Neurological function in Friedreich ataxia David Lynch

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.

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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.

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.

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

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

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

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

Cervical Spinal Cord Ventral Horn

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

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

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