Transcript Clinical Research Network in Friedreich ataxia

David Lynch
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.
Neuronal death
Cell
body
dies
XX
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
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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
Proprioceptive input (altered in FA)
Intended movement
Desired vs. Actual
movement
Compare
Cerebellar
cortex
Output (altered in FA slightly)
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
 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.
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, [email protected]
 Coordinators,
 Baali

[email protected] ,267-426-9738
 Sarah

[email protected], 267-426-9567
 Karlla

brigatti @email.chop.edu, 267-426-9608