Neurological function in Friedreich ataxia
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Transcript of Neurological function in Friedreich ataxia
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David Lynch
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Neuronal structure
Cell body
axon
synapse
A collection of axons in the brain is called a tract.
A collection of cell bodies is called a nucleus.
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Neuronal death
Cell body dies
Axon lost secondarily
Cell body spared
Axon lost first
XX
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Synaptic loss
Cell body spared
Axon spared SynapseLost-may be only loss of chemicals
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Neurological function in FAPrimary long-term disabilityAppears in classical form in all text books
Why rethink things?Different goal
Classical goal-diagnosisPresent goals- treatment and greater understanding
Start with review, then consider new questions
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Classical description of neurodegeneration in FALoss of large sensory neurons sub serving proprioception.Loss of spinocerebellar tracts.Loss of motor tracts to a lesser degree.Loss of dentate nucleus of the cerebellum.Loss of a few other specific sites.
Sparing of cerebellar cortex, cerebral cortex
Overall loss of <2% of brain neurons, loss of <10 % of long tracts
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What does this mean?Loss of large sensory neurons sub serving
proprioception/Loss of spino cerebellar tractsLoss of balance due to lack of input on where limbs are
located in spaceLoss of dentate nucleus of the cerebellum
Speech articulation difficulty, subtle eye movement abnormalities, ? other
Loss of a few other specific sites.Vision, hearing loss
Sparing of cerebellar cortex, cerebral cortexNormal cognition
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Proprioception in the Spinal Cord
From upper body
From lower body
DRG
Spinocerebellar tract
Motor tracts
Friedreich ataxia
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What does this mean?Loss of large sensory neurons sub serving proprioception/Loss
of spino cerebellar tractsLoss of balance due to lack of input on where limbs are located
in spaceLoss of dentate nucleus of the cerebellum
Speech articulation difficulty, subtle eye movement abnormalities, ? other
Loss of a few other specific sites.Vision, hearing loss
Sparing of cerebellar cortex, cerebral cortexNormal cognition
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Simplified wiring diagram of the cerebellum – a chance for Dave to talk really fast!
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Cerebellum-Internal wiringProprioceptive input (altered in FA)Intended movement
Compare
Output (altered in FA slightly)
Desired vs.Desired vs. Actual Actual movementmovement
Cerebellar Cerebellar cortexcortex
Dentate nucleusDentate nucleus
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What does this mean?
Ataxia in FA substantially reflects lack of input—improved by visual and tactile guidance
Other factors as well on output side.
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What does this mean?Loss of large sensory neurons sub serving proprioception/Loss
of spino cerebellar tractsLoss of balance due to lack of input on where limbs are located
in spaceLoss of dentate nucleus of the cerebellum
Speech articulation difficulty, subtle eye movement abnormalities, ? other
Loss of a few other specific sites.Vision, hearing loss
Sparing of cerebellar cortex, cerebral cortexNormal cognition
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Why reevaluate?Late onset vs. early onset FA
Less sensory difficulty in later onset (by comparison), more similar in speech dysfunction
Point mutation differences
Leads to new questionsDevise new approachesWhy some ideas fail
This is how to move forward
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New questionsWhy do only some neurons become affected?Answer- not clear
Some ideasFrataxin levelEnergy requirementsLengthSensory neuronsConnections
All of the above
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New questionsWhy do only some neurons become affected?Answer- not clear
Some ideasFrataxin level-less frataxin lead to cell deathEnergy requirements- some neurons are more activeLength-need to maintain long axon is energy requiringSensory neuronsConnections-
All of the above
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Next questionWhen do neurons become affected?
Answer not clearMRI scans of brain largely normal through out lifeSome neurons affected early
Loss of reflexes Babinski sign Is this typical? Yes
Different neurons at different times.
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Why are some neurons spared in FA?
I have no idea.
Recent investigations have tried to look for subtle effect on cognitive areas in FA.
The results are clinically unimpressive.
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Can we enhance function of remaining cells/regions?
Yes.
Can skills return?
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Synaptic loss
Cell body spared
Axon spared SynapseLost-may be only loss of chemicals
Strategies to improve synaptic Transmission may improve function
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Can the remaining regions take over for injured areas?Yes.
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Can Skills return?Touch and Proprioception
upper bodylower body
Spinal Cord
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Cervical Spinal CordCervical Spinal Cord
Ventral Horn
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Practical Neurological improvement
Physical therapyTeaches one ways to maximize skillProbably reinforces neuronal processes underlying synaptic
maintenance
Intensive coordinative training improves motor performance in degenerative cerebellar disease. Ilg W, Synofzik M, Brötz D, Burkard S, Giese MA, Schöls L. Neurology. 2009
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Conclusions
We know a lot about neurologic aspects of FA
We have a lot to learn
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Contact info Dave Lynch, 215-590-2242, [email protected] Coordinators,
Baali [email protected] ,267-426-9738
Sarah [email protected], 267-426-9567
Karlla brigatti @email.chop.edu, 267-426-9608