Neurological function in Friedreich ataxia

1. Neurological function in Friedreich ataxia David Lynch

2. Neuronal structure Cell body synapse axon A collection of axons in the brain is called a tract. A collection of cell bodies is called a nucleus.

3. Neuronal death Cell body dies XX 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 • 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. 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, 215-590-2242, lynchd@mail.med.upenn.edu • Coordinators, • Baali • Mugangab@email.chop.edu ,267-426-9738 • Sarah • lagedrosts@email.chop.edu, 267-426-9567 • Karlla • brigatti @email.chop.edu, 267-426-9608