HSP Flashcards
What are the four characteristics of HSP?
- Heterogenous group of NDD
- Clinically progressive spasticity and weakness of lower limbs
- Pathologically characterised by the retrograde axonal degeneration of the cortical spinal tracts and the posterior colums
- Hypothesis of axonal transport
Where did the axonal tranposrt hypothesis come from
In recent years genetic studies have identified crucial genes for the maintenance of axonal homeostasis in HSP. If disrupted, these genes lead to the disruption and dsyregulation of axonal transport of macromolecules, organelles and other cargoes, which predominantly effect distal neuronal regions.
Where does retrograde axonal degeneration occur?
In the longest nerve fibres of the cortical spinal tracts and posterior columns
What are the 4 key clinical diagnostic findings?
Progressive lower limb spasticity, pyramidal weakness, hyper-reflexia and extensor plantar responses
What is the prevelance of HSP in europe
Although few epidemiological studies have been performed it is predicted that between 3-4 in every 100,000 have HSP
How many loci have been mapped, and how many genes
41 loci, 17 genes
What is the most prevelant form of inheritence
Autosomal Dominant in 70% of cases
What gene is disupted in 40-50% of cases
SPG4 encoding spastin, onset caries between childhood to late adult life - complete loss of mobility occurs 20 years after onset, thanks to its prevelance it is the most widely studied form
What gene is disrupted in 10% of cases
SPG3 encoding atlastin - typically presenting with a pure yet late onset with a slow progression of symptoms
What was the original argument for the pathogenesis of HSP
Originally argued, along the findings of Casari et al. 1998, that it was owed to mitochondrial deficits
What did Casari et al. 1998 find?
In SPG7 mutant families they recognised clinical characteristics identical to that of mitochondrial dsyfunction in muscle biopsies of those with HSP and mito disease
How “mastered” the theory of mitochondrial disorder in the pathogenesis of HSP?
Ferreirinha et al. 2001 - findings - theory was made in 2004
What did Ferreirinha et al. 2001 discover
Following their study of SPG7 knockout mice they formulated their theory. They generated a successful mouse model which fully embodied the cellular characteristics of HSP. They demonstrated that long before physical phenotypes occured their were EM studies demonstrating axons to be filled with abnormal mitochondria, subsequently swollen axons containing accumulate organelles and neurofilaments were observed, suggestig mito dsyfunction may lead to neurodegen through impairing axonal transport. However, their motor assessment of the mice could be quarrelled, and ultimately SPG7 mutations (paraplegin) only account for ~30 families of HSP.
Who took the mito theory further with the development of the axonal transport theory
Crosby et al. 2012
What must the hypothesis of HSP pathogenesis take into account?
The pathophysiological mechanism proposed must explain why the longest neurons are effected
Why is the axonal transport theory so attractive?
It supports the selectivity of the disease pathogenesis, in that longer axons are more susceptible due to failures in axonal trafficking and transport, and are more dependent on mitochondrial function for their great energy demands.
Additionally the causitive mutations are all implicated in axonal transport and mito function.
Finally it has been supported by both in vivo and in vitro studies.
On what basis can the mito theory be argued against.
- Motor studies didnt show much
- ~30 families only
- EM studies were performed at large time intervals, potentially overlooking the intermediate stages involving other mechanisms
What are the genes implicated in trafficking dsyfunction?
KIF5A, SPG4, SPG3, NIPA1, ZFVE26, SG20
