DEGENERATIVE DISEASES AFFECTING MOTOR NEURONS Flashcards
These are a group of inherited or sporadic diseases that affect both lower motor neurons in the
- *anterior horns of the spinal cord** and brainstem motor nuclei and upper motor neurons in the
- *motor cortex (also known as Betz cells).**
These diseases occur in several age groups, and the course of the illnesses range from slowly
progressive or nonprogressive to rapidly progressive and fatal in a period of months or a few
years.
Denervation of muscles from loss of lower motor neurons and their axons results in
muscular atrophy, weakness, and fasciculations; the corresponding histologic changes in nerve
and muscle are discussed in Chapter 27 .
The clinical manifestations of upper motor neuron
loss include p________________
- aresis,
- hyperreflexia,
- spasticity,
- and extensor plantar responses (Babinski sign).
- Sensory systems are unaffected, but some of these diseases may be associated with manifestations of cortical dysfunction, such as behavioral abnormalities and dementia.
DEGENERATIVE DISEASES AFFECTING MOTOR NEURONS
- Amyotrophic Lateral Sclerosis (ALS; Motor Neuron Disease)
- Bulbospinal Atrophy (Kennedy Syndrome)
- Spinal Muscular Atrophy
What is ALS?
ALS is characterized by loss of lower motor neurons in spinal cord and brainstem and upper
motor neuronsthatproject in corticospinal tracts.
This relatively rare disease (incidence of
about 2 cases per 100,000 population) affects men slightly more frequently than women and
becomes clinically manifest in the fifth decade or later.
- *Five to 10%** of cases are familial (fALS),
- *mostly** with_______________
autosomal dominant inheritance
Close to a quarter of familial cases of ALS are caused by mutations in the gene encoding
___________________
copper-zinc superoxide dismutase (SOD1) on chromosome 21.
A wide variety of mutations,
nearly all missense mutations, have been identified throughout the gene; ALS seems to be
caused by an adverse gain-of-function phenotype associated with mutant SOD1. A mutation
resulting in an _____________- is the most common in the United
States; it is associated with a rapid course, and rarely has upper motor neuron signs.
alanine to valine substitution in residue 4
Other loci
for ALS have been mapped, although none appears in linkage with as large a fraction of the
patient population as SOD1.
These mendelian loci include the genes encoding___________
dynactin (a
VAMP-associated protein B
alsin
What is dynactin_______________
a protein involved in retrograde axonal transport
What is VAMP-associated protein B_____________
involved in
regulation of vesicle transport
What is alsin?
(containing guanine nucleotide exchange factor
domains and associated with regulation of endosomal trafficking through interaction with
Rab5b).
What is The pathogenesis of ALS?
It is still not understood despite the identification of numerous genetic
associations.
The discovery of SOD1 mutations initially suggested that a reduced capacity to
detoxify free radicals (the physiologic function of SOD) may account for neuronal death in ALS.
However, this hypothesis has not been proved, and currently a more accepted idea is that the
mutated SOD1 protein is misfolded and triggers an injurious unfolded protein response. [68]
- *Mutated SOD1** in non-neuronal (glial and smooth muscle) cells may also contribute to the
disease. [69]
Alterations in axonal transport, neurofilament abnormalities, toxicity mediated by
increased levels of the neurotransmitter glutamate, and aggregation of other proteins (such as
one called TDP-43 that is sometimes found in cytoplasmic inclusions in neurons in ALS) [70] ,
have all been suggested as mechanisms contributing to the progressive loss of motor neurons.
What is the appearance of ALS On gross examination, the anterior roots of the spinal cord are __________( Fig. 28-
42A ). The precentral gyrus may be atrophic in especially severe cases.
thin
What is the Microscopic appearance of ALS?
This demonstrates a reduction in the number of anterior-horn neurons throughout
the length of the spinal cord with associated reactive gliosis and loss of anterior-root
myelinated fibers.
Similar findings are seen in the hypoglossal, ambiguus, and motor
trigeminal cranial nerve nuclei.
Remaining neurons often contain PAS-positive cytoplasmic
inclusions, called Bunina bodies, that appear to be remnants of autophagic vacuoles.
Skeletal muscles innervated by the degenerated lower motor neurons show neurogenic
What are Bunina bodies,_______________
that appear to be remnants of autophagic vacuoles.
Skeletal muscles innervated by the degenerated lower motor neurons show neurogenic
Spinal cord showing loss of myelinated
fibers (lack of stain) in corticospinal tracts as well as degeneration of anterior roots.
What is the earlysymptom of ALS?
Early symptoms include asymmetric weakness of the hands, manifested as dropping objects
and difficulty in performing fine motor tasks, and cramping and spasticity of the arms and legs.
What happens in ALS As the disease progresses?
muscle strength and bulk diminish, and involuntary contractions of
individual motor units,termedfasciculations, occur.
The disease eventually involves the respiratory muscles, leading to recurrent bouts of pulmonary infection. The severity of involvement of the upper and lower motor neurons is variable; the term progressive muscular
atrophy applies to those relatively uncommon cases in whichlower motor neuron involvement
predominates.
In some affected individuals, degeneration of the lower brainstem cranial motor
nuclei occurs early and progresses rapidly, a pattern referred to as ________________ In these individuals, abnormalities of deglutition and phonation dominate, and the
clinical course is inexorable during a 1- or 2-year period; when bulbar involvement is less
severe, about half of affected individuals are alive 2 years after diagnosis.
Although it has been
suggested that the motor neurons innervating extra-ocular muscles were spared in ALS, it is
now clear that these cells are susceptible to the disease process when individuals survive
longer. Familial cases develop symptoms earlierthan most sporadic cases, but the clinical
course is comparable.
progressive bulbar palsy or
bulbar ALS.
What is Bulbospinal Atrophy (Kennedy Syndrome)?
This X-linked adult-onset disease is characterized by distal limb amyotrophy and bulbar signs
such as atrophy and fasciculations of the tongue and dysphagia.
Affected individuals manifest
androgen insensitivity, gynecomastia, testicular atrophy, and oligospermia.
What is the microscopic appearance of Bulbospinal atrophy?
On microscopic
examination there is degeneration of lower motor neurons in the spinal cord and brainstem.
The
gene defect is expansion of a CAG/polyglutamine repeat in the androgen receptor (40 to 60 for
affected males as opposed to 11 to 33 for normals); nuclear inclusions containing aggregated
androgen receptor can be found, although it remains unclear whether these inclusions are
critical to cellular injury
What is Spinal Muscular Atrophy?
This group of diseases affects mainly the lower motor neurons in children.
As in ALS, there is a
- *selective loss of anterior-horn cells** and atrophy of anterior spinal roots. It includes several
- *entities with distinct clinical courses**
