1. Neurological function in Friedreich ataxia
David Lynch

2. 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.

3. Neuronal death XX Cell body dies Axon lost secondarily
Cell body spared
Axon lost first

4. Synaptic loss Cell body spared Axon spared Synapse
Lost-may be only loss of chemicals

5. Neurological function in FA
Primary long-term disability
Appears in classical form in all text books
Why rethink things?
Different goal
Classical goal-diagnosis
Present goals- treatment and greater understanding
Start with review, then consider new questions

6. Classical description of neurodegeneration in FA
Loss 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

7. What does this mean?
Loss of large sensory neurons sub serving proprioception/Loss of spino cerebellar tracts
Loss of balance due to lack of input on where limbs are located in space
Loss 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 cortex
Normal cognition

8. Proprioception in the Spinal Cord
From upper body
From lower body
Friedreich ataxia
DRG
Spinocerebellar tract
Motor tracts

9. What does this mean?
Loss of large sensory neurons sub serving proprioception/Loss of spino cerebellar tracts
Loss of balance due to lack of input on where limbs are located in space
Loss 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 cortex
Normal cognition

11. Simplified wiring diagram of the cerebellum –
a chance for Dave to talk really fast!

12. Cerebellum-Internal wiring
Desired vs. Actual
movement
Proprioceptive input (altered in FA)
Intended movement
Compare
Output (altered in FA slightly)
Cerebellar cortex
Dentate nucleus

13. 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.

14. What does this mean?
Loss of large sensory neurons sub serving proprioception/Loss of spino cerebellar tracts
Loss of balance due to lack of input on where limbs are located in space
Loss 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 cortex
Normal cognition

15. Why reevaluate? Late onset vs. early onset FA Leads to new questions
Less sensory difficulty in later onset (by comparison), more similar in speech dysfunction
Point mutation differences
Leads to new questions
Devise new approaches
Why some ideas fail
This is how to move forward

16. New questions Why do only some neurons become affected?
Answer- not clear
Some ideas
Frataxin level
Energy requirements
Length
Sensory neurons
Connections
All of the above

17. New questions Why do only some neurons become affected?
Answer- not clear
Some ideas
Frataxin level-less frataxin lead to cell death
Energy requirements- some neurons are more active
Length-need to maintain long axon is energy requiring
Sensory neurons
Connections-
All of the above

18. Next question When do neurons become affected?
Answer not clear
MRI scans of brain largely normal through out life
Some neurons affected early
Loss of reflexes
Babinski sign
Is this typical? Yes
Different neurons at different times.

19. 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.

20. Can we enhance function of remaining cells/regions?
Yes.
Can skills return?

21. Synaptic loss Cell body spared Axon spared Synapse
Lost-may be only loss of chemicals
Strategies to improve synaptic
Transmission may improve function

22. Can the remaining regions take over for injured areas?
Yes.

23. Touch and Proprioception
Can Skills return?
Touch and Proprioception
upper body
lower body
Spinal Cord

24. Cervical Spinal Cord
Ventral Horn

26. Practical Neurological improvement
Physical therapy
Teaches one ways to maximize skill
Probably 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

27. Conclusions We know a lot about neurologic aspects of FA
We have a lot to learn

28. Contact info
Dave Lynch, ,
Coordinators,
Baali ,
Sarah
Karlla