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

Cell body dies

Axon lost secondarily

Cell body spared

Axon lost first

XX

Synaptic loss

Cell body spared

Axon spared SynapseLost-may be only loss of chemicals

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

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

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

Proprioception in the Spinal Cord

From upper body

From lower body

DRG

Spinocerebellar tract

Motor tracts

Friedreich ataxia

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

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

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

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 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

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

New questionsWhy do only some neurons become affected?Answer- not clear

Some ideasFrataxin levelEnergy requirementsLengthSensory neuronsConnections

All of the above

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

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.

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 SynapseLost-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 bodylower body

Spinal Cord

Cervical Spinal CordCervical Spinal Cord

Ventral Horn

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

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