Lecture 9: Amyotrophic Lateral Sclerosis Clinical and Genetic Features Flashcards
Amyotrophic Lateral Sclerosis
Clinical and Genetic Features
Stephen J. Kolb, M.D., Ph.D.
September 30, 2014
“Final Common Pathway”
“…to move things is all that mankind can do, for such the
sole executant in muscle, whether in whispering a syllable
or felling a forest.”
-Charles Sherrington, 1924
Neurons consume a lot of energy.
Motor neurons project very far.
Clinical Features of ALS
Asymmetric Atrophy of the Hand =Split Hand Syndrome
Shoulders, Chest, & Back are atrophied
Ruffling of the tongue, looks like it has worms just underneath the surface of the tongue.
Trouble protruding the tongue, pooling of saliva
Charcot’s Disease:
Amyotropic Lateral
1869 - Suggested grouping together diseases that affect the lateral horn of the spinal cord
Degeneration of corticospinal tracts and extensive loss of lower motor neurons
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis, or ALS, is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement. ALS is also known as Lou Gehrig’s disease.
Disease of both the lower and upper motor neurons
Ubiquitin-positive inclusions
Dense anti-ubiquitin positive deposit
“Skein-like” filamentous arrays
Epidemiology of Amyotrophic Lateral Sclerosis
Incidence of ALS in Europe = 2.2 per 100,000
Men = 3 per 100,000; Women = 2.4 per 100,000
Overall lifetime risk:
Men = 1:350 / Women = 1:400
Peak age at onset:
Sporadic = 58 – 63 yrs; Familial = 47 – 52
Rates of ALS in Cuba are 60% lower than in US or Europe
Pathophysiology of ALS
Denervation of the muscle
ALS, therefore, is not a primary disease of the muscle, but of the nerves.
If you lose a motor neuron, the naked muscle fibers call out to be innervated, they spontaneously move. Other neurons will send projections to the connect and innervate them. The only thing that
You can listen to the electrophysiological activity to help diagnose what’s going on in the motor neurons.
A single motor neuron innervates a single muscle fiber
Manyyy genes can be involved in the development of this disease.
Diagnostic Criteria
The diagnosis of amyotrophic lateral sclerosis [ALS] requires:
(A) the presence of
(1) evidence of lower motor neuron (LMN) degeneration by clinical,
electrophysiological or
neuropathological
examination
(2) evidence of upper motor neuron (UMN) degeneration by clinical examination; and
(3) progressive spread of symptoms or signs within a region or to other
regions, as determined by history, physical examination, or
electrophysiological tests
(B) the absence of
(1) electrophysiological or pathological evidence of other disease
processes that might explain the signs of LMN and/or UMN
degeneration, and
(2)
neuroimaging
evidence of other disease processes that might
explain the observed clinical and electrophysiological signs
Diagnostic Criteria
Shorter version
(A) the presence of
(1) lower motor neuron (LMN) degeneration
(2) upper motor neuron (UMN) degeneration
(3) progressive spread of symptoms or signs within a region or to other
regions
(B) the absence of
(1) other disease processes that might explain the signs of LMN and/or UMN degeneration
(2) neuroimaging
evidence of other disease processes that might
explain the observed clinical and electrophysiological signs
Diagnostic Criteria
Clinically definite ALS is defined by clinical or electrophysiological evidence by the presence of LMN and UMN signs in the bulbar region and at least 2 spinal regions or the presence of LMN and UMN signs in 3 spinal regions
Clinically probable ALS is defined on clinical or electrophysiological evidence by LMN and UMN signs in at least 2 regions with some UMN signs necessarily rostral to the LMN signs
Clinically possible ALS is defined when clinical or electrophysiological signs of UMN and LMN dysfunction are found in only one region; or UMN signs are found alone in 2 or more regions; or LMN signs are found rostral to UMN signs.
Neuroimaging and clinical laboratory studies will have been performed and other diagnoses must have been excluded
“There’s no pregnany test for ALS…”
No easy “yes or no” test
So it’s hard to diagnose.
Differential Diagnosis
ALS mimics…
Multifocal motor neuropathy => EDX, ganglioside GM1 antibodies
X-linked spinobulbar muscular atrophy => CAG repeats in AR
gene
Poliomyelitis => History, EDX
Hexosaminidase A deficiency => white cell enzyme testing
Spinal muscular atrophy =>
SMN deletion
Heavy metal poisoning => urine and blood screens
Cramp-fasciculation syndrome => EDX
Differential Diagnosis:
Error Rate
False Positive = 8%
False Negative = up to 44%
Management Goal
Optimize health care delivery, prolong survival, and enhance quality of life
Management
Referral to multidisciplinary ALS clinic:
Prolongs survival and increased
utilization of therapies in multiple studies.
Riluzole should be offered:
4 clinical trials have confirmed
prolonged survival 2-3 months. Large retrospective studies indicate that benefit may be more substantial ( ~6-21 months)
Percutaneous endoscopic
gastrostomy (PEG) tube should be considered:
Probably improves survival although current studies unable to quantity survival advantage
Non-invasive ventilatory (NIV) support should be considered:
Prospective studies indicate a survival benefit of 5–11 months (excluding bulbar predominant patients)
Sialorrhea
Sialorrhea = drooling
Should be treated aggressively:
An important cause of aspiration pneumonia and embarrassing, prevalence of 50%.
Anticholinergic medication tried first.
Botulinum toxin type B injections into parotid and
submandibular glands has been effective in clinical trials
Pseudobulbar affect should be treated:
Dis-inhibition of emotional response, like giggling at a funeral.
Occurs in 20-50% and should not be confused with a mood disorder.
Dextromethorphan and quinidine combination is effective (Nuedexta).
Screening for cognitive impairment should be considered:
Estimates of cognitive impairment range from 10–75%.
Dementia in 15 – 41%.
Insufficient data to support treatment of cognitive impairment.
Evidence for Genetic Contribution to ALS
Familial ALS by family history: 5–20%
Mutations in Mendelian
genes account for:
• 75% of inherited forms
• 14% of those with no obvious family history
Twin studies indicate heritability of apparently sporadic ALS is ~0.61
There is clustering of neurodegenerative diseases in relatives of PALS
C9orf72 hexanucleotide
repeat expansion
-‐ Identified in large families with FTD/ALS
-‐ Length of expansion ranges from 700‐1600 repeats.
Majority of controls have 2 repeats
- ‐ Accounts for ~12% of familial FTD and 3% sporadic FTD
- ‐ Accounts for ~24% of familial ALS and 4% sporadic ALS
- ‐ More severe course on average for familial ALS
Rate of progression in ALS depends on mutation
…
“Final Common Pathway?”
Protein degradation pathway Axonal transport disruption Oxidative Stress RNA metabolism defect Prion-like progression
