) and heat shock proteins in HMN have provided new insights into the pathogenesis of the motor neuropathies. Definition of amyotrophic lateral sclerosis Amyotrophic lateral sclerosis is also known as Lou Gehrig's disease in the United States and motor neuron disease in the United Kingdom. Amyotrophic lateral sclerosis was originally thought to be a degenerative muscular condition until Charcot published clinicopathological studies, in 1869, emphasizing the involvement of both upper motor neurons (UMNs) and LMNs with sparing of the sensory and autonomic pathways. He used the words amyotrophic (muscle wasting), lateral (corticospinal tracts), and sclerosis (scarring) to describe the principal features. The features that distinguish ALS from other disorders affecting the motor system are rapid progression (survival of approximately 3–5 years), a combination of UMN and LMN signs, and in many cases, mild cognitive impairment (an under-recognized feature). When LMNs degenerate, the muscles they innervate fasciculate, waste, and become profoundly weak. Upper motor neurons reside in the precentral gyrus of the cerebral cortex, and when they degenerate, there is a loss of inhibitory input to the LMNs resulting in muscle spasticity, brisk reflexes, and an extensor plantar response. Motor neurons controlling eye movements, and bladder and bowel sphincters are relatively spared as are sensory and autonomic pathways. The El Escorial Diagnostic Criteria describe a hierarchy of diagnostic certainty based on the number of regions clinically affected and supplemented by neurophysiological tests confirming muscle denervation. These criteria are useful in clinical trials but should not be used clinically as they may add to diagnostic delay.

AB - Introduction In this chapter, we will critically review the epidemiology, clinical phenotype, and genetic basis of the heritable forms of amyotrophic lateral sclerosis (ALS) and other disorders of the lower motor neuron (LMN) including Kennedy's disease (spinobulbar muscular atrophy), the spinal muscular atrophies (SMA), and hereditary motor neuropathies (HMN). The identification of mutations in ALS genes in both sporadic (SALS) and familial ALS (FALS) has blurred any distinction between inherited and acquired ALS. The discovery that the TAR DNA binding protein (TDP-43) forms cytoplasmic inclusions within motor neurons and glia in ~90% of ALS cases and that mutations in the gene (TARDBP) segregate with disease confirms its pathogenicity. The discovery of mutations in other RNA processing genes, survival motor neuron 1 (SMN1) in SMA, and fused in sarcoma (FUS) and heat shock proteins in HMN have provided new insights into the pathogenesis of the motor neuropathies. Definition of amyotrophic lateral sclerosis Amyotrophic lateral sclerosis is also known as Lou Gehrig's disease in the United States and motor neuron disease in the United Kingdom. Amyotrophic lateral sclerosis was originally thought to be a degenerative muscular condition until Charcot published clinicopathological studies, in 1869, emphasizing the involvement of both upper motor neurons (UMNs) and LMNs with sparing of the sensory and autonomic pathways. He used the words amyotrophic (muscle wasting), lateral (corticospinal tracts), and sclerosis (scarring) to describe the principal features. The features that distinguish ALS from other disorders affecting the motor system are rapid progression (survival of approximately 3–5 years), a combination of UMN and LMN signs, and in many cases, mild cognitive impairment (an under-recognized feature). When LMNs degenerate, the muscles they innervate fasciculate, waste, and become profoundly weak. Upper motor neurons reside in the precentral gyrus of the cerebral cortex, and when they degenerate, there is a loss of inhibitory input to the LMNs resulting in muscle spasticity, brisk reflexes, and an extensor plantar response. Motor neurons controlling eye movements, and bladder and bowel sphincters are relatively spared as are sensory and autonomic pathways. The El Escorial Diagnostic Criteria describe a hierarchy of diagnostic certainty based on the number of regions clinically affected and supplemented by neurophysiological tests confirming muscle denervation. These criteria are useful in clinical trials but should not be used clinically as they may add to diagnostic delay.

UR - http://www.scopus.com/inward/record.url?scp=84925685398&partnerID=8YFLogxK

U2 - 10.1017/CBO9781139087711.010

DO - 10.1017/CBO9781139087711.010

M3 - Chapter

AN - SCOPUS:84925685398

SN - 9780521543729

SP - 136

EP - 147

BT - Neurogenetics

PB - Cambridge University Press

ER -