Motor Neuron disease, Trinucleotide Repeat Disorders AK Flashcards
Amyotrophic Lateral Sclerosis is a MOTOR NEURON DISEASE INVOLVING?
Post synaptic NMJ
Progressive degeneration of upper and LMN
ALS FEATURES:
The most common form of MND, progressive weakness leading to paralysis.
The incidence is 2 per 100,000.
Peak age at onset is 58-63 years for sporadic disease and 47-52 years for familial disease.
Death usually occurs 2-5 years from diagnosis.
Death is usually from Respiratory failure. Weirdly, common for sports players to develop it- Lou Gehrig is a good example of this.
Symptoms of ALS
Limb onset or Bulbar onset. Occulomotor neurons (eyes) and onus nucleus (controls bladder) are spared in this disease. Cognition is affected in a proportion of cases (10-15%- often associated with fronto-temporal dementia). Sensory changes are not generally involved
What are the UMN signs of ALS?
LMN signs?
UMN signs • Weakness • Spacisity • Increased tone • Hyperactive reflexes • Babinskis sign • Clonus- Involuntary muscular contractions • Loss of voluntary movement
Lower Motor Neuron Signs • Weakness of paralysis • Decreased reflexes • Decreased tone • Fasciculations (muscle twitching) • Severe muscle atrophy
What are the symptoms of BULBAR onset ALS
Symptoms of ALS: Bulbar Onset
Often affects the tongue, get slurring of speech (dysarthria); difficulty swallowing (dysphagia); usually rapidly progressing.
Symptoms of ALS: Spinal Onset
Symptoms of ALS: Spinal Onset
Usually presents with an asymetrical weakness of one of the limbs (eg stumbling, dropping things). Occasionally there is symmetrical weakness, which is called flail arm syndrome. Split hand syndrome occurs in the hand.
Diagnosis of ALS
Definite ALS: upper and LMN signs in three regions
Probably ALS: upper and lower motor neuron signs in at least two regions with UMN signs rostral to LMN signs
Possible ALS: upper and lower motor neuron signs in one region, UMN signs alone in two or more regions, or lower motor neuron signs above upper motor neuron signs.
Suspected ALS: LMN signs only in two or more regions.
Causes of ALS can be genetic or sporadic. what are the %? and what are sporadic causes?
Causes of ALS
10% inherited, 90% sporadic.
Sporadic ALS: known risk factors are age (common 40-60), slight male predominance in disease. Suspected risk factors for sporadic ALS: military service, elite athletes, electric shock, toxin exposure.
Causes of ALS can be genetic or sporadic.What are the genetic causes? (6)
Mutations: SOD1 ASL1 TDP-43 FUS C9RF72 C90RF72 protein
A bit about the genetic causes of ALS
Familial inherited ALS causes (genetics): Mutations have been identified; (1) superoxide dismutase 1 (SOD1) (ALS1): important antioxidant enzyme expressed in all cells of the body. (3) TAR DNA binding protein (TDP-43): function unknown, possibly RNA processing. TDP-43 may also be associated with sporadic disease. (3) FUS: Recently discovered as the cause of 5% of familial cases. Involved in RNA processing. (4) C9RF72 → major cause of CLS and frontotemporal dementia worldwide. Recently discovered. Accounts for 34% of familial ALS. Caused by these hexanucleotide repeats. (4) current proposed mechanisms: altered expression of the C90RF72 protein; sequestrion of RNA binding proteins; abnormal translation of the non coding region. Question we all want to know- what makes motor neurons vulnerable to degernation caused by ubiquitously expressed proteins?
C90RF72: Most recently discovered mutation; major genetic causes of ALS and FTD worldwide. Accounts for 34% of familial ALS. Hexanucleotide repeat (GGGGGCC) in non-coding region of C90RF72. C90RF72 is a completely uncharacterized protein. Mechanism of pathogenesis is unknown, but mutation is often associated with other ALS/FTD mutations- disease modifiers? There are current proposed mechanisms as to how this protein causes ALS: altered expression of C90RF72; sequestration of RNA binding protein; Abnormal translation of the non coding region.
Pathology of ALS:
UMNs
LMN
Pathology of ALS:
the upper motor neurons: that are lost from the motor cortex are from layer five Betz cells. Some loss of inhibitory neurons in these areas has been reported. Corticospinal tract degeneration which suggests that the axons of the upper motor neurons are degenerating.
Pathology of ALS: Lower motor neuron pathology: loss of LMN- you will see Bunina Bodies (arrow B) – most unique marker for ALS, and these are likely to be by lysosomal in origin. Ubiquitinated Hyaline inclusions (f) in spinal cord. Axonal pathology Spheroids (White and red arrows in A) – within the axon.
Describe the proximal axon pathology in ALS
Describe the muscle pathology in ALS
• Proximal Axon Pathology:
o Spheroids: accumulations of neurofilament proteins and organelles in the proximal axon. May indicate sites of impaired transport
• Pathology of ALS: Muscle.
o Pathology includes- muscle atrophy, mixed grouping of atrophied fibre types; collateral sprouting of nerve fibres; dying back of NMJs.
what is the link between excitotoxicity and ALS
What is excitotoxicity? A phenomenon whereby the excitatory action of glutamate and related excitatory amino acids becomes transformed into a neuropathological process that can rapidly kill CNS neurons. Glutamate is one of the major excitatory neurotranmitters in the CNS. Neurons have several types of receptors for glutamate. Too much glutamate is toxic to the neuron.
Evidence for excitotoxicity in ALS: Glutamate uptake (by glia) is impaired in ALS. Raised glutamate levels have been reported in the CSF of patients with MND. Drugs that block excitotoxiity show some protection in ALS (Riluzole). Ingested excitotoxins cause diseases involving loss of motor neuron function. Hyperexcitability of the cortex and fasciculation of the lower motor neurons.
What are some proposed mechanisms of damage which occur in ALS
Excitotoxicity - killing neurons
Protein abnormalities- misfolding
activated non neuronal cells- Astrocytes and microglia are activated in ALS tissue (gliosis). Activated glia produce factors which can be toxic or protective. Mutant SOD mouse models have demonstrated that the mutant protein must be in glial cells as well as motor neurons for disease.
Neurofilament accumulation
Defects in RNA processing (as evidenced by TDP-43, C90RF72
Treatment for ALS
Riluzole (glutamate inhibitor)
